ReVIeWS

I­mmune cell regulation of glia during

CNS injury and disease
Andrew D. Greenhalgh   1 ✉, Sam David2 and F. Chris  Bennett   3
Abstract | Glial cells are abundant in the CNS and are essential for brain development and
homeostasis. These cells also regulate tissue recovery after injury and their dysfunction is a
possible contributing factor to neurodegenerative and psychiatric disease. Recent evidence
suggests that microglia, which are also the brain’s major resident immune cells, provide
disease-modifying regulation of the other major glial populations, namely astrocytes and
oligodendrocytes. In addition, peripheral immune cells entering the CNS after injury and in
disease may directly affect microglial, astrocyte and oligodendrocyte function, suggesting an
integrated network of immune cell–glial cell communication.

Macrophages
Phagocytic immune cells
involved in homeostasis and
inflammation. They may be
tissue resident or recruited
from circulating monocyte
populations to sites of
inflammation.
1
INRA, Laboratoire Nutrition
et Neurobiologie Intégrée,
University of Bordeaux,
Bordeaux, France.
2
Centre for Research in
Neuroscience, The Research
Institute of the McGill
University Health Center,
Montreal, Quebec, Canada.
3
Department of Psychiatry,
University of Pennsylvania
Perelman School of Medicine
and the Children’s Hospital
of Philadelphia,
Philadelphia, PA, USA.
✉e-​mail: adgreenhalgh@
gmail.com
https://doi.org/10.1038/
s41583-020-0263-9
Despite the neuron’s fundamental importance, it has
long been known that the vertebrate CNS cannot ade-
quately function without the brain’s non-​neuronal cells,
which mainly consist of glia1. Indeed, more than half of
the cells in the CNS are glia2. A traditional definition
suggests that glia are distinct from neurons in their lack
of axons, dendrites and synaptic junctions3; however,
many decades of research have refined this definition
by uncovering the unique and highly specialized mor-
phology and functions of different types of glial cell.
Furthermore, recent advances in technologies for cell
isolation, RNA sequencing and high-​d imensional,
single-​cell analyses have allowed researchers to probe
the details of the brain’s resident cell populations and
revealed their heterogeneity within and between dif-
ferent CNS structures4–8. As a result, we now have an
enormous wealth of data on the type of cells present in
the brain and what they look like.
The subtypes of mature CNS glia are astrocytes, oli-
godendrocytes and microglia. As the brain’s resident
macrophages, microglia are classified as both glia and
immune cells, making the immune system an omni-
present cellular feature of the brain. Beyond microglia,
recent work shows that the brain and its barriers host a
surprisingly diverse cohort of other immune cells that
are more traditionally associated with the periphery9–12
(Fig. 1). During injury or disease, these resident immune
cells are joined by their infiltrating counterparts from
the circulation12,13. Brain immune cells, whether resident
or actively recruited, can directly interact with neurons;
we refer the reader to multiple excellent reviews of this
topic14–17. Less widely appreciated, however, is the fact
that microglia and infiltrating peripheral immune cells
can also modulate brain function via their interactions
with glia. These functional interactions appear to have
great bearing on the pathogenesis of many diseases
and present an unrealized opportunity to create new
therapeutics.
In this Review, we briefly describe the major glial sub-
types in the brain and review a growing body of research
that demonstrates the direct engagement of the immune
system with glia. In addition to glial and immune cells,
other non-​neuronal cells in the CNS include endothelial
cells, smooth muscle cells and pericytes that are asso-
ciated with and form the cerebrovasculature18, menin-
geal fibroblasts that can produce extracellular matrix
after injury19, and progenitor cells expressing the pro-
teoglycan NG2 that can give rise to glia and neurons20.
The effect of immune cell-​derived inflammation on the
cerebrovasculature as a whole has been well investigated
and reviewed elsewhere21,22, whereas little is known of
direct immune cell modulation of NG2-expressing cells.
Therefore, these non-​neuronal cells are not considered
further herein.
CNS glial cells
Astrocytes. Astrocytes are found throughout the CNS,
with each cell containing numerous stellate processes
forming a well‐delineated bushy territory23. The complex
fine morphology of these processes results in intimate
contacts with synapses, blood vessels and other glial
cells. Indeed, astrocytes are required for the formation
and function of synapses24,25. They also support neurons
through tight metabolic coupling26,27, modulate neuronal
excitability and plasticity28, and directly affect local syn-
aptic function through rapid neurotransmitter uptake29
and extracellular potassium buffering30,31. Astrocytes are
a critical component of the ‘neurovascular unit’, contain-
ing cerebral blood vessels, pericytes and neurons, which,
among other things, helps maintain cerebral blood flow
under physiological and pathological conditions32. The
consequences of astrocyte function are seen in many

Nature Reviews | Neuroscience

Reviews

a
Mature CNS-resident glia

Astrocytes Microglia CNS-resident Monocytes Monocyte- Dendritic Neutrophils Lymphocytes Natural Innate
(parenchymal macrophages derived cells killer cells lymphoid cells
macrophages) (perivascular, macrophages B cells
subdural and
meningeal)

T cells Eosinophils Mast cells

Established during Reside in the borders of the

embryonic development and CNS and can be recruited from
form stable populations the circulation during injury
Oligodendrocytes
(derived from OPCs)
CNS-resident immune cells

Activated
microglial cell

Fig. 1 | cNs resident cell types. a | Astrocytes, oligodendrocytes and microglia represent the major glial populations
of the CNS. Microglia are also a stable population of CNS-​resident immune cells, as are the populations of perivascular,
subdural and meningeal macrophages that are established during embryonic development. Other immune cells reside
in the borders of the CNS and can also be recruited from the circulation during disease and injury. This allows the direct
signalling of monocytes, monocyte-​derived macrophages, dendritic cells, neutrophils and lymphocytes (T cells and B cells)
to CNS-​resident glia. Other immune cell populations found in the borders of the CNS also include natural killer cells, innate
lymphoid cells, eosinophils and mast cells12, but little is known of their modulation of glia. b | Schematic illustrating a possible
integrated network of glia–immune cell interactions: solid arrows represent the known immune cell to glia communication
pathways that are the subject of the present review , dashed arrows represent direct interaction pathways that are either
not covered in this review or are yet to be investigated. OPC, oligodendrocyte progenitor cell.

domains, from memory consolidation to the generation
of circadian rhythms33,34. Astrocytes also have the capac-
ity to propagate inflammation, which can contribute to
disease development and progression35. Following CNS
injury and during CNS disease, astrocytes form func-
tional barriers that restrict the entry of inflammatory
cells into CNS parenchyma36 and, although long thought
to restrict neuronal regeneration37, may in some cases
provide support to regenerating neurons36,38. Due to the
critical functions of astrocytes in health, disease and
injury, the influence of the immune system on astrocytes
is of burgeoning interest.
Oligodendrocytes. Mature oligodendrocytes are found
throughout the grey and white matter in the CNS,
where their processes wrap around neuronal axons
and are responsible for the production of myelin,
which maximizes axonal conduction velocity39. Myelin
sheaths are in fact large extensions of the oligodendro-
cyte cell membrane and are highly complex structures40.
Myelinating oligodendrocytes are derived from oligo-
dendrocyte progenitor cells (OPCs) during embryo-
genesis and in the early stages of postnatal life41. An
undifferentiated pool of OPCs is maintained in the
adult CNS42, which can give rise to myelinating oligo-
dendrocytes throughout adulthood39. This is important
because the proliferation and differentiation of OPCs
into myelinating oligodendrocytes increase after CNS
injury and disease and may be crucial for the recovery
phases of such pathologies39. In addition, recent evidence
suggests that oligodendrocytes may also have immune-​
related functions43, modulate network activity through
direct connections with the neuronal soma44 and have
important interactions with the vasculature45. Therefore,

www.nature.com/nrn

Genome-​wide association
studies
Studies that integrate whole
genomes across populations to
identify genetic variants in
individuals and associate those
variants with a trait.
Lymphatic system
A vascular network that drains
fluid from the extracellular
space and traffics this and
immune cells to lymphoid
organs and the systemic
circulation.
Adaptive immune cell
A T cell or B cell that can
acquire and maintain specific
knowledge of non-​
self-pathogens (or self-​antigens
during disease) to mount a
specific immune response.
Neutrophils
Innate immune cells that are
often the first recruits to sites
of inflammation, where they
release antimicrobial agents,
enzymes, nitrogen oxides and
other proteins.
Monocytes
Cells that develop in the bone
marrow, are released into the
circulation and can be
recruited during inflammation.
Monocytes give rise to
monocyte-​derived cells such as
macrophages (but are often
functionally distinct from
tissue-​resident macrophage
populations).
Dendritic cells
Antigen-​presenting cells that
exert immune surveillance for
exogenous and endogenous
antigens for the activation of
naive T cells giving rise to
various immunological
responses.
Innate lymphoid cells
Immune cells that belong to
the lymphoid lineage but do
not express antigen-​specific
receptors and are therefore
involved in innate immune
regulation of homeostasis and
inflammation.
Lymphocyte
A cell that is derived from a
haematopoietic stem cell.
Lymphocytes ultimately form
the cells of the adaptive
immune system.
Nature Reviews | Neuroscience
immune cell regulation of oligodendrocytes is likely to
have wide ranging consequences in health and disease.
Microglia. Microglia are found in all regions of the
CNS and can be broadly defined as both glia and
immune cells; more specifically, they can be defined
as process-​bearing, highly ramified myeloid cells and
tissue-​resident macrophages46. They are the principle
immune cell of the brain and have, for many decades,
been known to be involved in the brain’s response to
injury47. Interest in these cells has grown in recent years
due to four distinct findings. First, it was shown that
the cellular processes of microglia are highly dynamic
in the healthy brain and respond rapidly to injury48,49.
Second, genome-​wide association studies have implicated
mutations in many genes expressed selectively or at
high levels in microglia as risk factors for neurodegen-
erative disease50,51. Third, microglia have been shown to
perform critical roles during neuronal circuit develop-
ment, including a role in complement-​mediated synapse
elimination52,53. Finally, unlike other tissue-​resident macro­
phages, microglia have been shown to be derived from
the embryonic yolk sac, suggesting early divergence
from the postnatal blood system during development
and functional adaptation to the brain environment54,55.
Indeed, the introduction of a somatic mutation specif-
ically in the erythro-​myeloid progenitor lineage from
which microglia are derived can drive late-​onset neuro­
degeneration in mice, suggesting an intrinsic role of these
tissue-​specific macrophages in adult disease56.
Although still poorly understood, it has become clear
that microglia are more than quiescent sentinels that
stand ready to mount an immune response57. Instead,
they are highly reactive to changes in the brain, actively
producing signalling molecules to facilitate homeo­
stasis or to contribute to disease14–17. The study of ‘reac-
tive’ microglia has traditionally relied on the use of their
morphological phenotype to indicate their distinct
functional states, wherein the classification of ‘quiescent’
versus ‘reactive’ is usually signified by a reduction in
ramification57. However, microglial morphology is more
nuanced and highly dynamic and, although changes in
morphology are likely to reflect changes in the cell state,
it does not yet have robustly described molecular under-
pinnings in vivo. New technologies that can capture fine
morphology prior to the extraction of high-​dimensional
gene or protein signatures have the potential to create a
lexicon that will allows us to better describe dynamic
microglial states; however, with the exception of clear
phagocytic activity, where phagosomes can be clearly
visualized58, it is currently impossible to ascribe function
to morphology alone. Here, we define microglia ‘activa-
tion’ or ‘reactivity’ as any induced change in morphology or
gene/protein expression from the homeostatic state,
which will be further qualified by functional or molecular
information if described.
Microglia are both first responders and long-​lived
resident immune cells of the CNS, containing hetero-
geneous and plastic populations, which places them in
a unique position to shape disease and injury outcomes.
Therefore, microglial regulation of other non-​neuronal
cell types is of great interest.
Reviews
CNS resident immune cells
Microglia are the numerically dominant CNS resi-
dent immune cell type under steady-​state conditions12.
However, single-​cell RNA sequencing, mass cytome-
try and fate-​mapping techniques have revealed other
immune cell populations in the CNS, largely residing in
the interfaces between the brain and the periphery7,11,12,59
(Fig. 1). One such interface is the brain’s lymphatic system,
which is quickly becoming a new frontier in neuro­
immunological research60. The cerebrospinal fluid (CSF)
also contains a variety of immune cells61,62 and several
reports highlight distinct adaptive immune cell popu-
lations in the meninges and choroid plexus62,63. In the
steady state, over 20% of the brain’s immune cell com-
partment is comprised of cells other than microglia12.
Half of these cells are described as barrier-​associated
macrophages, with distinct profiles from parenchy-
mal microglia11,59. The remaining brain immune cells
in the steady state consist of neutrophils, monocytes,
dendritic cells, innate lymphoid cells and lymphocyte sub-
sets, which differ in abundance and marker expression
to those circulating in the blood from which they are
thought to be derived12,59,64. The brain and its barriers
are replete with innate and adaptive immune cells. How
these cells interact with glia in health and disease is
discussed below.
Microglial regulation of other glia
Microglial regulation of astrocytes. Interest in the inter-
action of glial cell subtypes is not new65. For example,
in vitro studies have long suggested that astrocytes are
important for microglial homeostasis66,67. The tech-
niques used to isolate and culture astrocytes and microg­
lia are being continuously refined to ensure that the
cultured cells provide the best representation of the cells
in vivo; however, it should be noted that it is likely that
the recreation of in vivo conditions in a dish is simply
not possible68–74. For example, gene expression is rapidly
altered when microglia, astrocytes or oligodendrocytes
are placed in culture68–75. In addition, there are critical
species differences in disease-​related genes, such as
APOE, and microglial immune responses can differ
between mouse and human cells when in culture76.
However, these caveats should not preclude the use of
these techniques and data; indeed, mixed culture, trans-​
well culture and conditioned medium culture experi-
ments have shed light on many mechanisms by which
microglia modulate astrocyte function and we now have
multiple methodologies for the further study of these
immune cell–glial cell interactions (Box 1).
The investigation of inflammatory processes in vitro,
with subsequent in vivo validation, has provided strong
evidence for a direct microglial modulation of astro-
cytes. In vitro, combinations of the microglia-​derived
cytokines IL-1β, IL-6 and tumour necrosis factor (TNF)
drive the inhibition of astrocytic gap junctions, neces-
sary for normal glial function77,78, and increase astrocytic
glucose uptake while restricting its intercellular traffick-
ing79. The activation of cultured astrocytes during man-
ganese neurotoxicity is contingent on nuclear factor-​κB
(NF-​κ B)-dependent microglial release of TNF 80.
Additionally, irradiation-​induced astrogliosis (defined as
Reviews

the molecular, cellular and functional changes in astro- microglia release TNF, IL-1α and the complement com-
cytes that occur in response to an insult)81 only occurs ponent C1q, and microglia-​conditioned medium that
in vitro in the presence of microglia and requires their contains these factors induces the activation of cul-
release of IL-1β and TNF82,83. Finally, activated cultured tured astrocytes, characterized by the upregulation of

Box 1 | Methodological considerations for studying immune cell–glial cell interactions

choice of model
Glia–immune cell interactions involve cells of different lineages, across regionally complex CNs tissues in which the
immune cells are often invaders and not residents. these layered and dynamic processes are not readily modelled
in vitro224. in addition, microglia, astrocytes and oligodendrocytes undergo dramatic transcriptional changes during
cell culture, which may compromise their in vivo relevance68–75. Despite this, reduced in vitro models are necessary to
answer many experimental questions and can open important lines of investigation for further validation225. In vivo
experimentation may raise ethical issues but provides the complexity necessary to model human processes, though
consideration of species differences is paramount. Organoids and other ‘in vivo like’ models may provide a compromise
between these competing considerations, with the additional potential to use human cells220,226. recent advances show
that microglia, astrocytes and oligodendrocytes can be present in or engrafted to organoids221,227; however, these have
not yet been extensively used to study glia–immune cell interactions.
identifying and isolating cells
Glia subsets are readily distinguishable from one another; however, different types of immune cells express overlapping
sets of genetic or protein markers and exhibit within-​cell-type heterogeneity, making it challenging to identify intended
populations for study. a major advance was the identification of a set of microglia ‘signature genes’, allowing for the
development of ‘microglia-​specific’ genetic tools and reagents70,102,111,228,229. it must be noted, however, that microglia
signature gene expression is often unstable in disease states, presenting a problem for cell identification, although this may
be addressed by genetic fate labelling218. isolation of specific CNs glial and immune cell populations from the brain can also
dramatically affect gene expression in those cells216,230,231. therefore, it is critical to optimize cell isolation strategies and, in
any presentation of the work using these techniques, to describe the methods used in detail. In the analysis of isolated cells,
high-​dimensional, single-​cell approaches (such as single-​cell RNA sequencing, mass cytometry and spatial transcriptomics)
are now used to avoid prospective cell purification and therefore reduce the bias of targeting predefined lineages7,12,216.
in addition, new analysis methods can identify ligand–receptor interaction pairs within and between cell lineages,
thereby identifying cell–cell communication in single-​cell RNA sequencing datasets223,232. However, removing cells from
their environment risks preferentially selecting those that survive isolation procedures and therefore requires further
systematic study.
Targeting or modifying cells
Genetic targeting and modification (most commonly with the Cre–lox system) provides temporal control of gene
modification in specific cell types but is dependent on the existence of specific and efficient Cre lines102,233,234. the use of
viral tools (such as adeno-​associated viruses) as vectors to transfer genes to areas of interest can increase the feasibility
and provide anatomical specificity. Currently, adeno-​associated viruses have been developed to target astrocytes and
oligodendrocytes but it remains unfeasible to target microglia in vivo using this method235. an alternative method to target
cell–cell communication is through the depletion of one cell type. Genetic strategies (such as mice expressing diphtheria
toxin receptor (DTR) or herpes simplex virus thymidine kinase (HSVTK) in target cells) or pharmacologic strategies (such as
inhibition of CSF1R) can be used to remove microglia from the CNS to varying degrees236–240. recently, deletion of the
fms-​intronic regulatory element (FIRE) of the mammalian Csf1r locus was shown to result in a complete lack of microglia
with no overt developmental abnormalities241, overcoming an issue observed in Csf1r−/− mice74. similarly, immunodeficient
mice, such as severe combined immunodeficient (SCID) mice or RAG1-deficient mice242, or more specific peripheral
immune cell depletion, such as using Ly6G-​targeting antibodies to deplete neutrophils in mice243, offer a practical but
non-​specific method to study the impacts of immune function on glia.

Problem Approach Features

Choice of model In vitro models Reductionist, tractable, variable validity
In vivo models Complex, challenging implementation, broader validity
‘In vivo like’ models (such as Technically challenging, improved validity
organoids or 3D cultures)
Identifying and Cell type-​specific markers Increasingly specific, requires valid detection tools (such as
isolating cells antibodies or transgenic Cre lines), often unstable in disease
Cell isolation Dramatically affects cell phenotypes, requires cell type-specific
optimization and customization to assay and cell type
Single-​cell approaches Reduces cell type marker bias, costly , technically challenging
Targeting/ Genetic targeting Allows temporally and cell type-​specific manipulations, limited
modifying cells by line availability
Viral recombination High specificity possible, immune stimulatory , cannot
manipulate microglia
Cell ablation Widely used for immune populations, practical, lack of
molecular control, off-​target/non-​specific effects

www.nature.com/nrn

a cassette of reactivity genes, loss of normal astrocyte
functions (such as promotion of synapse formation) and
gain of neurotoxic functions84. To summarize, in vitro
studies show that communication between microglia
and astrocytes occurs largely through inflammatory
mediators, which is not surprising when the immune
functions of microglia are considered.
The effects of microglia-​driven inflammation may
be detrimental and/or beneficial for the nervous system
depending on timing and context85–87, and microglia-​
driven astrocyte activation is not necessarily harmful.
For example, it has recently been shown that astro-
cytes provide a supportive substrate and are necessary
for recovery after spinal cord injury38. Recent in vivo
studies have therefore built upon in vitro data in mul-
tiple disease settings. To further assess the potentially
detrimental role of astrocytes activated by microglial
TNF, IL-1α and C1q, astrocyte reactivity was prevented
through the generation of transgenic mice lacking all
three cytokines, inhibiting neuronal cell death follow-
ing optic nerve crush84. Neurotoxic astrocytes with a
similar phenotype to those induced by microglia in
culture and in animal models are also observed in the
post-​mortem brain tissue of individuals with neuro-
degenerative diseases, including multiple sclerosis and
Alzheimer disease84. Glucagon-​like peptide 1 receptor
(GLP1R) agonist treatment has been shown to reduce
pathology in two mouse models of Parkinson disease
by decreasing the microglia-​mediated activation of
astrocytes to a neurotoxic activation state88. On the
other hand, in a rodent traumatic brain injury (TBI)
model, inhibition of microglial activity or microglial
ablation significantly disrupts the formation of the
astrocytic scar and increases brain injury, suggesting
that there is a neuroprotective microglia–astrocyte
interaction after TBI89. In experimental autoimmune
encephalomyelitis (EAE) in mice, microglia-​derived
transforming growth factor-​α (TGFα) reduces disease
severity by signalling directly to astrocytes, whereas
microglia-​derived vascular endothelial growth factor-​β
(VEGFβ) increases disease burden 90. Interestingly,
the microglial control of astrocyte function in EAE
is, in turn, directly regulated by microbially derived
tryptophan metabolite signalling through the aryl
hydrocarbon receptor (AHR), suggesting that gut
microbiota composition may modulate both the
microglial response and disease severity90. The valida-
tion of microglial control of astrocytes in various CNS
pathologies demonstrates the importance of microglial–
astrocyte relays (Fig. 2). However, these studies also
highlight the complexity and context-​d ependent
nature of such cell-​to-cell interactions.
Microglial regulation of oligodendrocytes. Oligo­
dendrocytes are essential for proper neuronal function
and depend on signals derived from astrocytes and
microglia for their differentiation and survival91,92. In vivo
studies have shown that, during brain develop­ment
in mice, microglia support oligodendrocyte matura­
tion and function93,94. Indeed, selective depletion of a
developmentally regulated CD11c-​expressing microg­
lial subset leads to impaired primary myelination95.
Nature Reviews | Neuroscience
Reviews
In addition, the effects of the depletion of microglia
after development suggest that microglia also maintain
oligod­endrocyte progenitor numbers in the healthy adult
mouse brain93, though this may be dependent on the
microglial depletion strategy96. However, the influence
of microglia on oligodendrocytes is not always trophic:
the production of TNF, nitric oxide and complement
after microglial activation can facilitate oligodendro-
cyte cell death and phagocytosis by microglia in rat cells
in vitro97,98. In human cell cultures, activated microglia
produce factors that have direct cytotoxic effects on neu-
ral progenitors, which results in a decreased number of
oligodendrocyte lineage cells either directly or indirectly
via astrocyte signalling to their progenitors99.
The studies described above suggest that microglia
support the normal development of oligodendrocytes
but can be toxic in inflammatory environments. Due
to the plasticity of microglia, studies have also assessed
their trophic potential and ability to modulate oligoden-
drocyte function and improve remyelination in diseases
such as multiple sclerosis100. For example, conditioned
medium from mouse microglia treated with IL-13 or
IL-10 enhances oligodendrocyte survival and differen-
tiation in vitro101. The targeted depletion of microglia
expressing CD206 (a receptor that is upregulated in
microglia after IL-13 or IL-10 treatment) in an in vivo
mouse model of demyelination decreases oligoden-
drocyte differentiation and delays remyelination101. In
EAE, conditional depletion of TGFβ-​activated kinase 1
(TAK1) in microglia suppresses disease and reduces CNS
inflammation and axonal and myelin damage through
the cell-​autonomous inhibition of the NF-​κ B, Jun
N-​terminal kinase (JNK) and extracellular-​signal-
regulated kinase 1 (ERK1)/ERK2 pathways102. However,
it is not known whether these beneficial effects are due to
the loss of direct signalling from microglia to oligoden-
drocytes. Oligodendrocyte differentiation and survival
also requires signalling from the extracellular matrix103.
The adhesion G protein-​coupled receptor ADGRG1
(also known as GPR56) is an evolutionarily con-
served regulator of oligodendrocyte development104,105.
Transglutaminase 2 is produced by microglia signals
to ADGRG1 on OPCs in the presence of the extra-
cellular matrix and promotes OPC proliferation and
remyelination in animal models106.
The complex influence of microglia on oligodendro-
cytes may also affect cognitive function. Humans that
receive chemotherapy have cognitive problems and per-
sistent depletion of oligodendrocyte lineage cells107. In a
mouse model, methotrexate chemotherapy was shown
to induce persistent microglial activation, driving neuro-
logical and cognitive dysfunction, depletion and dysreg-
ulation of OPCs, deficits in myelination, and astrocyte
activation107. Therefore, chemotherapy has been pro-
posed to induce a ‘tri-​glial’ dysregulation, with microglia
as the key detrimental modulator of both astrocytes and
oligodendrocytes.
In summary, combined evidence from in vitro and
in vivo experiments reveals that microglia directly
and indirectly modulate oligodendrocyte survival and
function in development and can be either beneficial
or detrimental in different pathological contexts (Fig. 2).
Reviews

Steady-state
microglial cell
TNF, IL-1α and C1q
Activated (neurodegenerative
microglial cell disease/acute injury),
VEGFβ (EAE) or
Oligodendrocyte IL-1β, IL-6 and iNOS Astrocyte
(in vitro)
??

Microglial context Microglial context

Detrimental effect
on oligodendrocytes
and outcome, and
reduced myelination
• Methotrexate chemotherapy • Neurodegenerative disease
• High levels of iron • Acute injury
• Inflammation • EAE
• Developmental loss of CD11c • Methotrexate Detrimental effects
expression in microglia chemotherapy on astrocytes and
outcome
IL-13, IL-10 and
transglutaminase 2 TGFα
de(re)myelination (EAE)

Microglial context
• TBI
Beneficial effects • EAE Beneficial effects
on oligodendrocytes • Demyelination or on astrocytes and
and outcome remyelination outcome

Fig. 2 | context-​dependent signalling of microglia to astrocytes and oligodendrocytes. Microglia respond to a variety
of injuries and CNS pathologies through the activation of different signalling pathways that allow them to communicate
to oligodendrocytes and astrocytes in different ways, depending on the context. Both beneficial and detrimental
microglial effects on oligodendrocytes and astrocytes in disease and injury have been described84,88,90,101,106,107. In the
schematic, three different contexts in which microglia may be activated and the downstream effects of their activation
on astrocytes and oligodendrocytes are illustrated. Microglial activation is indicated by the solid arrows and microglial
signalling to other glial cells is indicated by the dashed arrows. Microglial activation during chemotherapy , when iron
levels are high, during inflammation or as a result of a developmental loss of CD11c expression results in detrimental
effects on oligodendrocytes and reduced myelination, although the soluble mediators are unknown. Microglial activation
in traumatic brain injury (TBI), experimental autoimmune encephalomyelitis (EAE) or as a result of demyelination or
remyelination can have a beneficial effect on oligodendrocytes through IL-10, IL-13 or transglutaminase 2 release
and on astrocytes via transforming growth factor-​α (TGFα) signalling. In neurodegenerative disease, acute injury , EAE and
chemotherapy , microglia can drive astrocytes to a detrimental disease-​modifying activation state through a variety of
inflammatory mediators. These effects highlight the highly context-​dependent nature of microglia–oligodendrocyte and
microglia–astrocyte interactions. C1q, complement component C1q; iNOS, inducible nitric oxide synthase; TNF, tumour
necrosis factor ; VEGFβ, vascular endothelial growth factor-​β.

Peripheral immune regulation of glia
Peripheral immune cell entry to the CNS. At sites of
CNS injury and disease, the recruitment of peripheral
immune cells can also modulate tissue-​resident glia
(Fig. 3). In healthy conditions, immune cell entry into
the parenchyma is restricted by multiple specialized
cellular structures such as the blood–brain barrier and
the blood–CSF barrier32,108. During perturbations to the
CNS, immune cells, such as neutrophils, monocyte-​
derived macrophages and lymphocytes, can traffic
through intact or compromised barriers and enter
the brain108. Distinguishing these peripheral immune
cell populations from most glia is relatively straight-
forward due to their unique morphology and specific
lineage markers109. However, it has historically been
difficult to distinguish resident microglia from infiltrat-
ing monocyte-​derived macrophages as they are both
phagocytic myeloid cells that share many common fea-
tures8,70,110,111. Nevertheless, to evaluate the communica-
tion of infiltrating immune cells to resident glia, the two
cell types must be distinguishable. Fortunately, microglia
and infiltrating monocyte-​derived macrophages are now
known to have different ontogeny112 and the advent of
transcriptional profiling techniques has revealed unique
features of each cell type that have helped address this
question8,70,110,111.
Many ‘microglia-​specific’ proteins (those that are
highly enriched in microglia in comparison with mono-
cytes and monocyte-​derived macrophages) have now
been described in mouse and humans, and antibodies
and genetic tools to investigate these cells are avail­
able13. Despite this, work is ongoing to determine the
stability of such markers in disease and injury contexts,
as it has been shown that some highly specific micro-
glial markers, such as TMEM119 and P2RY12, are
susceptible to downregulation during inflammation
and disease111,113,114. Indeed, the concept of a ‘homeo-
static’ signature of microglia was coined to describe
how microglia-​defining genes are downregulated in
disease contexts115. Adding to the complexity of distin-
guishing microglia from other macrophages, several
groups have shown that blood monocytes can begin to
express many microglia signature genes after engraft-
ing in the brain, including TMEM119 (refs73,74,111,116).
These data show that some portion of microglial iden-
tity reflects the exposure to brain parenchymal signals

www.nature.com/nrn
 Reviews

a b c d e f

Microglia-mediated injury response Acute

injury

Hours Days Weeks

Time after acute injury

a Neutrophil T cell b c
Parenchyma CNS barriers Blood vessel

Monocyte

CNS-resident
macrophage

Homeostatic Activated
microglial cell microglial cell

Homeostasis Acute injury triggers resident Neutrophil entry and

immune cell activation phagocytosis by microglia

d Monocyte-derived e f
macrophage

??

Monocyte-derived macrophage Lymphocyte entry and Treg cell Resolution of microglial activation
entry and signalling to microglia signalling to microglia

Fig. 3 | Peripheral immune cell infiltration and their dynamic interaction with microglia after cNs injury. After
various types of acute CNS injury , there is a stereotyped infiltration of immune cells over time. Current evidence predicts
that a direct interaction between peripheral immune cells infiltrating the CNS and microglia can reduce microglial
activation after injury71,160,198,199. This hypothesis is illustrated in the graph at the top of the figure. The y-​axis represents
the level of microglial response after acute injury , that is, the magnitude of each cell’s response and/or the number of
cells involved. The x-​axis represents time after the injury. a | Immune cell populations of the CNS in their homeostatic
state prior to injury. b | Microglia respond (are activated), within minutes, to acute injury and initiate a cascade of
inflammatory events that further activate other microglial cells and are involved in the recruitment of immune cells to
the injury site148. Little is known of specific responses of other resident immune cells in injury and disease. c | Neutrophils
are the first blood-​borne immune cells to respond to acute tissue damage, entering the CNS within hours of injury87,134,149.
Phagocytosis of neutrophils by microglia partly resolves the microglial inflammatory phenotype161. d | The first
monocyte-​derived macrophages arrive in the parenchyma after 2–3 days87,134,149 and can also suppress the activation
of microglia after acute injury71. e | Lymphocytes are recruited over a period of days to weeks after the original injury176–178.
Regulatory T (Treg) cell signalling to microglia suppresses proinflammatory cytokine and chemokine production and
further reduces microglial activation179–185. f | Weeks after the initial injury , infiltrating immune cells can still be found
at the injury site in reduced numbers, though it is unknown whether they continue to signal to microglia and affect
recovery in the long-​term.

Nature Reviews | Neuroscience

Reviews

in the cellular environment rather than cell origin. disease onset and progression114,143–147 and the direct
Nevertheless, blood-​derived macrophages engrafted in signalling of infiltrating macrophages to microglia has
the brain remain morphologically and transcriptom- not been studied.
ically different from microglia even after long-​term In the context of injury, microglial cells are activated
residence, suggesting functional non-​e quivalence. prior to the arrival of monocyte-​derived macrophages
The impact of developmental origin on brain macro­ and may actively participate in their recruitment148.
phage function thus remains unresolved and a topic of In acute injuries associated with frank tissue dam-
ongoing study. age, the first monocyte-​derived macrophages arrive
in the parenchyma after 2–3 days87,134,149. In models of
Monocyte-​derived macrophage regulation of CNS glia. SCI, EAE, TBI and stroke, the arrival of monocyte-​
Relatively few studies have addressed how monocyte-​ derived macrophages coincides with the downregul­
derived macrophages modulate resident microglia, ation of microglial inflammation and phagocytic
despite evidence of their infiltration into the CNS in functions71,140,141,150,151. In a bilaminar culture system
injury and disease. Early after injury and before the entry designed to assess direct macrophage–microglial
of peripheral macrophages, microglia have been shown interactions, it was shown that macrophages directly
to limit the initial damage caused by a variety of insults, suppress microglial phagocytosis 71. Interestingly,
including laser lesion in acute brain slices117, ischae- microglia were found to have the reciprocal effect on
mic stroke in animal models118, hippocampal lesions119 macrophages, acting to enhance macrophages’ phago-
and spinal cord trauma120. However, it also known that cytic activity71. Mathematical modelling of cytokine
microglia can, after injury, be driven to an inflamma- signalling indicates that the inflammatory cytokines
tory state that has detrimental effects on neuronal sur- IL-1β, TNF, IL-6 and IL-10 are key nodes in inflamma-
vival121,122 and their chronic activation is detrimental tory networks85,152 and it has been shown that macro­
to the brain123. Monocyte-​derived macrophage arrival phages suppress these nodes in both adult mouse and
into the CNS may have a role in modulating these microg­ human microglia in culture71. Macrophage-​derived
lial functions and thus affect outcome in CNS injury prostaglandin E2 mediates suppression of microglial
and disease. phagocytosis in the bilaminar culture system and can
During viral or bacterial CNS infections, inflam- release trophic factors to reduce microglia-​mediated
matory monocyte-​derived macrophages infiltrate the injury of cultured neurons153. In vivo, preventing infil-
brain124. It has been shown that infected peripherally tration of macrophages to the CNS increases microg­
derived macrophages can prime naive microglial cells lial activation after trauma in the brain and spinal
(that is, they can cause them to adopt a state such that cord71,154,155. Therefore, after acute injury, macrophages
subsequent stimuli produce an exaggerated response125), entering the CNS may provide a regulatory mechanism
causing microglia to express a range of inflamma- that controls acute and long-​term microglia-​mediated
tory mediators in vitro126–128. Similarly, peripherally inflammation.
derived macrophages that are directly stimulated with Fewer studies have investigated monocyte-​derived
interferon-​γ (IFNγ), a factor critical for innate and macrophage communication to astrocytes; how-
adaptive immunity against viral infection, produce ever, evidence suggests that soluble factors released
mediators that induce TNF and inducible nitric oxide by inflammatory macrophages induce a reactive gene
synthase expression in cultured microglia129. Such stud- expression pattern in these cells in vitro156. In culture,
ies show that activated peripheral macrophages can alter human monocytes potentiate the production and release
microglia function and provide a proof-​of-concept that of CCL2 from astrocytes, potentially providing a feed-
myeloid cells from the periphery may modulate myeloid forward mechanism to increase the further recruitment
cells of the CNS. of monocytes157. Indeed, human monocytes infected
There is a long history of investigation as to whether with Mycobacterium tuberculosis in culture can drive
monocyte-​derived macrophages are detrimental or ben- astrocytes to produce the matrix-​degrading enzyme
eficial to recovery after acute injury87,130,131. Studies in spi- MMP9, which is also localized to astrocytes in post
nal cord injury (SCI), TBI and stroke have shown both mortem tissue sections from patients with CNS tuber-
detrimental and beneficial effects of these cells132–134. The culosis158. In a brain stab wound injury model, reducing
route of entry (either through a compromised blood– monocyte-​derived macrophage invasion results in a
brain barrier or the blood–CSF barrier) has been pro- marked increase in astrocyte proliferation but reduced
posed to confer beneficial or detrimental properties scar formation due to less extracellular matrix deposi-
on infiltrating immune cells in models of stroke, SCI tion155. This results in a smaller lesion site and increased
and amyotrophic lateral sclerosis (ALS)135–139. In acute neuronal preservation155. These results suggest that, in
injury, recruited monocyte-​d erived macrophages both sterile and infectious CNS injury, monocytes drive
quickly become the numerically dominant myeloid cell astrocytes to detrimental phenotypes.
in lesions and their boundary zones; however, unlike Interestingly, these early studies suggest that infiltrat-
microglia, they are not thought to be long-​lived in the ing macrophages may have direct beneficial actions on
CNS140–142. In neurodegenerative disease, the slow pro- microglia but modulate astrocytes in a detrimental way.
gression of pathology makes the infiltration dynamics More studies are required to clearly define the macro­
of immune cells more difficult to quantify. In Alzheimer phage-microglia–astrocyte interaction and whether
disease, numerous studies report conflicting results oligo­dendrocytes play a defined role in such immune–glia
regarding the contribution of recruited monocytes to network signalling.

www.nature.com/nrn

Neutrophil regulation of CNS glia. Neutrophils are
the first blood-​b orne immune cells to respond to
acute tissue damage, entering the CNS within hours
of injury87,134,149,159 (Fig. 3), and are also reported to be
present in the CNS in neurodegenerative conditions160.
The clearance of neutrophils from the CNS by macro­
phages is one of the key events in the resolution of
inflammation161,162. Neutrophil clearance is mediated
by the production of specialized pro-​resolution medi-
ators from macrophages that actively resolve inflam-
mation. These bioactive lipids, derived from omega-3
polyunsaturated fatty acids (including maresins, neuro-
protectins and resolvins), promote recovery after CNS
injury163,164. Intravital microscopy reveals that microglia
react to passing neutrophils, interacting with them and
engulfing them165 through mechanisms likely mediated
by specialized pro-​resolution mediators164. It has long
been established that the phagocytosis of neutrophils by
macrophages, including microglia, results in a pheno-
typic and functional change of the phagocytic cells and
is therefore a major form of microglia regulation122,166. In
triple-​transgenic Alzheimer disease model mice, which
develop age-​related progressive neuropathology, neutro­
phil depletion results in less microglial activation160;
however, to our knowledge, evidence for direct signal-
ling from neutrophils to microglia (rather than an effect
mediated via phagocytosis) is lacking.
With regard to the communication of neutrophils
to astrocytes, data from zebrafish indicate that, in the
context of tumour progression, impaired neutrophil
function reduces the proliferation of astrocytes and
limits the progression of tumorigenesis167. However,
in human cell culture experiments, components of the
complement system released by neutrophils are reported
to promote astroglial differentiation from neural stem
cells and to promote migration168. Despite the limited
investigation into direct neutrophil signalling to resident
glial cells, it is interesting to note that neutrophils pro-
duce an array of cytokines and proteolytic enzymes that
can affect microglia, astrocytes and oligodendrocytes169.
Therefore, signalling between neutrophils and glial cells
can be expected to occur. The role of such signalling in
disease and injury is an important area for future study.
Lymphocyte communication to CNS glia. Lymphocytes
in the healthy brain are relatively scarce but their capac-
ity to secrete modulatory factors puts them in a good
position to influence the resident cells of the CNS.
Direct signalling between T cells and CNS cells has
been shown in animal models to have a role in phys-
iological processes such as social behaviour15,170 and
learning, and it has been suggested that meningeal
T cells increase astrocytic brain-​derived neurotrophic
factor (BDNF) expression through the release of IL-4
(ref.171). It is therefore reasonable to assume that lympho-
cytes recruited to the brain as part of an inflammatory
response may have equally measurable effects on CNS
glia. A large body of literature exists describing IFNγ
and IL-4, which are known T cell derived cytokines, as
factors that respectively drive proinflammatory and
anti-​inflammatory states in microglia in culture172. As
a result, there is mounting evidence that T cells directly
Nature Reviews | Neuroscience
Reviews
signal to resident microglia during injury and disease to
alter pathophysiology.
In CNS disease, lymphocytes are best known for their
role in multiple sclerosis pathology. Multiple sclerosis is
a chronic, demyelinating, inflammatory disease, a hall-
mark of which is infiltration of immune cells into the
CNS173. Multiple sclerosis stands alone as a major CNS
disease for which multiple effective disease-​modifying
drugs are available174. Several of these target lymphocyte
function and/or entry to the CNS174,175. The investigation
of direct lymphocyte action on glia is still in its early
stages in the context of multiple sclerosis and lympho-
cyte function in the disease is the subject of several excel-
lent reviews to which we refer the reader173–175. Due to
space limitations, we focus herein on lymphocyte–glia
interactions on acute injury and other diseases.
Following acute injuries such as stroke or CNS
trauma, lymphocytes are recruited after neutrophils and
monocyte-​derived macrophages over a period that starts
days after the original injury and lasts for several further
weeks176–178. Multiple lines of evidence from studies in
animal models demonstrate that lymphocytes may play
a role in injury progression176,179. Furthermore, although
the numbers of T cells and B cells in human post mortem
lesions are low180,181, it has been shown that lymphocytes
accumulate in the meninges and that T cell numbers
increase in injured human CNS tissue over time130,180,182.
In the chronic setting of neurodegenerative diseases,
lymphocytes (mainly T cells) are present in post mortem
tissue taken from individuals with Alzheimer disease,
ALS and Parkinson disease, and have also been found
in tissue derived from corresponding mouse models of
these diseases183–190. Perhaps the most intensive interest
in how lymphocytes affect CNS-​resident cells, at least in
commercial drug discovery, lies in the search for immuno­
therapies for neurodegenerative diseases, particularly
in Alzheimer disease191. These therapies include active
vaccines that aim to stimulate lymphocytes to produce
antibodies against amyloid-​β (one of the key proteins
implicated in Alzheimer disease pathogenesis) or passive
immunization through the administration of exogenous
antibodies. In both cases, the ultimate aim is to stimulate
the clearance of amyloid-​β plaques through microglial
phagocytosis192. There is much hope surrounding these
therapies but there have also been many setbacks, as
reviewed elsewhere191. Here, we focus on evidence for
direct signalling of lymphocytes to resident CNS cells.
Although critical players in the peripheral immune
response, the role of B cells in CNS injury and neuro­
degenerative disease is only beginning to be understood.
Mice treated with IL-10-producing B cells have reduced
numbers of activated microglia after stroke, though it is
unclear whether B cell-​derived IL-10 acts directly on the
microglia193. In models of traumatic SCI and stroke, B cells
synthesize autoantibodies194,195, which are deposited
together with C1q and activate cells bearing Fc recep-
tors, including microglia194. Removal of B cells in both
contexts improves recovery, though the direct detrimen-
tal effect of B cells remains to be determined. Indeed,
modulation of B cell-​dependent pathological mecha-
nisms may be more important in the periphery than in
the CNS as infections such as pneumonia are a major
Reviews
complication of stroke and SCI and cause increased
morbidity and mortality196.
Many studies show that specific T cell subsets are
either beneficial, such as regulatory T (Treg) cells, or det-
rimental, such as γδ T cells, after acute injury in animal
models62,197. Fewer studies have investigated the direct
signalling of T cells to resident glia. In in vivo stroke
models, IL-10-producing Treg cells reduce the activa-
tion of resident and invading immune cells, including
TNF-​producing microglia198,199. Interestingly, in cul-
tures of cells isolated from the brains of mice undergo-
ing beneficial immunosuppressive treatments, Treg cells
directly suppress microglial proinflammatory cytokine
and chemokine production200,201. In animal models,
Treg cells continue to accumulate in the brain 2 weeks
after injury and appear to be important in long-​term
neurological recovery as a result of their signalling to
astrocytes 182: they suppress neurotoxic astrogliosis
by producing amphiregulin, a low-​affinity epidermal
growth factor receptor (EGFR) ligand182. In studies with
less specific targeting of immune cells before SCI, such
as the complete removal of T cell and B cell subsets (in
Rag2–/– mice), recovery from injury is improved and
there is reduced microglia/macrophage activation but
increased astrocyte numbers202, suggesting differential
effects of lymphocytes on the two glia subtypes.
In human Alzheimer disease post mortem tissue,
T cells are observed in close proximity to microglia,
suggesting that direct signalling is possible183. However,
it is still unclear whether the endogenous lymphocyte
response in Alzheimer disease is beneficial. When
transgenic APP/PS1 mice (which accumulate amyloid-​
β deposits at a young age) are crossed with Rag2–/– mice,
brain amyloid-​β pathology is decreased in association
with enhanced microglial activation and increased
phagocytosis of amyloid-​β peptide aggregates 203.
Amyloid-​β-specific type 1 T helper CD4-expressing
cells, adoptively transferred to APP/PS1 mice, release
IFNγ, increase microglial activation and impair cogni-
tive function204. By contrast, immunodeficient Rag2–/–
mice crossed with 5xfAD mice (which express human
transgenes with a total of five Alzheimer disease-​linked
mutations) exhibit a greater than twofold increase in
amyloid-​β pathology and increased microglia-​mediated
neuroinflammation with reduced phagocytic capacity205.
This suggests that the adaptive immune cell populations
restrain Alzheimer disease pathology through microg­
lial actions205. These studies highlight important roles
for lymphocyte regulation of microglia in different dis-
ease models, yet it is clear that the various in vivo animal
models differ greatly in their recapitulation of the disease.
ALS is characterized by selective degeneration of
motor neurons and, in some cases, is linked to mutations
in the superoxide dismutase (SOD1) gene206. In humans
and mutant Sod1-transgenic mice, loss of motor neurons
is accompanied by robust microglia and astrocyte acti-
vation207. Mutant Sod1 mice bred onto a T cell receptor
β-​chain-deficient background, ablating αβ T cells, show
accelerated disease progression and reduced microglial
reactivity, indicating that these T cells play an endo­g­
enous neuroprotective role in ALS by modulating a
beneficial inflammatory response to neuronal injury208.
In support of such a beneficial T cell response, the expan­
sion of endogenous Treg cells in a mouse model of ALS
significantly prolonged survival time and was associ-
ated with a marked suppression of glial cell immuno-
reactivity209. In vitro evidence suggests that the cytokine
IL-33 may drive T cells to reduce astrocyte activation
in ALS210. However, it is also known that oligodendro-
cytes can release IL-33 in the injured spinal cord, which
can directly affect astrocytes and microglia211; therefore,
the actions of IL-33 on resident glia may also be derived
from sources other than T cells.
In contrast to the evidence of beneficial actions in
models of ALS, in Parkinson disease models, it has
been shown that T cells must be present for activation
of microglia and the resulting dopaminergic neuro­
degeneration after viral overexpression of α-​synuclein212.
In vitro, T cells significantly reduced α-​synuclein phago-
cytosis by microglia213 and the absence of mature CD4-
expressing T cells in vivo reduced microglial activation
in a MPTP model of the disease186.
Lastly, in a model of chronic stress, mitochondrial fis-
sion in peripheral CD4-expressing T cells drives anxiety-​
like behaviour through the production of the purine
xanthine214. Using almost all of the in vivo techniques
described in Box 1, it was shown that oligodendrocytes
in the left amygdala were modulated by CD4-expressing
T cell-​derived xanthine through the adenosine A1 recep-
tor, and that this pathway is responsible for the anxiety-​
like behaviour after chronic stress214. This highlights
the power of the peripheral lymphocyte response to
modulate behaviour through glia.
In summary, there is now clear evidence that lympho­
cytes can directly modulate resident glia and affect the
outcome of disease states in various animal models
(Fig. 3). However, the nature of these interactions var-
ies not only between different disease models but also
within models of the same disease.
Future perspectives
An abundance of in vitro and in vivo data now demon-
strates the powerful effects of immune signals on other
non-​n euronal CNS cells throughout the lifespan.
Targeting these interactions therefore holds enormous
promise for the treatment of neurological diseases of
development, injury and ageing. Indeed, the preclinical
efficacy of this approach has already been demonstrated.
For example, altering brain macrophage polarization fol-
lowing demyelination appears to improve remyelination
by supporting oligodendrocyte maturation, while microg­
lial depletion resolves chemotherapy-​induced cognitive
decline101,107. However, immune signals appear to have
highly context-​specific effects and simultaneous direct
and indirect contributions from both peripheral and
resident immune cells can modulate resident glia. To
add to this complexity, it is now apparent that immune
cells in brain barriers are bona fide resident populations,
distinct from parenchymal microglia and their counter-
parts in the periphery7. It is largely unknown how the
heterogeneity of these cells contributes to CNS disease
or injury, but their presence must be considered as a fac-
tor when developing therapies targeting immune–glia
interactions.
www.nature.com/nrn
 Reviews

This leads to a broad conceptual question — given the
extensive data showing functionally relevant communi-
cation between glia and nearly all classes of immune cells,
is there a hierarchy of responses? In a sea of complexity,
it is often useful to build conceptual frameworks. The
evolving categorization of macrophage states provides a
useful case study. The field previously adopted a bipolar
metric for microglial activation121, which rightly ignited
great interest in the subject but was subsequently con-
sidered as an oversimplification215. It is being replaced by
the emerging concept of multidimensional state catego-
rization, made increasingly possible by high throughput
single-​cell analyses5–7,12,114,216–218. These methods have
uncovered great complexity within canonically defined
populations, but the reproducibility of ‘subpopulations’
across samples, experiments and labs, in addition to their
functional relevance, is still being established.
With increased cellular resolution, our language
for describing cell states has become more accurate
but, ironically, less concrete. At the level of microglial
function, a similar pattern emerges. For example, in
the context of EAE, microglia-​derived TGFα reduces
disease severity by signalling directly to astrocytes,
whereas microglia-​derived VEGFβ increased disease
burden90; microglia are thus both ‘good’ and ‘bad’,
depending on what one prevents them for producing.
Limiting astrocyte-​specific type I interferon signalling
in EAE increases microglial activation, suggesting that
astrocytes restrain CNS inflammation through microg­
lia219. Here, whether one set of responses precedes the
other is unknown. In neurodegenerative disease,
the emergence of multiple immune-​related risk factor
genes points to a potential cellular origin50,51, but the
above examples argue strongly that the next frontier in
glial–immune biology is to define the network activity
of complex cellular responses and prioritize the most
biologically important pathways.
Though challenging, the complexity of immune cell–
glia interactions holds great opportunity for the develop-
ment of targeted molecular therapies. Such efforts will
benefit greatly from new tools to extensively characterize
and interrogate complex cell–cell interactions in devel-
opment and disease. These include cerebral organoids,
CRISPR screening, high content imaging and constantly
improving sequencing technologies to map complex
pathways at single-​cell resolution. Recent glia–immune
cell-​specific advances include a 3D cell culture model
of Alzheimer disease220, the generation of microglia in
brain organoids221, massive single-​cell sequencing data-
sets of microglia in health and disease6,7,216,222, and rap-
idly developing analysis methods223. In the coming years,
these and other approaches stand to revolutionize our
understanding of immune–glia interactions and how to
modulate them.
Published online xx xx xxxx

1. Barres, B. A. The mystery and magic of glia:
a perspective on their roles in health and disease.
Neuron 60, 430–440 (2008).
2. Azevedo, F. A. C. et al. Equal numbers of neuronal
and nonneuronal cells make the human brain an
isometrically scaled-​up primate brain. J. Comp.
Neurol. 513, 532–541 (2009).
3. Morest, D. K. & Silver, J. Precursors of neurons,
neuroglia, and ependymal cells in the CNS:
what are they? Where are they from? How do
they get where they are going? Glia 43, 6–18
(2003).
4. Saunders, A. et al. Molecular diversity and
specializations among the cells of the adult mouse
brain. Cell 174, 1015–1030 (2018).
5. Böttcher, C. et al. Human microglia regional
heterogeneity and phenotypes determined by
multiplexed single-​cell mass cytometry. Nat. Neurosci.
22, 78–90 (2019).
6. Masuda, T. et al. Spatial and temporal heterogeneity
of mouse and human microglia at single-​cell resolution.
Nature 566, 388–392 (2019).
7. Van Hove, H. et al. A single-​cell atlas of mouse brain
macrophages reveals unique transcriptional identities
shaped by ontogeny and tissue environment.
Nat. Neurosci. 22, 1021–1035 (2019).
8. Grabert, K. et al. Microglial brain region-​dependent
diversity and selective regional sensitivities to aging.
Nat. Neurosci. 19, 504–516 (2016).
This was the first study to show microglial
heterogeneity across brain regions.
9. Prinz, M., Erny, D. & Hagemeyer, N. Ontogeny and
homeostasis of CNS myeloid cells. Nat. Immunol. 18,
385–392 (2017).
10. Kipnis, J. Multifaceted interactions between adaptive
immunity and the central nervous system. Science
353, 766–771 (2016).
11. Goldmann, T. et al. Origin, fate and dynamics of
macrophages at central nervous system interfaces.
Nat. Immunol. 17, 797–805 (2016).
This study determined that non-​microglial
CNS macrophages arise from haematopoietic
precursors during embryonic development
and establish stable populations, with the
notable exception of choroid plexus
macrophages.
12. Mrdjen, D. et al. High-​dimensional single-​cell mapping
of central nervous system immune cells reveals distinct
myeloid subsets in health, aging, and disease.
Immunity 48, 380–395 (2018).
This study provides an excellent description of the
different immune cell populations that reside
within the CNS using CyTOF.
13. David, S., Kroner, A., Greenhalgh, A. D., Zarruk, J. G.
& López-​Vales, R. Myeloid cell responses after spinal
cord injury. J. Neuroimmunol. 321, 97–108 (2018).
14. Herz, J., Filiano, A. J., Smith, A., Yogev, N. & Kipnis, J.
Myeloid cells in the central nervous system. Immunity
46, 943–956 (2017).
15. Filiano, A. J., Gadani, S. P. & Kipnis, J. How and why
do T cells and their derived cytokines affect the injured
and healthy brain? Nat. Rev. Neurosci. 18, 375–384
(2017).
16. Kierdorf, K. & Prinz, M. Microglia in steady state.
J. Clin. Invest. 127, 3201–3209 (2017).
17. Pósfai, B., Cserép, C., Orsolits, B. & Dénes, Á. New
insights into microglia–neuron interactions: a neuron’s
perspective. Neuroscience 405, 103–117 (2019).
18. Kisler, K., Nelson, A. R., Montagne, A. & Zlokovic, B. V.
Cerebral blood flow regulation and neurovascular
dysfunction in Alzheimer disease. Nat. Rev. Neurosci.
18, 419–434 (2017).
19. Heindryckx, F. & Li, J.-P. Role of proteoglycans in
neuro-​inflammation and central nervous system
fibrosis. Matrix Biol. 68–69, 589–601 (2018).
20. Valny, M., Honsa, P., Kriska, J. & Anderova, M.
Multipotency and therapeutic potential of NG2 cells.
Biochem. Pharmacol. 141, 42–55 (2017).
21. Shechter, R., London, A. & Schwartz, M. Orchestrated
leukocyte recruitment to immune-​privileged sites:
absolute barriers versus educational gates. Nat. Rev.
Immunol. 13, 206–218 (2013).
22. Wohleb, E. S. & Godbout, J. P. Basic aspects of the
immunology of neuroinflammation. Mod. Trends
Pharmacopsychiatry 28, 1–19 (2013).
23. Zhou, B., Zuo, Y.-X. & Jiang, R.-T. Astrocyte morphology:
diversity, plasticity, and role in neurological diseases.
CNS Neurosci. Ther. 25, 665–673 (2019).
24. Allen, N. J. et al. Astrocyte glypicans 4 and 6 promote
formation of excitatory synapses via GluA1 AMPA
receptors. Nature 486, 410–414 (2012).
25. Christopherson, K. S. et al. Thrombospondins are
astrocyte-​secreted proteins that promote CNS
synaptogenesis. Cell 120, 421–433 (2005).
Together with reference 24, this study
demonstrated that astrocyte-​secreted factors
promote the formation of functional and structural
synapses.
26. Chuquet, J., Quilichini, P., Nimchinsky, E. A. &
Buzsáki, G. Predominant enhancement of glucose
uptake in astrocytes versus neurons during activation
of the somatosensory cortex. J. Neurosci. 30,
15298–15303 (2010).
27. Ioannou, M. S. et al. Neuron-​astrocyte metabolic
coupling protects against activity-​induced fatty acid
toxicity. Cell 177, 1522–1535 (2019).
28. Magistretti, P. J. & Allaman, I. Lactate in the brain:
from metabolic end-​product to signalling molecule.
Nat. Rev. Neurosci. 19, 235–249 (2018).
29. Bergles, D. E. & Jahr, C. E. Synaptic activation of
glutamate transporters in hippocampal astrocytes.
Neuron 19, 1297–1308 (1997).
30. Hertz, L. Possible role of neuroglia: a potassium-​
mediated neuronal–neuroglial–neuronal impulse
transmission system. Nature 206, 1091–1094
(1965).
31. Rusakov, D. A. Disentangling calcium-​driven
astrocyte physiology. Nat. Rev. Neurosci. 16,
226–233 (2015).
32. Abbott, N. J., Patabendige, A. A. K., Dolman, D. E. M.,
Yusof, S. R. & Begley, D. J. Structure and function of
the blood–brain barrier. Neurobiol. Dis. 37, 13–25
(2010).
33. Santello, M., Toni, N. & Volterra, A. Astrocyte function
from information processing to cognition and cognitive
impairment. Nat. Neurosci. 22, 154–166 (2019).
34. Hastings, M. H., Maywood, E. S. & Brancaccio, M.
Generation of circadian rhythms in the suprachiasmatic
nucleus. Nat. Rev. Neurosci. 19, 453–469 (2018).
35. Heneka, M. T., McManus, R. M. & Latz, E.
Inflammasome signalling in brain function and
neurodegenerative disease. Nat. Rev. Neurosci. 19,
610–621 (2018).
36. Anderson, M. A. et al. Astrocyte scar formation aids
central nervous system axon regeneration. Nature
532, 195–200 (2016).
37. Bradbury, E. J. et al. Chondroitinase ABC promotes
functional recovery after spinal cord injury. Nature
416, 636–640 (2002).
38. Anderson, M. A. et al. Required growth facilitators
propel axon regeneration across complete spinal cord
injury. Nature 561, 396–400 (2018).
39. Boulanger, J. J. & Messier, C. From precursors to
myelinating oligodendrocytes: contribution of intrinsic

Nature Reviews | Neuroscience

Reviews
and extrinsic factors to white matter plasticity in the
adult brain. Neuroscience 269, 343–366 (2014).
40. Butt, A. M. in Encyclopedia of Neuroscience (ed.
Squire, L. R.) 203–208 (Academic Press, 2009).
41. Zhu, X., Bergles, D. E. & Nishiyama, A. NG2 cells
generate both oligodendrocytes and gray matter
astrocytes. Development 135, 145–157 (2008).
42. Dawson, M. R., Polito, A., Levine, J. M. & Reynolds, R.
NG2-expressing glial progenitor cells: an abundant
and widespread population of cycling cells in the adult
rat CNS. Mol. Cell. Neurosci. 24, 476–488 (2003).
43. Falcão, A. M. et al. Disease-​specific oligodendrocyte
lineage cells arise in multiple sclerosis. Nat. Med. 24,
1837–1844 (2018).
44. Battefeld, A., Klooster, J. & Kole, M. H. P. Myelinating
satellite oligodendrocytes are integrated in a glial
syncytium constraining neuronal high-​frequency
activity. Nat. Commun. 7, 11298–11298 (2016).
45. Niu, J. et al. Aberrant oligodendroglial–vascular
interactions disrupt the blood–brain barrier,
triggering CNS inflammation. Nat. Neurosci. 22,
709–718 (2019).
46. Greter, M., Lelios, I. & Croxford, A. L. Microglia versus
myeloid cell nomenclature during brain inflammation.
Front. Immunol. 6, 249–249 (2015).
47. Perry, V. H. & Gordon, S. Macrophages and microglia
in the nervous system. Trends Neurosci. 11, 273–277
(1988).
48. Davalos, D. et al. ATP mediates rapid microglial
response to local brain injury in vivo. Nat. Neurosci. 8,
752–758 (2005).
Together with reference 49, these studies were
the first to demonstrate the dynamic nature of
microglial processes at steady state and in
response to injury.
49. Nimmerjahn, A., Kirchhoff, F. & Helmchen, F. Resting
microglial cells are highly dynamic surveillants of brain
parenchyma in vivo. Science 308, 1314–1318 (2005).
50. Jansen, I. E. et al. Genome-​wide meta-​analysis
identifies new loci and functional pathways influencing
Alzheimer’s disease risk. Nat. Genet. 51, 404–413
(2019).
51. Villegas-​Llerena, C., Phillips, A., Garcia-​Reitboeck, P.,
Hardy, J. & Pocock, J. M. Microglial genes regulating
neuroinflammation in the progression of Alzheimer’s
disease. Curr. Opin. Neurobiol. 36, 74–81 (2016).
52. Schafer, D. P. et al. Microglia sculpt postnatal neural
circuits in an activity and complement-​dependent
manner. Neuron 74, 691–705 (2012).
Together with reference 53, this study demonstrated
the role of complement molecules in synapse
elimination by microglia during development.
53. Stevens, B. et al. The classical complement cascade
mediates CNS synapse elimination. Cell 131,
1164–1178 (2007).
54. Ginhoux, F. et al. Fate mapping analysis reveals that
adult microglia derive from primitive macrophages.
Science 330, 841–845 (2010).
This study used elegant fate mapping approaches
to demonstrate the embryonic origin of microglia.
55. Schulz, C. et al. A lineage of myeloid cells independent
of Myb and hematopoietic stem cells. Science 336,
86–90 (2012).
56. Mass, E. et al. A somatic mutation in erythro-​myeloid
progenitors causes neurodegenerative disease. Nature
549, 389–393 (2017).
This work showed that somatic mutations specifically
in embryonic progenitors of microglia can cause
neuronal loss, likely explaining why some patients
with histiocytosis develop neurodegenerative
disease.
57. Kreutzberg, G. W. Microglia: a sensor for pathological
events in the CNS. Trends Neurosci. 19, 312–318
(1996).
58. Beccari, S., Diaz-​Aparicio, I. & Sierra, A. Quantifying
microglial phagocytosis of apoptotic cells in the brain
in health and disease. Curr. Protoc. Immunol. 122,
e49 (2018).
59. Korin, B. et al. High-​dimensional, single-​cell
characterization of the brain’s immune compartment.
Nat. Neurosci. 20, 1300–1309 (2017).
60. Da Mesquita, S., Fu, Z. & Kipnis, J. The meningeal
lymphatic system: a new player in neurophysiology.
Neuron 100, 375–388 (2018).
61. Kivisäkk, P. et al. Human cerebrospinal fluid central
memory CD4+ T cells: evidence for trafficking through
choroid plexus and meninges via P-​selectin. Proc. Natl
Acad. Sci. USA 100, 8389–8394 (2003).
62. Benakis, C., Llovera, G. & Liesz, A. The meningeal and
choroidal infiltration routes for leukocytes in stroke.
Ther. Adv. Neurol. Disord. 11, 1756286418783708
(2018).
63. Radjavi, A., Smirnov, I., Derecki, N. & Kipnis, J.
Dynamics of the meningeal CD4+ T-​cell repertoire are
defined by the cervical lymph nodes and facilitate
cognitive task performance in mice. Mol. Psychiatry
19, 531–533 (2014).
64. Quintana, E. et al. DNGR-1+ dendritic cells are located
in meningeal membrane and choroid plexus of the
noninjured brain. Glia 63, 2231–2248 (2015).
65. McCarthy, K. D. & de Vellis, J. Preparation of separate
astroglial and oligodendroglial cell cultures from rat
cerebral tissue. J. Cell Biol. 85, 890–902 (1980).
66. Sievers, J., Parwaresch, R. & Wottge, H.-U. Blood
monocytes and spleen macrophages differentiate
into microglia-​like cells on monolayers of astrocytes:
morphology. Glia 12, 245–258 (1994).
67. Tanaka, J. & Maeda, N. Microglial ramification
requires nondiffusible factors derived from astrocytes.
Exp. Neurol. 137, 367–375 (1996).
68. Bohlen, C. J. et al. Diverse requirements for microglial
survival, specification, and function revealed by defined-
medium cultures. Neuron 94, 759–773.e8 (2017).
69. Foo, L. C. et al. Development of a method for the
purification and culture of rodent astrocytes. Neuron
71, 799–811 (2011).
70. Butovsky, O. et al. Identification of a unique TGF-​β
dependent molecular and functional signature in
microglia. Nat. Neurosci. 17, 131–143 (2014).
Together with references 110 and 111, this study
showed that microglia can be defined by a specific
molecular signature in mice.
71. Greenhalgh, A. D. et al. Peripherally derived
macrophages modulate microglial function to reduce
inflammation after CNS injury. PLOS Biol. 16,
e2005264 (2018).
72. Gosselin, D. et al. An environment-​dependent
transcriptional network specifies human microglia
identity. Science 356, eaal3222 (2017).
This study comprehensively characterized the
transcriptional phenotype of human microglia.
73. Cronk, J. C. et al. Peripherally derived macrophages
can engraft the brain independent of irradiation
and maintain an identity distinct from microglia.
J. Exp. Med. 215, 1627–1647 (2018).
Together with reference 74, this study showed that
microglial transcriptomic identity is garnered by
both origin and environment.
74. Bennett, F. C. et al. A combination of ontogeny and
CNS environment establishes microglial identity.
Neuron 98, 1170–1183 (2018).
75. Esmonde-​White, C. et al. Distinct function-​related
molecular profile of adult human A2B5-positive
pre-oligodendrocytes versus mature oligodendrocytes.
J. Neuropathol. Exp. Neurol. 78, 468–479 (2019).
76. Healy, L. M., Yaqubi, M., Ludwin, S. & Antel, J. P.
Species differences in immune-​mediated CNS tissue
injury and repair: a (neuro)inflammatory topic. Glia
https://doi.org/10.1002/glia.23746(2019) (2019).
77. Même, W. et al. Proinflammatory cytokines released
from microglia inhibit gap junctions in astrocytes:
potentiation by β-​amyloid. FASEB J. 20, 494–496
(2006).
78. Watanabe, M. et al. Th1 cells downregulate connexin
43 gap junctions in astrocytes via microglial activation.
Sci. Rep. 6, 38387 (2016).
79. Retamal, M. A. et al. Cx43 hemichannels and gap
junction channels in astrocytes are regulated
oppositely by proinflammatory cytokines released
from activated microglia. J. Neurosci. 27,
13781–13792 (2007).
80. Kirkley, K. S., Popichak, K. A., Afzali, M. F., Legare, M. E.
& Tjalkens, R. B. Microglia amplify inflammatory
activation of astrocytes in manganese neurotoxicity.
J. Neuroinflammation 14, 99 (2017).
81. Sofroniew, M. V. Astrogliosis. Cold Spring Harb.
Perspect. Biol. 7, a020420 (2014).
82. Hwang, S.-Y. et al. Ionizing radiation induces astrocyte
gliosis through microglia activation. Neurobiol. Dis.
21, 457–467 (2006).
83. Kyrkanides, S., Olschowka, J. A., Williams, J. P.,
Hansen, J. T. & O’Banion, M. K. TNFα and IL-1β
mediate intercellular adhesion molecule-1 induction
via microglia-​astrocyte interaction in CNS radiation
injury. J. Neuroimmunol. 95, 95–106 (1999).
84. Liddelow, S. A. et al. Neurotoxic reactive astrocytes
are induced by activated microglia. Nature 541,
481–487 (2017).
85. Anderson, W. D. et al. Computational modeling of
cytokine signaling in microglia. Mol. Biosyst. 11,
3332–3346 (2015).
86. David, S. & Kroner, A. Repertoire of microglial and
macrophage responses after spinal cord injury.
Nat. Rev. Neurosci. 12, 388–399 (2011).
87. Schwab, J. M., Zhang, Y., Kopp, M. A., Brommer, B.
& Popovich, P. G. The paradox of chronic
neuroinflammation, systemic immune suppression,
autoimmunity after traumatic chronic spinal cord
injury. Exp. Neurol. 258, 121–129 (2014).
88. Yun, S. P. et al. Block of A1 astrocyte conversion by
microglia is neuroprotective in models of Parkinson’s
disease. Nat. Med. 24, 931–938 (2018).
89. Shinozaki, Y. et al. Transformation of astrocytes to
a neuroprotective phenotype by microglia via P2Y1
receptor downregulation. Cell Rep. 19, 1151–1164
(2017).
90. Rothhammer, V. et al. Microglial control of astrocytes
in response to microbial metabolites. Nature 557,
724–728 (2018).
91. Barres, B. A. et al. Cell death and control of cell
survival in the oligodendrocyte lineage. Cell 70,
31–46 (1992).
92. Nicholas, R. S. J., Wing, M. G. & Compston, A.
Nonactivated microglia promote oligodendrocyte
precursor survival and maturation through the
transcription factor NF-​κB. Eur. J. Neurosci. 13,
959–967 (2001).
93. Hagemeyer, N. et al. Microglia contribute to normal
myelinogenesis and to oligodendrocyte progenitor
maintenance during adulthood. Acta Neuropathol.
134, 441–458 (2017).
94. Schonberg, D. L. et al. Ferritin stimulates
oligodendrocyte genesis in the adult spinal cord and
can be transferred from macrophages to NG2 cells
in vivo. J. Neurosci. 32, 5374–5384 (2012).
95. Wlodarczyk, A. et al. A novel microglial subset plays
a key role in myelinogenesis in developing brain.
EMBO J. 36, 3292–3308 (2017).
96. Liu, Y. et al. Concentration-​dependent effects of CSF1R
inhibitors on oligodendrocyte progenitor cells ex vivo
and in vivo. Exp. Neurol. 318, 32–41 (2019).
97. Merrill, J. E., Ignarro, L. J., Sherman, M. P.,
Melinek, J. & Lane, T. E. Microglial cell cytotoxicity
of oligodendrocytes is mediated through nitric oxide.
J. Immunol. 151, 2132–2141 (1993).
98. Zajicek, J., Wing, M., Scolding, N. & Compston, D.
Interactions between oligodendrocytes and microglia:
a major role for complement and tumour necrosis
factor in oligodendrocyte adherence and killing.
Brain 115, 1611–1631 (1992).
99. Moore, C. S. et al. Direct and indirect effects of
immune and central nervous system-​resident cells on
human oligodendrocyte progenitor cell differentiation.
J. Immunol. 194, 761–772 (2015).
100. Miron, V. E. Microglia-​driven regulation of
oligodendrocyte lineage cells, myelination, and
remyelination. J. Leukoc. Biol. 101, 1103–1108
(2017).
101. Miron, V. E. et al. M2 microglia and macrophages
drive oligodendrocyte differentiation during CNS
remyelination. Nat. Neurosci. 16, 1211–1218 (2013).
102. Goldmann, T. et al. A new type of microglia gene
targeting shows TAK1 to be pivotal in CNS
autoimmune inflammation. Nat. Neurosci. 16,
1618–1626 (2013).
103. Wheeler, N. A. & Fuss, B. Extracellular cues influencing
oligodendrocyte differentiation and (re)myelination.
Exp. Neurol. 283, 512–530 (2016).
104. Giera, S. et al. The adhesion G protein-​coupled
receptor GPR56 is a cell-​autonomous regulator of
oligodendrocyte development. Nat. Commun. 6, 6121
(2015).
105. Ackerman, S. D., Garcia, C., Piao, X., Gutmann, D. H.
& Monk, K. R. The adhesion GPCR Gpr56 regulates
oligodendrocyte development via interactions with
Gα12/13 and RhoA. Nat. Commun. 6, 6122 (2015).
106. Giera, S. et al. Microglial transglutaminase-2 drives
myelination and myelin repair via GPR56/ADGRG1
in oligodendrocyte precursor cells. eLife 7, e33385
(2018).
107. Gibson, E. M. et al. Methotrexate chemotherapy
induces persistent tri-​glial dysregulation that underlies
chemotherapy-​related cognitive impairment. Cell 176,
43–55.e13 (2019).
This work showed that glial cell dysfunction is the
likely cause of methotrexate-​induced cognitive
impairment.
108. Engelhardt, B., Vajkoczy, P. & Weller, R. O. The movers
and shapers in immune privilege of the CNS.
Nat. Immunol. 18, 123–131 (2017).
109. Ransohoff, R. M. & Brown, M. A. Innate immunity
in the central nervous system. J. Clin. Invest. 122,
1164–1171 (2012).
110. Hickman, S. E. et al. The microglial sensome revealed
by direct RNA sequencing. Nat. Neurosci. 16,
1896–1905 (2013).
www.nature.com/nrn

111. Bennett, M. L. et al. New tools for studying microglia
in the mouse and human CNS. Proc. Natl Acad. Sci.
USA 113, E1738–E1746 (2016).
112. Ginhoux, F., Lim, S., Hoeffel, G., Low, D. & Huber, T.
Origin and differentiation of microglia. Front. Cell.
Neurosci. 7, 45 (2013).
113. Sousa, C. et al. Single-cell transcriptomics reveals
distinct inflammation-induced microglia signatures.
EMBO Rep. 19, e46171 (2018).
114. Krasemann, S. et al. The TREM2-APOE pathway
drives the transcriptional phenotype of dysfunctional
microglia in neurodegenerative diseases. Immunity
47, 566–581 (2017).
Together with references 216 and 217, this study
profiled microglia during development and injury,
and introduced the concept of a disease-​associated
microglial transcriptomic signature.
115. Butovsky, O. & Weiner, H. L. Microglial signatures and
their role in health and disease. Nat. Rev. Neurosci.
19, 622–635 (2018).
116. Shemer, A. et al. Engrafted parenchymal brain
macrophages differ from microglia in transcriptome,
chromatin landscape and response to challenge.
Nat. Commun. 9, 5206 (2018).
117. Hines, D. J., Hines, R. M., Mulligan, S. J. &
Macvicar, B. A. Microglia processes block the spread
of damage in the brain and require functional chloride
channels. Glia 57, 1610–1618 (2009).
118. Szalay, G. et al. Microglia protect against brain injury
and their selective elimination dysregulates neuronal
network activity after stroke. Nat. Commun. 7, 11499
(2016).
119. Rice, R. A. et al. Elimination of microglia improves
functional outcomes following extensive neuronal loss
in the hippocampus. J. Neurosci. 35, 9977–9989
(2015).
120. Bellver-​Landete, V. et al. Microglia are an essential
component of the neuroprotective scar that forms
after spinal cord injury. Nat. Commun. 10, 518
(2019).
121. Kigerl, K. A. et al. Identification of two distinct
macrophage subsets with divergent effects causing
either neurotoxicity or regeneration in the injured
mouse spinal cord. J. Neurosci. 29, 13435–13444
(2009).
122. Kroner, A. et al. TNF and increased intracellular iron
alter macrophage polarization to a detrimental M1
phenotype in the injured spinal cord. Neuron 83,
1098–1116 (2014).
123. Colonna, M. & Butovsky, O. Microglia function in
the central nervous system during health and
neurodegeneration. Annu. Rev. Immunol. 35,
441–468 (2017).
124. Rock, R. B. et al. Role of microglia in central nervous
system infections. Clin. Microbiol. Rev. 17, 942–964
(2004).
125. Neher, J. J. & Cunningham, C. Priming microglia for
innate immune memory in the brain. Trends Immunol.
40, 358–374 (2019).
126. Lee, H.-M., Kang, J., Lee, S. J. & Jo, E.-K. Microglial
activation of the NLRP3 inflammasome by the priming
signals derived from macrophages infected with
mycobacteria. Glia 61, 441–452 (2013).
127. Qin, Y. et al. Macrophage-​microglia networks drive M1
microglia polarization after mycobacterium infection.
Inflammation 38, 1609–1616 (2015).
128. Renner, N. A. et al. Microglia activation by SIV-​infected
macrophages: alterations in morphology and cytokine
secretion. J. Neurovirol. 18, 213–221 (2012).
129. Wolfe, H., Minogue, A. M., Rooney, S. & Lynch, M. A.
Infiltrating macrophages contribute to age-​related
neuroinflammation in C57/BL6 mice. Mechanisms
Ageing Dev. 173, 84–91 (2018).
130. Shechter, R. & Schwartz, M. Harnessing monocyte-​
derived macrophages to control central nervous
system pathologies: no longer ‘if’ but ‘how’. J. Pathol.
229, 332–346 (2013).
131. David, S., López-​Vales, R. & Wee Yong, V. in Handbook
of Clinical Neurology Vol. 109 (eds Verhaagen, J.
& McDonald, J. W.) 485–502 (Elsevier, 2012).
132. Kim, E. & Cho, S. Microglia and monocyte-​derived
macrophages in stroke. Neurotherapeutics 13,
702–718 (2016).
133. Hu, X. et al. Microglial and macrophage polarization
— new prospects for brain repair. Nat. Rev. Neurol.
11, 56–64 (2015).
134. McKee, C. A. & Lukens, J. R. Emerging roles for
the immune system in traumatic brain injury.
Front. Immunol. 7, 556–556 (2016).
135. Ge, R. et al. Choroid plexus-​cerebrospinal fluid route
for monocyte-​derived macrophages after stroke.
J. Neuroinflammation 14, 153 (2017).
Nature Reviews | Neuroscience
136. Shechter, R. et al. Recruitment of beneficial M2
macrophages to injured spinal cord is orchestrated by
remote brain choroid plexus. Immunity 38, 555–569
(2013).
137. Kertser, A. et al. IFN-​γ-dependent activation of the
brain’s choroid plexus for CNS immune surveillance
and repair. Brain 136, 3427–3440 (2013).
138. Kunis, G., Baruch, K., Miller, O. & Schwartz, M.
Immunization with a myelin-​derived antigen activates
the Brain’s choroid plexus for recruitment of
immunoregulatory cells to the CNS and attenuates
disease progression in a mouse model of ALS.
J. Neurosci. 35, 6381–6393 (2015).
139. Szmydynger-​Chodobska, J. et al. Posttraumatic
invasion of monocytes across the blood—cerebrospinal
fluid barrier. J. Cereb. Blood Flow Metab. 32, 93–104
(2012).
140. Zarruk, J. G., Greenhalgh, A. D. & David, S. Microglia
and macrophages differ in their inflammatory profile
after permanent brain ischemia. Exp. Neurol. 301,
120–132 (2018).
141. Greenhalgh, A. D. & David, S. Differences in the
phagocytic response of microglia and peripheral
macrophages after spinal cord injury and its effects on
cell death. J. Neurosci. 34, 6316–6322 (2014).
142. Ajami, B., Bennett, J. L., Krieger, C., McNagny, K. M.
& Rossi, F. M. V. Infiltrating monocytes trigger EAE
progression, but do not contribute to the resident
microglia pool. Nat. Neurosci. 14, 1142–1149
(2011).
143. Baruch, K. et al. PD-1 immune checkpoint blockade
reduces pathology and improves memory in mouse
models of Alzheimer’s disease. Nat. Med. 22,
135–137 (2016).
144. Prinz, M. & Priller, J. The role of peripheral
immune cells in the CNS in steady state and disease.
Nat. Neurosci. 20, 136–144 (2017).
145. Guillot-​Sestier, M.-V. et al. IL10 deficiency rebalances
innate immunity to mitigate Alzheimer-​like pathology.
Neuron 85, 534–548 (2015).
146. Koronyo, Y. et al. Therapeutic effects of glatiramer
acetate and grafted CD115+ monocytes in a mouse
model of Alzheimer’s disease. Brain 138, 2399–2422
(2015).
147. Wang, Y. et al. TREM2-mediated early microglial
response limits diffusion and toxicity of amyloid
plaques. J. Exp. Med. 213, 667–675 (2016).
148. Fekete, R. et al. Microglia control the spread of
neurotropic virus infection via P2Y12 signalling and
recruit monocytes through P2Y12-independent
mechanisms. Acta Neuropathol. 136, 461–482
(2018).
149. Grønberg, N. V., Johansen, F. F., Kristiansen, U. &
Hasseldam, H. Leukocyte infiltration in experimental
stroke. J. Neuroinflammation 10, 115 (2013).
150. Taylor, R. A. et al. TGF-​β1 modulates microglial
phenotype and promotes recovery after intracerebral
hemorrhage. J. Clin. Invest. 127, 280–292 (2017).
151. Yamasaki, R. et al. Differential roles of microglia and
monocytes in the inflamed central nervous system.
J. Exp. Med. 211, 1533–1549 (2014).
152. Anderson, W. D., Greenhalgh, A. D., Takwale, A.,
David, S. & Vadigepalli, R. Novel influences of IL-10
on CNS inflammation revealed by integrated analyses
of cytokine networks and microglial morphology.
Front. Cell. Neurosci. 11, 233 (2017).
153. Sharma, S. et al. Bone marrow mononuclear cells
protect neurons and modulate microglia in cell culture
models of ischemic stroke. J. Neurosci. Res. 88,
2869–2876 (2010).
154. Shechter, R. et al. Infiltrating blood-​derived
macrophages are vital cells playing an anti-​
inflammatory role in recovery from spinal cord injury
in mice. PLOS Med. 6, e1000113 (2009).
155. Frik, J. et al. Cross-talk between monocyte invasion
and astrocyte proliferation regulates scarring in brain
injury. EMBO Rep. 19, e45294 (2018).
156. Haan, N., Zhu, B., Wang, J., Wei, X. & Song, B.
Crosstalk between macrophages and astrocytes
affects proliferation, reactive phenotype and
inflammatory response, suggesting a role during
reactive gliosis following spinal cord injury.
J. Neuroinflammation 12, 109 (2015).
157. Andjelkovic, A. V., Kerkovich, D. & Pachter, J. S.
Monocyte:astrocyte interactions regulate MCP-1
expression in both cell types. J. Leukoc. Biol. 68,
545–552 (2000).
158. Harris, J. E. et al. Monocyte-​astrocyte networks
regulate matrix metalloproteinase gene expression
and secretion in central nervous system tuberculosis
in vitro and in vivo. J. Immunol. 178, 1199–1207
(2007).
Reviews
159. Kurimoto, T. et al. Neutrophils express oncomodulin
and promote optic nerve regeneration. J. Neurosci.
33, 14816–14824 (2013).
160. Zenaro, E. et al. Neutrophils promote Alzheimer’s
disease-​like pathology and cognitive decline via LFA-1
integrin. Nat. Med. 21, 880–886 (2015).
161. Schwab, J. M., Chiang, N., Arita, M. & Serhan, C. N.
Resolvin E1 and protectin D1 activate inflammation-​
resolution programmes. Nature 447, 869–874
(2007).
162. Davies, C. L., Patir, A. & McColl, B. W. Myeloid cell
and transcriptome signatures associated with
inflammation resolution in a model of self-​limiting
acute brain inflammation. Front. Immunol. 10, 1048
(2019).
163. Serhan, C. N., Dalli, J., Colas, R. A., Winkler, J. W. &
Chiang, N. Protectins and maresins: New pro-​resolving
families of mediators in acute inflammation and
resolution bioactive metabolome. Biochim. Biophys.
Acta 1851, 397–413 (2015).
164. Francos-​Quijorna, I. et al. Maresin 1 promotes
inflammatory resolution, neuroprotection, and
functional neurological recovery after spinal cord
injury. J. Neurosci. 37, 11731–11743 (2017).
165. Neumann, J. et al. Beware the intruder: real time
observation of infiltrated neutrophils and neutrophil–
microglia interaction during stroke in vivo. PLOS ONE
13, e0193970 (2018).
166. Gordon, S. Alternative activation of macrophages.
Nat. Rev. Immunol. 3, 23–35 (2003).
167. Powell, D., Lou, M., Barros Becker, F. & Huttenlocher, A.
Cxcr1 mediates recruitment of neutrophils and
supports proliferation of tumor-​initiating astrocytes
in vivo. Sci. Rep. 8, 13285 (2018).
168. Hooshmand, M. J. et al. Neutrophils induce astroglial
differentiation and migration of human neural stem
cells via C1q and C3a synthesis. J. Immunol. 199,
1069–1085 (2017).
169. Ng, L. G., Ostuni, R. & Hidalgo, A. Heterogeneity of
neutrophils. Nat. Rev. Immunol. 19, 255–265 (2019).
170. Filiano, A. J. et al. Unexpected role of interferon-​γ in
regulating neuronal connectivity and social behaviour.
Nature 535, 425–429 (2016).
171. Derecki, N. C. et al. Regulation of learning and
memory by meningeal immunity: a key role for IL-4.
J. Exp. Med. 207, 1067–1080 (2010).
172. Murray, P. J. et al. Macrophage activation and
polarization: nomenclature and experimental
guidelines. Immunity 41, 14–20 (2014).
173. Filippi, M. et al. Multiple sclerosis. Nat. Rev.
Dis. Primers 4, 43 (2018).
174. Dobson, R. & Giovannoni, G. Multiple sclerosis –
a review. Eur. J. Neurol. 26, 27–40 (2019).
175. Li, R., Patterson, K. R. & Bar-​Or, A. Reassessing B cell
contributions in multiple sclerosis. Nat. Immunol. 19,
696–707 (2018).
176. Brennan, F. H. & Popovich, P. G. Emerging targets
for reprograming the immune response to promote
repair and recovery of function after spinal cord injury.
Curr. Opin. Neurol. 31, 334–344 (2018).
177. Raposo, C. et al. CNS repair requires both effector and
regulatory T cells with distinct temporal and spatial
profiles. J. Neurosci. 34, 10141–10155 (2014).
178. Vindegaard, N. et al. T-​cells and macrophages peak
weeks after experimental stroke: spatial and temporal
characteristics. Neuropathology 37, 407–414 (2017).
179. Cramer, J. V., Benakis, C. & Liesz, A. T cells in the
post-​ischemic brain: troopers or paramedics?
J. Neuroimmunol. 326, 33–37 (2019).
180. Zrzavy, T. et al. Dominant role of microglial and
macrophage innate immune responses in human
ischemic infarcts. Brain Pathol. 28, 791–805 (2018).
181. Fleming, J. C. et al. The cellular inflammatory
response in human spinal cords after injury.
Brain 129, 3249–3269 (2006).
182. Ito, M. et al. Brain regulatory T cells suppress
astrogliosis and potentiate neurological recovery.
Nature 565, 246–250 (2019).
183. Unger, M. S. et al. Doublecortin expression in CD8+
T-cells and microglia at sites of amyloid-​β plaques:
a potential role in shaping plaque pathology?
Alzheimers Dement. 14, 1022–1037 (2018).
184. Merlini, M., Kirabali, T., Kulic, L., Nitsch, R. M. &
Ferretti, M. T. Extravascular CD3+ T cells in brains of
Alzheimer disease patients correlate with tau but not
with amyloid pathology: an immunohistochemical
study. Neurodegener. Dis. 18, 49–56 (2018).
185. Togo, T. et al. Occurrence of T cells in the brain of
Alzheimer’s disease and other neurological diseases.
J. Neuroimmunol. 124, 83–92 (2002).
186. Brochard, V. et al. Infiltration of CD4+ lymphocytes
into the brain contributes to neurodegeneration in a
Reviews
mouse model of Parkinson disease. J. Clin. Invest.
119, 182–192 (2009).
187. Troost, D., van den Oord, J. J. & Vianney de Jong, J. M.
Immunohistochemical characterization of the
inflammatory infiltrate in amyotrophic lateral sclerosis.
Neuropathol. Appl. Neurobiol. 16, 401–410 (1990).
188. Engelhardt, J. I., Tajti, J. & Appel, S. H. Lymphocytic
infiltrates in the spinal cord in amyotrophic lateral
sclerosis. Arch. Neurol. 50, 30–36 (1993).
189. Beers, D. R. & Appel, S. H. Immune dysregulation
in amyotrophic lateral sclerosis: mechanisms and
emerging therapies. Lancet Neurol. 18, 211–220
(2019).
190. González, H., Contreras, F. & Pacheco, R. Regulation of
the neurodegenerative process associated to Parkinson’s
disease by CD4+ T-​cells. J. Neuroimmune Pharmacol.
10, 561–575 (2015).
191. van Dyck, C. H. Anti-​amyloid-β monoclonal antibodies
for Alzheimer’s disease: pitfalls and promise. Biol.
Psychiatry 83, 311–319 (2018).
192. Bachmann, M. F., Jennings, G. T. & Vogel, M. A vaccine
against Alzheimer’s disease: anything left but faith?
Expert Opin. Biol. Ther. 19, 73–78 (2019).
193. Bodhankar, S., Chen, Y., Vandenbark, A. A.,
Murphy, S. J. & Offner, H. Treatment of experimental
stroke with IL-10-producing B-​cells reduces infarct size
and peripheral and CNS inflammation in wild-​type
B-cell-sufficient mice. Metab. Brain Dis. 29, 59–73
(2014).
194. Ankeny, D. P., Guan, Z. & Popovich, P. G. B cells
produce pathogenic antibodies and impair recovery
after spinal cord injury in mice. J. Clin. Invest. 119,
2990–2999 (2009).
195. Doyle, K. P. et al. B-​lymphocyte-mediated delayed
cognitive impairment following stroke. J. Neurosci. 35,
2133–2145 (2015).
196. Westendorp, W. F., Nederkoorn, P. J., Vermeij, J. D.,
Dijkgraaf, M. G. & de Beek, D. V. Post-​stroke infection:
a systematic review and meta-​analysis. BMC Neurol.
11, 110 (2011).
197. Sun, G. et al. γδ T cells provide the early source
of IFN-γ to aggravate lesions in spinal cord injury.
J. Exp. Med. 215, 521–535 (2018).
198. Liesz, A. et al. Regulatory T cells are key
cerebroprotective immunomodulators in acute
experimental stroke. Nat. Med. 15, 192–199 (2009).
This was one of the first studies to show a
protective role of Treg cells in experimental
stroke.
199. Na, S.-Y., Mracsko, E., Liesz, A., Hünig, T. &
Veltkamp, R. Amplification of regulatory T cells using
a CD28 superagonist reduces brain damage after
ischemic stroke in mice. Stroke 46, 212–220
(2015).
200. Xie, L. et al. mTOR signaling inhibition modulates
macrophage/microglia-​mediated neuroinflammation
and secondary injury via regulatory T cells after focal
ischemia. J. Immunol. 192, 6009–6019 (2014).
201. Xie, L., Choudhury, G. R., Winters, A., Yang, S. H. &
Jin, K. Cerebral regulatory T cells restrain microglia/
macrophage-​mediated inflammatory responses via
IL-10. Eur. J. Immunol 45, 180–191 (2015).
202. Wu, B. et al. Improved regeneration after spinal cord
injury in mice lacking functional T- and B-​lymphocytes.
Exp. Neurol. 237, 274–285 (2012).
203. Späni, C. et al. Reduced β-​amyloid pathology in an
APP transgenic mouse model of Alzheimer’s disease
lacking functional B and T cells. Acta Neuropathol.
Commun. 3, 71 (2015).
204. Browne, T. C. et al. IFN-​γ production by amyloid
β-specific Th1 cells promotes microglial activation
and increases plaque burden in a mouse model of
Alzheimer’s disease. J. Immunol. 190, 2241–2251
(­20­13­).
205. Marsh, S. E. et al. The adaptive immune system
restrains Alzheimer’s disease pathogenesis by
modulating microglial function. Proc. Natl Acad.
Sci. USA 113, E1316–E1325 (2016).
206. Pasinelli, P. & Brown, R. H. Molecular biology of
amyotrophic lateral sclerosis: insights from genetics.
Nat. Rev. Neurosci. 7, 710–723 (2006).
207. McGeer, P. L. & McGeer, E. G. Inflammatory processes
in amyotrophic lateral sclerosis. Muscle Nerve 26,
459–470 (2002).
208. Chiu, I. M. et al. T lymphocytes potentiate endogenous
neuroprotective inflammation in a mouse model of
ALS. Proc. Natl Acad. Sci. USA 105, 17913–17918
(2008).
209. Sheean, R. K. et al. Association of regulatory T-​cell
expansion with progression of amyotrophic lateral
sclerosis: a study of humans and a transgenic mouse
model. JAMA Neurol. 75, 681–689 (2018).
210. Korhonen, P. et al. Long-​term interleukin-33 treatment
delays disease onset and alleviates astrocytic
activation in a transgenic mouse model of amyotrophic
lateral sclerosis. IBRO Rep. 6, 74–86 (2019).
211. Gadani, S. P. et al. The glia-​derived alarmin IL-33
orchestrates the immune response and promotes
recovery following CNS injury. Neuron 85, 703–709
(2015).
212. Harms, A. S. et al. MHCII is required for α-​synuclein-
induced activation of microglia, CD4 T cell proliferation,
and dopaminergic neurodegeneration. J. Neurosci. 33,
9592–9600 (2013).
213. Sommer, A. et al. Infiltrating T lymphocytes reduce
myeloid phagocytosis activity in synucleinopathy
model. J. Neuroinflammation 13, 174 (2016).
214. Fan, K.-Q. et al. Stress-​induced metabolic disorder in
peripheral CD4+ T cells leads to anxiety-​like behavior.
Cell 179, 864–879 (2019).
This study showed that T cell-​mediated actions on
oligodendrocytes in a specific brain region affect
behaviour.
215. Ransohoff, R. M. A polarizing question: do M1 and
M2 microglia exist? Nat. Neurosci. 19, 987–991
(2016).
216. Hammond, T. R. et al. Single-​cell RNA sequencing of
microglia throughout the mouse lifespan and in the
injured brain reveals complex cell-​state changes.
Immunity 50, 253–271 (2019).
217. Keren-​Shaul, H. et al. A unique microglia type
associated with restricting development of Alzheimer’s
disease. Cell 169, 1276–1290 (2017).
218. O’Koren, E. G. et al. Microglial function is distinct
in different anatomical locations during retinal
homeostasis and degeneration. Immunity 50,
723–737.e7 (2019).
219. Rothhammer, V. et al. Type I interferons and microbial
metabolites of tryptophan modulate astrocyte activity
and central nervous system inflammation via the aryl
hydrocarbon receptor. Nat. Med. 22, 586–597 (2016).
220. Park, J. et al. A 3D human triculture system modeling
neurodegeneration and neuroinflammation in
Alzheimer’s disease. Nat. Neurosci. 21, 941–951
(2018).
221. Ormel, P. R. et al. Microglia innately develop within
cerebral organoids. Nat. Commun. 9, 4167 (2018).
222. Li, Q. et al. Developmental heterogeneity of microglia
and brain myeloid cells revealed by deep single-​cell
RNA sequencing. Neuron 101, 207–223 (2019).
223. Cohen, M. et al. Lung single-​cell signaling interaction
map reveals basophil role in macrophage imprinting.
Cell 175, 1031–1044 (2018).
224. Guttenplan, K. A. & Liddelow, S. A. Astrocytes and
microglia: models and tools. J. Exp. Med. 216, 71–83
(2019).
225. Bohlen, C. J., Bennett, F. C. & Bennett, M. L. Isolation
and culture of microglia. Curr. Protoc. Immunol. 125,
e70 (2019).
226. Qian, X., Song, H. & Ming, G. L. Brain organoids:
advances, applications and challenges. Development
146, dev166074 (2019).
227. Marton, R. M. et al. Differentiation and maturation of
oligodendrocytes in human three-​dimensional neural
cultures. Nat. Neurosci. 22, 484–491 (2019).
228. Zhang, Y. et al. An RNA-​sequencing transcriptome and
splicing database of glia, neurons, and vascular cells of
the cerebral cortex. J. Neurosci. 34, 11929–11947
(2014).
229. Buttgereit, A. et al. Sall1 is a transcriptional regulator
defining microglia identity and function. Nat. Immunol.
17, 1397–1406 (2016).
230. Haimon, Z. et al. Re-evaluating microglia expression
profiles using RiboTag and cell isolation strategies.
Nat. Immunol. 19, 636–644 (2018).
231. van den Brink, S. C. et al. Single-cell sequencing
reveals dissociation-​induced gene expression in
tissue subpopulations. Nat. Methods 14, 935–936
(2017).
232. Bonnardel, J. et al. Stellate cells, hepatocytes, and
endothelial cells imprint the Kupffer cell identity on
monocytes colonizing the liver macrophage niche.
Immunity 51, 638–654 (2019).
233. Srinivasan, R. et al. New transgenic mouse lines for
selectively targeting astrocytes and studying calcium
signals in astrocyte processes in situ and in vivo.
Neuron 92, 1181–1195 (2016).
234. Sun, L. O. et al. Spatiotemporal control of CNS
myelination by oligodendrocyte programmed cell
death through the TFEB-​PUMA axis. Cell 175,
1811–1826 (2018).
235. von Jonquieres, G. et al. Glial promoter selectivity
following AAV-​delivery to the immature brain. PLOS
ONE 8, e65646 (2013).
236. Varvel, N. H. et al. Microglial repopulation model
reveals a robust homeostatic process for replacing
CNS myeloid cells. Proc. Natl Acad. Sci. USA 109,
18150–18155 (2012).
237. Heppner, F. L. et al. Experimental autoimmune
encephalomyelitis repressed by microglial paralysis.
Nat. Med. 11, 146–152 (2005).
238. Kitic, M., See, P., Bruttger, J., Ginhoux, F. &
Waisman, A. in Microglia: Methods and Protocols
(eds Garaschuk, O. & Verkhratsky, A.) 217–230
(Springer, 2019).
239. Elmore, M. R. P. et al. Colony-​stimulating factor 1
receptor signaling is necessary for microglia viability,
unmasking a microglia progenitor cell in the adult
brain. Neuron 82, 380–397 (2014).
This was the first study to use a CSF1R antagonist
to ablate microglia from the adult mouse brain.
240. Han, J., Harris, R. A. & Zhang, X.-M. An updated
assessment of microglia depletion: current concepts
and future directions. Mol. Brain 10, 25 (2017).
241. Rojo, R. et al. Deletion of a Csf1r enhancer selectively
impacts CSF1R expression and development of tissue
macrophage populations. Nat. Commun. 10, 3215
(2019).
242. The Jackson Laboratory. Immunodeficient mouse and
xenograft host comparisons. Jackson Lab. https://
www.jax.org/jax-​mice-and-services/find-and-order-jax-
mice/most-​popular-jax-​mice-strains/immunodeficient-​
mouse-and-​xenograft-host-​comparisons (2019).
243. Herz, J. et al. Role of neutrophils in exacerbation
of brain injury after focal cerebral ischemia in
hyperlipidemic mice. Stroke 46, 2916–2925
(2015).
Acknowledgements
The authors thank the all the scientists involved in producing
the original work and we hope we have done justice to their
findings.
Author contributions
A.D.G. and F.C.B. researched data for the article and made
substantial contributions to the discussion of the content. All
the authors contributed equally to writing the article and to the
review and editing of the manuscript before submission.
Competing interests
The authors declare no competing interests.
Peer review information
Nature Reviews Neuroscience thanks O. Butovsky, J. Schwab
and B. Stevens for their contribution to the peer review of this
work.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional
claims in published maps and institutional affiliations.
© Springer Nature Limited 2020
www.nature.com/nrn