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Interleukin-34, a comprehensive review

Article  in  Journal of leukocyte biology · August 2018


DOI: 10.1002/JLB.MR1117-457R

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DOI: 10.1002/JLB.MR1117-457R

REVIEW

Interleukin-34, a comprehensive review


Muhammad Baghdadi Yui Umeyama Naoki Hama Takuto Kobayashi
Nanumi Han Haruka Wada Ken-ichiro Seino

Division of Immunobiology, Institute for Genetic


Medicine, Hokkaido University, Sapporo, Japan Abstract
Correspondence IL-34 is a novel cytokine that was identified in 2008 in a comprehensive proteomic analysis as
Muhammad Baghdadi (M.D., Ph.D.) and a tissue-specific ligand of CSF-1 receptor (CSF-1R). IL-34 exists in all vertebrates including fish,
Ken-ichiro Seino (M.D., Ph.D.), Division of
amphibians, birds, and mammals, showing high conservation among species. Structurally, IL-34
Immunobiology, Institute for Genetic Medicine,
Hokkaido University, Kita-15, Nishi-7, Kita-ku, belongs to the short-chain helical hematopoietic cytokine family but shows no apparent consen-
Sapporo 060–0815 Japan. sus structural domains, motifs, or sequence homology with other cytokines. IL-34 is synthesized
Email: Muhammad Baghdadi: as a secreted homodimeric glycoprotein that binds to the extracellular domains of CSF-1R and
drmhb@igm.hokudai.ac.jp
or Ken-ichiro Seino: seino@igm.hokudai.ac.jp
receptor-type protein-tyrosine phosphatase-zeta (PTP-𝜁 ) in addition to the chondroitin sulfate
chains of syndecan-1. These interactions result in activating several signaling pathways that reg-
ulate major cellular functions, including proliferation, differentiation, survival, metabolism, and
cytokine/chemokine expression in addition to cellular adhesion and migration. In the steady state,
IL-34 contributes to the development and maintenance of specific myeloid cell subsets in a tissue-
specific manner: Langerhans cells in the skin and microglia in the brain. In pathological conditions,
changes in IL-34 expression—increased or decreased—are involved in disease pathogenesis and
correlate with progression, severity, and chronicity. One decade after its discovery, IL-34 has been
introduced as a newcomer to the big family of interleukins with specific physiological functions,
critical pathological roles, and promising clinical applications in disease diagnosis and treatment.
In this review, we celebrate the 10th anniversary of IL-34 discovery, introducing its biological char-
acteristics, and discussing the importance of IL-34 signaling network in health and disease.

KEYWORDS
CSF-1R ligands, cytokine, development, homeostasis, immunity, inflammation

1 INTRODUCTION cancer, metabolic disorders, and bone diseases.1 Mononuclear phago-


cytic cells depend largely on signaling mediated by CSF-1 receptor
The mononuclear phagocytic system comprises monocyte, M𝝓, den- (CSF-1R)—a type III high-affinity receptor tyrosine kinase expressed
dritic cell, Langerhans cell, osteoclast, Kupffer cell, and microglia, on myeloid progenitors—for their development, survival, prolifera-
which play crucial physiological roles in development, homeostasis, tion, and proper functioning.2 Activation of CSF-1R signaling was
tissue remodeling, in addition to immunoregulation of the humoral thought to be mediated only by the homodimeric growth factor
and cellular innate and adaptive immunity.1 Dysregulation of this CSF-1. However, Dai et al. reported an exciting issue that helped to
system is importantly involved in a wide range of pathological change the understanding of CSF-1R biology.3 In studies on knock-
conditions including autoimmunity, inflammation, infection, fibrosis, out mice, the deficiency of CSF-1R (Csf1r−/− ) resulted in a more
severe osteopetrosis phenotype and a severe systemic depletion of
M𝝓s compared to CSF-1-deficient (Csf1op/op ) mice.3 On the other
Abbreviations: AMPK, AMP-activated protein kinase; CSF-1R, CSF-1 receptor; ECFCs,
endothelial colony forming cells; EIAV, equine infectious anemia virus; FAK, focal adhesion hand, CSF-1-deficient mice showed relatively normal numbers of brain
kinase; HBV, hepatitis B virus; HCV, hepatitis C virus; HO-1, heme oxygenase-1; IAV, microglia and Langerhans cells of the skin.3 Furthermore, Csf1op/op
influenza A virus; IDE, insulin degrading enzyme; mHTTx1, amyloidogenic exon-1 fragment of
mutant huntingtin; NAFLD, non-alcoholic fatty liver disease; oA𝛽, oligomeric amyloid 𝛽; mice recover from osteopetrosis with age, suggesting that the lack
PAMPs, pathogen-associated molecular patterns; PKB/AKT, protein kinase B; PSCs, of CSF-1 is compensated by an unidentified mechanism. Such dis-
pluripotent stem cells; PTP-𝜁, receptor-type protein-tyrosine phosphatase-zeta; RA,
rheumatoid arthritis; RANKL, receptor activator of nuclear factor kappa-B ligand; SLE,
crepancies helped to predict the possible existence of another ligand
systemic lupus erythematosus; T2DM, type 2 diabetes mellitus; TAMs, tumor-associated M𝜙s for CSF-1R.

Received: 27 February 2018 Revised: 28 May 2018 Accepted: 9 July 2018


J Leukoc Biol. 2018;1–21. www.jleukbio.org 2018
c Society for Leukocyte Biology 1
2 BAGHDADI ET AL .

In a brilliant study that aimed to understand the system of secreted Pro-Ser-Thr amino acids, which is a typical characteristic of flexible
proteins and receptors involved in cell–cell signaling, Lin et al. iden- mucin-like O-linked glycosylation-rich sequences.14–19
tified a secreted protein with a high functional selectivity repre- Ribbon presentations show that IL-34 has a distinctive antiparallel
sented by stimulating monocytes survival in a CSF-1R-dependent 4-helix core with 2 additional helices integrally bundled to the core, 2
manner.4 This protein was encoded by a cDNA clone that differs by short 𝛽-strands (𝛽1 and 𝛽2) connecting the helices, and unique terminal
one amino acid residue from a hypothetical protein registered in the extensions used for receptor binding. The 6 𝛼-helices in the bundle are
GenBank database (C16orf77, NP_689669), and was designated as oriented in an “up–down” fashion with a kink disrupting the first helix
IL-34.4 Later, 2 separate studies by Wang et al. and Greter et al. into 2 stretches. The shorter 2 helices (𝛼2 and 𝛼5) are packed against
described a remarkable decrease in microglia and Langerhans cells 𝛼3 and 𝛼6 and associated with the 4 longer helices through continu-
in IL-34-deficient (Il34LacZ/LacZ ) mice, emphasizing the importance of ous hydrophobic interactions. The conserved Asn76 glycan serves to
IL-34 as a tissue-specific ligand for CSF-1R.5,6 When transgenically fill the cavity between the 𝛼2 and 𝛼5 helices, explaining its importance
expressed in Csf1op/op mice, IL-34 rescued all defects resulted from for IL-34 stability. In addition to the interhelical hydrophobic interac-
CSF-1 deficiency.7 Furthermore, Nakamichi et al. identified pivotal tions, the helix bundle of IL-34 is further locked by the Cys35-Cys180
roles of age-increased IL-34 in the development and maintenance of disulfide bridge between the first and the last helices (𝛼1 and 𝛼6) at
osteoclast precursors reservoir in the spleen and their transfer to the the fatter end of the bundle, and Cys177-Cys191 disulfide bridge that
bone in Csf1op/op mice.8 Hence, the discovery of IL-34 was undoubt- locks the C-terminal extension to the end of the 𝛼6 helix (Fig. 1A).14–19
edly the jigsaw piece that completed our understanding of CSF-1R biol- To form a dimer, 2 IL-34 protomers pack against each other with the
ogy. Structural studies have then revealed that CSF-1R binds both of thinner ends of their helical bundles, in a head-to-head fashion, forming
IL-34 and CSF-1, but through distinct surfaces that result in forming a noncovalently linked homodimer.14–19 Additionally, IL-34 was sug-
unique receptor conformations and intermolecular interfaces, and cul- gested to bind CSF-1 with a low affinity and form a heterodimeric
minating in unique downstream signaling events. Described as “ménage cytokine able to interact with CSF-1R.20
à trois”, this is the only reported case of a hematopoietic receptor
(CSF-1R) that possesses two distinct ligands (CSF-1 and IL-34); a novel
2.2 Receptors and regulators
axis that shows high conservation across vertebrates.9
One decade after the discovery of IL-34, research on the physio- Being identified as a highly selective protein that stimulates mono-
logical and pathological roles of IL-34 has helped to understand the cyte viability, Lin et al. searched for an IL-34 receptor in a collec-
biology of the mononuclear phagocytic system further, and gave new tion of extracellular domains of membrane-spanning proteins. Among
insight into the pathogenic mechanisms of several diseases, raising 10 of 858 extracellular domains that inhibited IL-34 activity in a pri-
IL-34 as a potential biomarker and therapeutic target in medicine.10–13 mary screen, only 1 protein gave reproducible, specific inhibition in
In this review, we celebrate the 10th anniversary of IL-34 discovery repeated testing, which was coded by a cDNA of the CSF-1R extracel-
by summarizing the literature focusing on the current knowledge of lular domain.4 In functional studies, the activity of IL-34 on monocyte
IL-34 biology and the importance of IL-34 signaling network in health viability was blocked by specific inhibitors or neutralizing Abs of CSF-
and disease. 1R, indicating that CSF-1R is a functional receptor for IL-34.4 Later,
studies on the crystal structure of IL-34 have nicely shown that the
noncovalently linked IL-34 homodimer recruits 2 copies of CSF-1R on
the sides of the helical bundles. IL-34 binds to a concave surface formed
2 IL-34 BIOLOGY
by the N-terminal immunoglobulin D2 and D3 domains of CSF-1R,
which is mediated by hydrophobic interactions rather than salt bridge
2.1 Gene and basic structure
networks, while D4 domain seems to be involved in IL-34-induced
Human Il34 gene is located on chromosome 16q22.1 between two oligomerization (Fig. 1B).14–19 The hydrophobic/hydrophilic binding
genes: Vac14 and Snord111 loci, and similarly in mouse on chromosome nature of IL-34:CSF-1R and CSF-1:CSF-1R complexes may determine
8E1. At the amino acid level, human IL-34 shares a sequence similarity the differences in functions and signaling activities between IL-34
of 99.6, 72, and 71% with that of chimpanzee, rat, and mouse orthologs, and CSF-1. In contrast to the CSF-1:CSF-1R complex that depends
respectively.4 IL-34 belongs to the short-chain helical hematopoietic on hydrophilic interactions, the IL-34:CSF-1R interface contains a
cytokines, with the smallest dimerization interface among the family large number of hydrophobic regions. Given that the disassociation of
members. IL-34 has no apparent consensus structural domain or motif hydrophobic contacts is kinetically slower than hydrophilic contacts,
and shares no sequence similarity with any other growth factor, includ- the IL-34:CSF-1R complex is expected to have a longer time span and
ing CSF-1. The mature full-length of human IL-34 comprises 242 amino thus produce longer and stronger transmembrane signals; an observa-
acids. The first 182 amino acids contain predicted N-glycosylation tion that is supported by in vitro evidence.4
sites at Asn76 and Asn100 positions, which are vital for IL-34 stabil- By examining the expression pattern of IL-34 in the brain, Nandi
ity and proper folding, in addition to 6 cysteine residues that are highly et al. noticed that IL-34 is expressed in regions where there is a min-
conserved among species. Four of these cysteines are critical for the imal expression of CSF-1R or CSF-1, which led to the hypothesis that
intramolecular disulfide bonding. The last ∼50 residues at the C ter- IL-34 may signal via an alternative receptor. By utilizing IL-34 affinity
minal are predicted to be largely disordered and highly enriched with chromatography of solubilized mouse brain membrane followed by
BAGHDADI ET AL . 3

A The discovery of additional receptors for IL-34 encouraged Segaliny


N 35 et al. to search for alternative binding of IL-34 on other cell types. In a
series of binding experiments, IL-34 was found to bind with low affin-
C
191 ity to chondroitin sulfates on cells lacking both CSF-1R and PTP-𝜁 .
177 180 Among these, syndecan-1 modulated the IL-34-induced CSF-1R acti-
vation. More interestingly, IL-34 was able to induce cellular migration
of myeloid cells in a syndecan-1-dependent mechanism. Syndecan-1 is
a type-I transmembrane heparan sulfate proteoglycan involved in cel-
lular proliferation, migration, and matrix interactions. Syndecan-1 also
B acts as a sponge that binds several growth factors via heparan sulfate
CSF-1R
chains. Thus, syndecan-1 may serve as a key regulator of IL-34 biology
D1 IL-34 by controlling IL-34 bioavailability, modulating the recruitment of CSF-
D2 1R chains or the affinity of IL-34 to the receptor chains, and by acting
as a regulator of CSF-1R signaling (Fig. 1C).22
D3
D4 Taken together, IL-34 exerts its biological activities through binding
D5 to CSF-1R in addition to interactions with chondroitin sulfate chains
such as PTP-𝜁 and syndecan-1. In studies on protein structure pre-
diction, Kryshtafovych et al. noticed a highly conserved receptor-free
face within the IL-34 structure, which may serve for a yet undiscov-
ered functional purpose.18 Thus, other molecules may also regulate the

Downstream
biological activities of IL-34, which may be unveiled in future works.
signaling
C
Syndecan-1
IL-34 2.3 Signaling networks
CS
CSF-1R
IL-34 homodimer binds to CSF-1R extracellular domain at the cleft
between D2 and D3, resulting in autophosphorylation of specific
tyrosine residues within the intracellular domain including Y556,
CSF-1R-downstream CSF-1R-downstream Y561, Y699, Y708, Y723, Y809, Y873, and Y923. The phosphorylated
signaling signaling
residues lead to the recruitment of other kinases and adaptor proteins
that activate several signaling pathways, such as ERK1/2, PKB/AKT,
focal adhesion kinase (FAK), STAT3, and NF-𝜅B (Fig. 2). These signaling
Syndecan-1: moderate Syndecan-1: high
pathways play essential roles in IL-34-mediated survival, prolifer-
FIGURE 1 The basic biology of IL-34. (A) Schematic representa- ation, differentiation, cytoskeletal organization, cell adhesion and
tion of the IL-34 structure. IL-34 has a distinctive antiparallel 4-helix
migration, and cytokine/chemokine expression.11,12 The activation
core with 2 additional helices integrally bundle to the core. Two short
of these signaling pathways by IL-34 can be observed in a wide range
𝛽 strands connect the helices. The helix bundle of IL-34 is locked by
disulfide bridges at two sites: C35-C180 and C177-C191. (B) CSF- of CSF-1R-expressing cells, such as myeloid cells, epithelial cells,
1R activation by IL-34. IL-34 homodimer binds to CSF-1R extracellu- endothelial cells, fibroblasts, neurons, and cancer cells. Additionally,
lar domain at the cleft between D2 and D3 resulting in dimerization a recent study by Boulakirba et al. suggested that the engagement of
and autophosphorylation of tyrosine residues within the intracellular CSF-1R by IL-34 activates caspase and autophagy signaling pathways
domain. D4 is involved in IL-34-induced oligomerization. (C) Syndecan-
through enhanced expression and activation of AMP-activated protein
1 as a regulator of IL-34 biological activities. Levels of syndecan-1
expression are suggested to control IL-34 bioavailability, modulate the kinase (AMPK)-1 and UNC-51 like autophagy activating kinase 1 in
interaction between IL-34 and CSF-1R, and regulate CSF-1R signaling monocytes, which were required for IL-34-induced macrophagic
differentiation and polarization.23 On the other hand, activation of
PTP-𝜁 by IL-34 induces tyrosine phosphorylation of FAK and paxillin,
resulting in inhibition of proliferation, clonogenicity, and motility in
mass spectrometric analysis, PTP-𝜁 was identified as a novel func- specific cellular targets such as glioblastoma cells (Fig. 2).21 IL-34-
tional receptor for IL-34. PTP-𝜁 is a cell surface chondroitin sulfate induced activation of signaling pathways is importantly modulated by
proteoglycan, primarily expressed on neuronal progenitors and glial the interaction between IL-34 and chondroitin sulfate chains at the
cells. IL-34 binds to the PTP-𝜁 extracellular domain in vitro and on the cellular surface, notably of syndecan-1. For example, low/moderate
cell surface, which was inhibited by chondroitin sulfates, indicating expression of syndecan-1 at the cell surface is associated with the
a dependence of binding on PTP-𝜁 chondroitin sulfate moieties. limited interaction between IL-34 and CSF-1R, while high expression
Via PTP-𝜁 , IL-34 can stimulate intracellular signaling pathways that of syndecan-1 remarkably enhanced IL-34-induced activation of
inhibit proliferation, clonogenicity, and motility of the cellular targets, CSF-1R.22 Thus, the outcome of IL-34-activated signaling pathways
indicating a CSF1-R-independent action of IL-34.21 depends on the receptor and regulator in each cellular target.
4 BAGHDADI ET AL .

Pro-inflammatory
cytokines

Chemical PAMPs
stressors
DNA Infection
damaging
agents Vitamin D

IL-34

F I G U R E 2 IL-34 signaling network. IL-34


expression can be induced by several stimuli,
such as DNA damaging agents, chemical stres-
CS
sors, pro-inflammatory cytokines, PAMPs, viral
infection, and vitamin D. The secreted IL-34
Syndecan-1 CSF-1R PTP-
binds to the extracellular domains of CSF-1R
and PTP-𝜁 in addition to the chondroitin sulfate
chains of syndecan-1, resulting in activation
of several signaling pathways that regulate
major cellular functions, including proliferation,
differentiation, survival, metabolism, cytokine/
Ras chemokine expression in addition to cellular
adhesion and migration
Migration PI3K Paxillin FAK
Raf Caspase AMPK1
Src/FAK ULK1

PDK1 STAT3
MEK1/2

Autophagy
AKT
ERK1/2 Proliferation
Motility
c/EBPb Clonogenicity

Cell adhesion, motility, proliferation, survival,


differentiation, polarization, migration,
cytokine/chemokine expression

2.4 IL-34 expression (Il34LacZ/LacZ ).5 This helped to visualize sites of IL-34 producing
sites by utilizing 𝛽-galactosidase substrate X-gal. At the tissue level,
2.4.1 IL-34 expression in health and disease
IL-34 expression was detected in the skin, brain, kidney, and testes. At
During embryogenesis, IL-34 shows early and robust expression in the cellular level, IL-34 expression was observed in keratinocytes, hair
the neuronal tube before CSF-1, as unveiled by 2 separate stud- follicles, neurons, proximal renal tubule cells, and seminiferous tubule
ies on the embryo of mice and chicken.7,24 Using whole-amount germ cells. In the brain, IL-34 expression was detected in the cerebral
Il34 in situ hybridization, Wei et al. showed that Il34 mRNA was cortex and hippocampus but not in the cerebellum.5 Nicely replicated
strongly expressed in the embryonic brain of mice at E11.5 before by Greter et al., these observations overlapped the pattern of Il34
Csf1 mRNA, suggesting functional importance of IL-34 during brain mRNA expression in the microarray dataset of the Biology Gene Portal
embryogenesis.7 Similarly, Garceau et al. observed a high expression System (BioGPS).5,6 Thus, while Il34 transcripts can be detected in
of Il34 mRNA in the chicken embryo, especially in the neural tube various tissues throughout the body, IL-34 can be recognized at the
of the head coincident with the proliferation of CSF-1R-expressing protein level in a tissue-specific manner; notably in keratinocytes of
myeloid populations.24 the skin and neurons of the brain.5,6
To identify the cellular resource of IL-34 in adults, Wang In humans, IL34 mRNA is expressed in various tissues, including
et al. generated transgenic mice in which exons 3–5 of Il34 gene heart, brain, lung, liver, kidney, spleen, thymus, testis, ovary, small
were replaced by an internal ribosome entry site-lacZ cassette intestine, prostate, and colon, with a remarkable expression in the
BAGHDADI ET AL . 5

spleen. At the protein level, IL-34 showed strong staining in the and adipocytes.11,12 Activation of TLRs with PAMPs such as peptido-
sinusoidal endothelium in the red pulp of the spleen, as unveiled glycan, lipopolysaccharide, and nucleic acids mimickers like poly I:C
by immunohistochemistry.4 Similarly, IL-34 shows tissue-enhanced and CpG induces IL-34 expression in M𝝓s,107 adipocytes,78 and lam-
expression patterns, such as in spleen, brain, and skin according to the ina propria mononuclear cells,51 while stimulation with I𝛼,25(OH)2 D3 ;
Human Protein Atlas.25 a hormonally active form of vitamin D, can increase IL-34 expres-
Since IL-34 is expressed at mRNA level in various tissues, this sion in neuroblastoma and normal gastric epithelial cells via vitamin
expression is expected to be changed under pathological condi- D receptor.93 The abnormal accumulation of amyloidogenic exon-1
tions. Indeed, several studies have confirmed the enhancement of fragment of mutant huntingtin (mHTTx1) modulates the expression of
IL-34 expression at mRNA and protein levels in the context of vari- IL-34 via an NF-𝜅B-dependent mechanism in dopaminergic neurons.89
ous diseases including autoimmune disorders,26–47 inflammation,48–63 Finally, hepatitis C virus (HCV)-infected hepatocytes show elevated
infections,64–76 metabolic diseases,77–80 neurological disorders,81–93 levels of IL-34, indicating that IL-34 expression can also be regulated by
and cancer.94–106 At the cellular level, IL-34-producing cells include infectious pathogens.66 This is supported by the evidence that showed
synovial fibroblasts, immune cells, epithelial cells, endothelial cells, a direct involvement of equine infectious anemia virus (EIAV)-derived
adipocytes, and cancer cells. On the other hand, a reduction in S2 viral protein in enhancing IL-34 expression in EIAV-infected M𝝓s.64
IL-34 expression can be observed in certain pathological conditions, On the contrast, IL-34 expression can be down-regulated by other
such as in brain tissues in Alzheimer’s disease,91 epidermis in atopic stimuli. For example, stimulation with TGF-𝛽1 and bone morpho-
dermatitis,50 viral infection such as hepatitis B virus (HBV),73 and genetic protein-2 results in decreased expression of IL-34 in TNF-𝛼-
periodontal disease.60 In both cases, growing evidence indicates an stimulated synovial fibroblasts and mesenchymal stem cells, which is
essential correlation between changes in IL-34 expression with disease mediated by activin receptor-like kinase 5 and activin receptor-like
pathogenesis, progression, and severity.12 kinase 1, respectively.38 However, TGF𝛽1 can induce IL-34 expres-
In addition to clinical studies, several reports have also evalu- sion in hepatocarcinoma cell lines,101 suggesting a cell type-dependent
ated the expression of IL-34 in experimental animal models. IL-34 effect in certain situations.
expression showed an enhancement in murine models of collagen-
or Ab-induced arthritis,39,42 Huntington’s disease,89 dextran sulfate
2.5 IL-34 secretion
sodium-induced colitis,52 kidney ischemia,49 systemic lupus erythe-
matosus (SLE) nephritis,43 and sepsis.74 The expression of IL-34 is IL-34 is synthesized as a secreted homodimeric glycoprotein, consist-
also increased in infection models such as in SIV with encephalitis in ing of 242 amino acids in human and 235 amino acids in mouse, with
rhesus macaques,68 Cryptocaryon irritans in grouper,69 Vibrio anguil- a molecular mass of 39 kD.4 Secreted IL-34 binds to the extracellular
larum in large yellow croaker,72 and in a fish-parasite infection model domains of CSF-1R and PTP-𝜁 , in addition to low-affinity interactions
(Enteromyxum leei in Sparus aurata).65 with chondroitin sulfate chains such as in syndecan-1.4,21,22 Several
reports suggested that IL-34 can bind to CSF-1R with higher affinity
than CSF-1 and induce stronger tyrosine phosphorylation of CSF-1R
2.4.2 Regulation of IL-34 expression and downstream molecules.4,100,108 This may be explained by the
Although patterns of IL-34 expression have been well identified, characteristics of IL-34:CSF-1R complex that depends on hydrophobic
the molecular mechanisms that control this expression remain to be interactions rather than the salt bridge networks observed in the
explored. Due to its highly specific expression patterns, it is of great case of CSF-1.14–19 The Il34 mRNA in both human and mouse exhibit
interest to examine whether the expression of IL-34 is regulated by alternative splicing of a CAG codon, resulting in isoforms that lack
common or different signaling pathways or even by master transcrip- glutamine residue (Q) at position 81. The absence of Q81 is predicted
tion factors in keratinocytes and neurons. to disrupt the second-most amino terminal of 4 𝛼-helices, thus altering
Experimentally, in vitro evidence has shown that IL-34 expres- the coiled coil to alpha helix in the nearby structure, which conse-
sion can be up-regulated by several stimuli relevant to cellular stress quently results in reduced biological activities of the secreted IL-34.7
such as stimulation with DNA damaging agents, chemical stres- The expression of IL-34 can be detected at mRNA and protein lev-
sors, pro-inflammatory cytokines, pathogen-associated molecular pat- els in various types of cells. However, the regulation of IL-34 secretion
terns (PAMPs), in addition to other stimuli such as viral infection may depend on cell type. For example, Kawabe et al. have noticed a rel-
and vitamin D. DNA damaging agents such as cisplatin, doxorubicin, atively small number of localization motifs for endoplasmic reticulum
and pemetrexed activate NF-𝜅B signaling pathway, resulting in up- Golgi transport vesicle membrane (YRSR) or the extracellular space
regulation of IL-34 expression in cancer cells such as in lung cancer and Golgi apparatus (KALLD) in the sequence of IL-34, indicating that
cells and malignant pleural mesothelioma cells.95,100 Not limited to the affinity to the protein-releasing pathway of IL-34 is weaker than
cancer cells, etoposide and chemical stressors such as N-methyl-D- that for CSF-1 in periodontal ligament cells.109 Consistent with this,
aspartic acid and staurosporine can similarly induce IL-34 expression Garceau et al. noticed that the amount of chicken IL-34 overexpressed
in normal neurons.89 Pro-inflammatory cytokines such as TNF-𝛼 and in the supernatants of HEK293 cells was considerably less than seen
IL-1𝛽 activates NF-𝜅B and JNK signaling pathways, which increase in cell lysates, which was suspected to be a result of some proteolytic
the expression of IL-34 in a wide range of cells including fibrob- cleavage by trypsin-like proteases in the medium since many recogni-
lasts, epithelial cells, periodontal ligament cells, osteosarcoma cells, tion sites are found at the C-terminal of IL-34.24 Schuster et al. also
6 BAGHDADI ET AL .

found that IL-34 can be measured in the lysates of in vitro generated Although IL-34 and CSF-1 can be found in all vertebrates, only IL-34
epidermal tissues, but not in cell supernatants.110 Furthermore, Lindau but not CSF-1 exists in elasmobranches.118 Thus, IL-34 may predate
et al. have recently found the IL-34 exists at the protein level at the CSF-1 evolutionary. This could be probably supported by the evidence
human fetal-maternal interface as confirmed by immunohistochem- that IL-34 mRNA is expressed during embryogenesis before the
istry. However, ELISA measurement showed detectable levels of IL-34 expression of CSF-1, and show higher levels in most regions of devel-
in the lysates of the first-trimester placenta and decidua tissues but oping brain in mice and chicken.7,24 Further investigations into the
not in the conditioned medium from these tissues. Since IL-34 was co- distinct roles of IL-34 and CSF-1 in various species will undoubtedly
expressed with CSF-1, detection of secreted IL-34 could be possibly enrich our understanding of the evolutionary origins and immunologic
impeded by the formed IL-34:CSF-1 heterodimer complex.111 Collec- mechanisms that control myeloid functional heterogeneity.
tively, the precise molecular mechanisms that control IL-34 secretion
remain to be explored in future studies.
In the extracellular biofluids, IL-34 can be detected at low concen-
3 BIOLOGICAL FUNCTIONS OF IL-34
trations in serum/plasma, cerebral spinal fluid, synovial fluid, and saliva.
Importantly, accumulating evidence from clinical studies has indicated
3.1 Physiological functions of IL-34
a correlation between changes in secreted IL-34 into these extracellu-
lar biofluids with disease parameters in various pathological conditions The physiological functions of IL-34 have been unveiled by the phe-
such as in rheumatoid arthritis (RA), SLE, heart failure, viral infections, notype of knockout mice. In contrast to Csf1r−/− and Csf1op/op mice,
sepsis, periodontal disease, non-alcoholic fatty liver disease (NAFLD), Il34lacZ/LacZ mice show normal lifespan, fertility, bone, blood mono-
obesity, and type 2 diabetes mellitus (T2DM; Table 1). Secreted lev- cytes, and mostly normal tissue M𝝓s except for Langerhans cells
els of IL-34 are reduced to normal levels upon successful treatment and microglia that are significantly decreased.5,6 In detail, IL-34 defi-
of disease, such as in TNF-𝛼-antagonist therapy in RA33 and gastric ciency resulted in decreased frequencies of F4/80+ CD11b+ CD45int
bypass surgery in obesity.78 Thus, secreted IL-34 may serve as a poten- microglia in the brain of neonatal and adult mice. Similarly, the frequen-
tial biomarker for predicting disease progression and responsiveness cies of F4/80+ CD11b+ CD45+ Langerhans cell precursors in embryo
to therapy. skin and F4/80+ CD11b+ CD45+ epidermal Langerhans cells in new-
born skin were decreased in IL-34-deficient mice, and CD11b+ CD45+
CD207+ MHC-II+ Langerhans cells in adult skin were almost absent.5,6
Additionally, IL-34-deficient mice show a partial reduction of CD11c+
2.6 IL-34 through the evolution journey
CD11b+ dendritic cells in the lung compared to wild-type mice.5,6 Con-
IL-34 exists in all types of vertebrates including fish, amphibians, birds, sidering its selective expression by keratinocytes and neurons, IL-34 is
and mammals.112–119 These species show a similar gene organization expected to specifically direct the differentiation of myeloid cells in the
of IL-34, consisting of 7 exons and 6 introns. The phylogenetic tree skin epidermis and brain.
analysis showed that IL-34 gene from the primate lineage, rodent lin- During murine embryogenesis, IL-34 is highly expressed in the epi-
eage, and teleost lineage forms a species-specific cluster. In the major- dermis as early as E17.5 and persists after birth. Therefore, IL-34 is
ity of genomes, IL-34 gene has 6 exons and 5 introns with similar likely to promote the development of Langerhans cells before birth and
lengths in different species. As suggested by Garceau et al., IL-34 maintain their homeostasis throughout life (Fig. 3).5,6,120 However, this
is under evolutionary constraint to remain relatively unchanged.112 function seems to be restricted to the steady state. Under inflamma-
Consistent with this, site-specific tests for positive selection suggests tory conditions such as in ultraviolet light-induced skin inflammation,
that mammalian IL-34 was under positive selection pressure with the Langerhans cells are dependent on neutrophils-derived CSF-1 rather
identified positively selected site, 196Val.113 than IL-34. Once inflammation is resolved, Langerhans cells recovery
IL-34 shows cross-specificity among species. For example, human and survival is again IL-34-dependent.58
IL-34 activates CSF-1R in human, cat, and pig but not in mouse. On In the nervous system, IL-34 and CSF-1 exhibit distinct devel-
the other hand, murine IL-34 is capable of activating CSF-1R in mouse, opmental brain expression patterns and regulate neuronal progeni-
human, and pig but not in cats. Both human and mouse IL-34 have sim- tor cell maintenance and maturation.121 In contrast to Langerhans
ilar activity on the pig and feline CSF-1R.7,114,115 At the amino acid cells, microglia and their yolk sac precursors develop independently of
sequence level, IL-34 is highly conserved among avian and mammalian IL-34 during embryogenesis but rely on it for their maintenance in spe-
species, in contrast to CSF-1.24,112 Consistent with this, a correlated cific regions of the adult brain (Fig. 3). During embryonic development
evolutionary co-variation with CSF-1R can only be detected for IL-34 in chicken, IL34 mRNA is highly expressed in the embryo, especially in
but not CSF-1. In other words, a change in the genetic composition the neural tube of the head at the time of proliferation of the M𝝓 pop-
of IL-34 would necessarily involve a reciprocal evolutionary change in ulations expressing CSF1R mRNA.24 In mouse, the expression of IL-34
CSF-1R. On the other hand, CSF-1 has the flexibility to evolve more and CSF-1 can be detected in the developing brain as early as E12.5,
quickly than IL-34 without the need for receptor co-evolving.112 Con- but this expression occurs in complementary regions of the cortex. At
sidering its specific expression patterns, IL-34 may perform a more day E15.5, IL-34 expression is restricted to the cortical marginal zone
trophic role in the regulation of M𝝓 functions in homeostasis and while CSF-1 is detected within the subventricular zone and the ven-
development as opposed to innate immunity. tricular zone. In the neonatal cortex, the CSF-1 expression is restricted
BAGHDADI ET AL . 7

TA B L E 1 in disease

Disease Clinical observations Reference


91
Alzheimer’s disease IL-34 is decreased in the inferior temporal gyrus in some patients with Alzheimer’s
disease
32
Ankylosing spondylitis Elevated levels of serum IL-34
Atopic dermatitis IL-34 is decreased in lesional compared to non-lesional atopic dermatitis and normal 50

epidermis
Cancer Breast cancer: high expression of Il34 mRNA in brain metastasis 97

Cholangiocarcinoma: elevated levels of serum IL-34 104

94
Giant cell tumors: IL-34 is strongly expressed in osteoclast cells, and inversely related
with CSF-1.
101
Hepatocellular Carcinoma: high expression of IL-34 correlates with poor prognosis and
recurrence
95
Malignant Pleural Mesothelioma: IL-34 is secreted by malignant pleural mesothelioma
cells and drives chemoresistance
106
Melanoma: high expression of IL-34 correlates with frequencies of CD163+ cells in
Nivolumab-resistant metastatic melanoma
100,105
Lung cancer: high expression of IL-34 correlates with tumor progression and poor
survival
97
Lung cancer: high expression of Il34 mRNA in brain metastasis
98
Osteosarcoma: heterogenous expression of IL-34 in human osteosarcomas
Sporadic colorectal cancer: overexpression of IL-34 in cancer tissues 102

Chronic apical periodontitis High expression of IL-34 in lymphocytes, plasma cells, and macrophages within chronic 54

periapical lesions
Chronic heart failure High levels of serum IL-34 correlates with increased risks of renal dysfunction, 53,61

cardiovascular death, hospitalization, and mortality


Coronary artery disease High levels of serum IL-34 correlates with high-sensitivity C-reactive protein 48

79
Diabetic nephropathy IL-34 correlates with increased risk of diabetic nephropathy in Han Chinese patients
with type 2 diabetes
73
Hepatitis B viral infection IL-34 is reduced in the serum and PBMCs of chronic HBV patients, and negatively
corelates with disease activity parameters 76

Serum IL-34 is increased in HBV infection and correlates with liver inflammation and
fibrosis in chronic HBV patients
66
Hepatitis C viral infection High levels of serum IL-34 correlates with advances stage of liver fibrosis
Inflammatory bowel disease (Crohn’s IL-34 expression is significantly increased in the epithelial layer and connective 51,52

disease, ulcerative colitis) tissues-infiltrating immune cells within the inflamed mucosa
Influenza A viral infection High levels of IL-34 in serum and PBMCs 71

56
Liver transplantation High levels of serum IL-34 during acute rejection
66
Microvesicular steatosis Enhanced expression of IL-34 in hepatocytes
57,66
Non-alcoholic fatty liver disease High levels of serum IL-34 correlates with disease stage
Obesity Elevated serum IL-34 in obese women associates with metabolic parameters, reduced 78

after gastric bypass surgery


Periodontal disease IL-34 is decreased in saliva of patients with periodontitis 60

62
High levels of IL-34 in gingival crevicular fluid and plasma of patients with chronic
periodontitis, further increased when accompanied with T2DM
47
Psoriasis and psoriatic arthritis High levels of serum IL-34 correlates positively with circulating osteoclast precursors
27,30–32,34,40
Rheumatoid arthritis High levels of IL-34 in serum correlates with disease activity
26,27,30–32,36,38
High levels of IL-34 in synovial fluid correlates with disease activity
High expression of IL-34 in the synovial lining layer (synoviocytes, multinucleated giant 26,32,35

cells, and macrophages) and the sibling layer (endothelial cells, inflammatory cells, and
fibroblasts) correlates with total leucocyte counts and synovitis severity
33
Serum IL-34 predicts good response of TNF𝛼 antagonist therapy at 3-months treatment
Sepsis High levels of IL-34 in the serum 74

46
Sjogren’s syndrome IL-34 is overexpressed in ductal epithelial cells and infiltrating mononuclear cells of the
inflamed salivary gland, and correlates with pro-inflammatory cytokines (TNF𝛼, IL-1𝛽)
and local expansion of pro-inflammatory CD14bright CD16+ monocytes
(Continues)
8 BAGHDADI ET AL .

TA B L E 1 (Continued)

Disease Clinical observations Reference


Systemic Lupus Erythematosus High levels of serum IL-34 correlates positively with SLE disease activity parameters 44,45

Type II diabetes mellitus IL34 is located within characteristic risk loci of T2DM 77

80
Serum IL-34 serves as a potential inflammatory factor for predicting the risk of vascular
diabetic complications

Central nervous system


Neurons

IL-34

CSF-1R

F I G U R E 3 Physiological functions of IL-34. IL-


Microglia
34 is constitutively expressed by neurons and ker-
atinocytes, and play critical roles in the development
and maintenance of microglia and Langerhans cells in
Skin epidermis Keratinocytes the brain and skin, respectively

IL-34
CSF-1R

Langerhans cells

to neurons in layer VI, while IL-34 expression extends from neurons germ cells, and spleen.4–6 In a recent study by Tribulo et al., IL-34
at layer V to layer II. IL-34 is expressed in regions of the brain other was identified as one of the candidate molecules used by the mater-
than the cortex, including the hippocampus and striatum. Expression of nal reproductive tract to regulate development of the preimplantation
IL-34 is comparatively lower in white matter and is essentially absent embryo in bovine. IL-34 with other 10 genes were highly expressed
from the cerebellum and brain stem. In addition to neurons, IL-34 is at the estrus and affected by day of the estrous cycle.122 Further-
present in ependymal cells lining the ventricular system and in the more, Lindau et al. have recently identified a possible involvement
choroid plexus, suggesting that IL-34 can be secreted into the cere- for IL-34 expressed by placental cyto- and syncytiotrophoblasts and
brospinal fluid. Consistent with the selective production of IL-34 in cer- decidual stromal cells at the human fetal–maternal interface in estab-
tain areas of the brain, Il34LacZ/LacZ mice show severely reduced num- lishing the tolerant milieu by altering M𝝓 polarization into a regula-
bers of microglia in corresponding regions of the brain, particularly the tory phenotype.111 Collectively, the physiological importance of IL-34
cortex and hippocampus.5–7 expression in these conditions remains to be explored in future works.
Collectively, IL-34 serves as a tissue-restricted ligand of CSF-1R
required for the development and maintenance of Langerhans cells
and microglia (Fig. 3). Adult Langerhans cells require IL-34 to contin-
ually self-renew in the steady state. Similarly, microglia relies on
3.2 The impact of IL-34 on cellular functions
IL-34 for survival and homeostasis is specific regions of the On the contrast of its tissue-specific expression and particular func-
brain.120,121 Despite their normal phenotype at the steady state, tions in vivo, IL-34 shows similar biological activities with CSF-1 in
Il34-deficient mice responded poorly to skin antigens and viral vitro, controlling the biology and function of mononuclear phagocytic
infections of the central nervous system, indicating the physiological cells. Consistent with this, when transgenically expressed in mice in
importance of IL-34.5,6 a spatiotemporal manner mimicking CSF-1, mouse IL-34 was able to
In addition to keratinocytes and neurons, IL-34 can be detected at rescue all defects in the bone, osteoclast, tissue M𝝓s, and fertility
the protein level in proximal renal tubule cells, seminiferous tubule observed in Csf-1op/op mice, indicating a functional overlap between
BAGHDADI ET AL . 9

IL-34 and CSF-1.7 However, several studies have also unveiled the abil- monocyte-like cells, characterized by alterations in specific cell mark-
ity of IL-34 to exhibit particular functions that differ from CSF-1 in cer- ers and functional ability to phagocytize foreign particles and perform
tain conditions, which will be together introduced here. respiratory burst activity.96

3.2.1 Cell proliferation and survival 3.2.3 Cell adhesion and migration
A novel role for IL-34 in cell adhesion and migration has been
IL-34 binds CSF-1R and induces activation of ERK1/2 and AKT signal-
described in several studies. The observation that IL-34 expression is
ing pathways required for the proliferation and survival of cells of the
accompanied with angiogenesis and M𝝓 recruitment in osteosar-
myeloid lineage including bone marrow cells, monocytes, M𝝓s, osteo-
coma has led Segaliny et al. to investigate whether IL-34 has a direct
clasts, and microglia.11,12 Similar biological effects can be observed
effect on monocyte adhesion to the endothelium. As expected, IL-34
in other cell types including endothelial cells, fibrocytes, and cancer
preconditioning was found to promote in vitro adhesion of CD14+
cells. IL-34 promotes proliferation of endothelial colony forming cells
monocytes or CD34+ hematopoietic stem cells into endothelial cell
(ECFC), which is dependent on the glycosaminoglycans at the cell
precursors and mature HUVEC monolayers.98 Similarly, IL-34 was also
surface.98 Furthermore, IL-34 induces STAT3 activation and miRNA-
found to promote the adhesion of osteoclast progenitors and M𝝓s in
21 increment in synovial fibroblast, resulting in increased resistance
vitro culture.27,108
of fibroblast to apoptosis in RA.36 In an autocrine manner, IL-34 pro-
Upon the identification of syndecan-1 as a regulator of IL-34 bio-
vides a critical survival signal to CSF-1R-expressing cancer cells by
logical activities, Segaliny et al. tried to elucidate the functional impli-
enhancing activation of ERK1/2 and AKT signaling pathways and thus
cation of the syndecan-1/IL-34 interactions. Interestingly, IL-34 was
contributes to chemoresistance such as in lung and colon cancer cells
found to induce a significant increase in the migration of syndecan-1-
in addition to malignant pleural mesothelioma cells.95,100,102 On the
expressing THP-1 monocyte cell line and M2a-polarized M𝝓s. A block-
other hand, IL-34 can inhibit the proliferation in other cells such as
ing anti-syndecan-1 Ab could inhibit the IL-34-induced THP-1 and
glioblastoma cells via a PTP-𝜁 -dependent mechanism.21
M2a M𝝓 migration, indicating that IL-34 can induce the migration of
myeloid cells in a syndecan-1-dependent mechanism.22
3.2.2 Cell differentiation
IL-34 can substitute for CSF-1 entirely for inducing the differentiation
3.2.4 Angiogenesis
of monocytes into M2-polarized M𝝓s that exhibit enhanced immuno-
The role of IL-34 in angiogenesis has been confirmed by Segaliny
suppressive properties.123,124 The activation of ERK1/2, AKT, AMPK,
et al. in a murine preclinical model of osteosarcoma. In this model,
and autophagy signaling pathways are required for IL-34-induced
the overexpression of IL-34 in osteosarcoma cells was associated
M𝝓 differentiation and polarization.23 In Kupffer cells, IL-34 alters
with enhanced tumor growth and lung metastases of osteosarcoma,
Kupffer cells polarization into an M2-phenotype, characterized by
in addition to an increase in neo-angiogenesis. Histological inves-
decreased expression of pro-inflammatory cytokines such as IL-12, and
tigations unveiled that the density of neo-vessels was significantly
increased expression of immunosuppressive cytokines, including Arg-
increased in tumors overexpressing IL-34 compared to the control
1, IL-10, and TGF-𝛽1. The responsible mechanism was mediated by the
group. The pro-angiogenic potential of IL-34 was further confirmed
IL-34-induced activation of the PI3K/Akt pathway, enhancement of the
experimentally in vitro, where IL-34 was able to recruit endothe-
phosphorylation of mTOR, S6K, and 4E-BP, and suppression of p65 and
lial cells to form vascular structures. In two endothelial cell lines,
p38 MAPK activation.125
ECFCs and HUVECs, IL-34 activates several kinases including PI3K,
Similar with CSF-1, the combination between IL-34 and receptor
Src, FAK, and ERK1/2, which importantly contribute to cell differ-
activator of NF-𝜅B ligand (RANKL) orchestrates osteoclast differen-
entiation into vascular cords. These effects were mediated by the
tiation and survival. IL-34 activates signaling pathways downstream
interaction between IL-34 and glycosaminoglycans at the cellular
of CSF-1R, which modulate cell adhesion, differentiation, fusion, and
surface, indicating a CSF-1R-independent mechanism.98 Addition-
resorbing activity in osteoclast precursors, while RANKL is dedicated
ally, IL-34 can exert additional pro-angiogenic functions via CSF-1R-
to osteoclast fusion, activation, and survival.94,126 However, IL-34
dependent mechanisms, by inducing the secretion of several factors
shows selective biological effects on the differentiation of specific cell
that contribute to angiogenesis such as IP-10, MCP-1, and IL-8 in
types. For example, when combined with GM-CSF, IL-34 but not CSF-1
PBMCs.132 Added to its effects on the mononuclear phagocytes adhe-
can induce monocytes differentiation into microglia-like cells, referred
sion to the endothelium,98 IL-34 is expected to play essential roles
to as induced microglia, which serves as a novel translational research
in angiogenesis.
tool for analyzing the underlying microglial pathophysiology in psychi-
atric disorders, such as Nasu-Hakola disease.127,128 On the other hand,
a mixture of IL-34, CSF-1, GM-CSF, and TGF-𝛽1 can induce microglial 3.2.5 Metabolism
differentiation from pluripotent stem cells (PSCs).129,130 More inter- In a cohort of female Koreans, Chang et al. described a potential role
estingly, IL-34 can selectively induce the differentiation of splenocytes for IL-34 in metabolism. Serum IL-34 levels were elevated in obese
into follicular DC-induced monocytic cells that show B cell-stimulating women and associated with several metabolic parameters. IL-34
activity.131 Finally, an interesting study by Booker et al. has described expression was detectable in adipose tissues, and this expression
the ability of IL-34 to induce differentiation of leukemia cell lines into increased during adipogenesis or inflammation under the effects
10 BAGHDADI ET AL .

of pro-inflammatory cytokines such as TNF-𝛼 and IL-1𝛽. Thus, deregulation. Through a complex signaling network that involves
adipocytes-derived IL-34 may contribute to M𝝓 recruitment into various types of cells and molecules, IL-34 play important roles in
adipose tissues, which is one of the central features of obesity-induced orchestrating innate and adaptive immune responses during inflam-
inflammation. Additionally, IL-34 can exert direct biological effects mation, which has been well established by in vitro experiments and
on adipocytes. For example, treatment of adipocytes with high con- animal models. The expression of IL-34 can be induced by various
centrations of IL-34 significantly inhibited the stimulatory effects of stimuli relevant to inflammation such as pro-inflammatory cytokines,
insulin on the uptake of 2-deoxyglucose. Furthermore, the presence of PAMPs, infections, chemical stressors, and tissue injuries.11,12 Several
IL-34 during adipogenesis increases the accumulation of triglycerides studies have shown that IL-34 expression is regulated by NF-𝜅B,
in pre-adipocytes. From these observations, IL-34 was expected to be which is a central molecule that governs all signaling pathways
involved in insulin resistance in obesity.78 related to inflammation.133,134 Upon secretion into the inflamma-
In addition to adipocytes, Boulakirba et al. noticed a robust tory loci, IL-34 is expected to play multiple roles that seem to be
activation of the AMPK metabolic signaling pathway in IL-34- highly dependent on the cellular and molecular components of the
differentiated M𝝓s, which importantly contribute to their M2- local microenvironment.
polarized phenotype.23 Furthermore, several genes related to lipid IL-34 has the potential to amplify the inflammatory circle by induc-
metabolism, transport processes, in addition to enzymatic regulators ing the expression of several pro-inflammatory cytokines, chemokines,
of cholesterol and triglyceride pathways are remarkably activated dur- and metalloproteases in a wide range of cells including monocytes,
ing IL-34-induced M𝝓 differentiation.124 M𝝓s, microglia, fibroblasts, and epithelial cells.11,12 The existence of
IL-34 is accompanied by the expansion of pro-inflammatory mono-

3.2.6 Neuroprotection cytes in the inflamed loci, such as in the inflamed salivary glands.46,63
Additionally, Foucher et al. have identified an important characteristic
The central nervous system is one of the few places that show constitu-
of IL-34-differentiated M𝝓s, represented by the constitutive expres-
tive expression of IL-34 in the steady state. Growing evidence from in
sion of the membrane IL-1𝛼. Membrane IL-1𝛼 is involved in rendering
vitro experiments, animal models, and clinical studies suggests a neuro-
noncommitted memory T cells into a conventional Th17-cell pheno-
protective role of IL-34 in brain injury and neurodegeneration. IL-34 is
type. Thus, this mechanism allows M𝝓s to maintain locally restrained
constitutively expressed by neurons, and this expression is significantly
and smoldering inflammation by favoring the switch of memory CD4+
increased in damaged neurons. IL-34 is released from injured neurons
T into Th17 cells.135 Boulakirba et al. showed a similar function of
and acts as a “Help-me” signal that induces potent neuroprotective
IL-34-differentiated M𝝓s in the regulation of T cell response, which
functions by exerting critical biological effects on neurons, microglia,
was importantly affected by stimuli available at the local microen-
and endothelial cells of the blood–brain barrier.92 As suggested by Luo
vironment. In detail, the expression of cytokines/chemokines differs
et al., CSF-1R is expressed in neurons and up-regulated after brain
in IL-34-differentiated M𝝓s depending on their polarization status,
injury. IL-34 protects neurons against excitotoxic-induced neurode-
which importantly impacts their ability to polarize naïve T lympho-
generation by maintaining CREB signaling downstream of CSF-1R in an
cytes into Th1 cells. For example, IL-10 production is increased in
autocrine manner. Consistent with this, in vivo administration of IL-34
IL-34-differentiated M𝝓s polarized into M1-phenotype by LPS and
protected mice from excitotoxin-induced neuronal loss and gliosis.84
IFN-𝛾 stimulation, resulting in a decrease in Th1 cell polarization. On
In microglia, IL-34 enhances microglial neuroprotective functions by
the contrast, IL-4 induces a shift in IL-34-differentiated M𝝓s into an
inducing the expression of 2 enzymes, insulin degrading enzyme (IDE)
M2-polarized phenotype that showed enhanced expression of CCL17
and heme oxygenase-1 (HO-1). IDE is an enzyme required for the
and CCL22, thus favored an increase in Th1 polarization.23
degradation and clearance of oligomeric amyloid 𝛽 (oA𝛽), while HO-
On the other hand, IL-34 can also act as an immunosuppressive
1 is an antioxidant enzyme that suppresses reactive oxygen products
cytokine that contributes to inflammation resolution and immune
induced by oA𝛽.81 Additionally, IL-34 induces microglial production of
tolerance. IL-34 induces monocytes differentiation into M2-polarized
TGF-𝛽1, which in turns negatively regulates microglial proliferation but
M𝝓s characterized by enhanced immunosuppressive capacities to
attenuated oA𝛽-mediated neurotoxicity.82 Finally, IL-34 is suggested
inhibit NK and T cell responses.66,100,123 Additionally, IL-34 medi-
to have a novel role in restoring the integrity of blood–brain barrier
ates an anti-inflammatory shift in cytokine/chemokine production
within the brain. Tight junction proteins of the capillary endothelial
in stimulated M𝝓s, and down-regulation of TLRs such as TLR2
cells play essential roles in the barrier function of the blood–brain bar-
and Dectin-1.23,70 Furthermore, Bézie et al. demonstrated a novel
rier and are frequently downregulated by pro-inflammatory cytokines
connection between IL-34-differentiated M𝝓s and Tregs that medi-
such as TNF-𝛼 and IL-1𝛽. In an interesting study by Jin et al., IL-34
ates immune tolerance. In the presence of IL-34, M𝝓s significantly
was able to antagonize the effects of TNF-𝛼 and IL-1𝛽 on endothelial
expanded CD8+ and CD4+ FoxP3+ Tregs with a superior suppressive
cells, resulting in the up-regulation of tight junction proteins including
potential to control immune responses and induce immune tolerance,
claudin-5 and occludin via a CSF-1R-mediated mechanism.85
such as in a rat cardiac allograft model and graft vs. host disease
in humanized mice.136–138 Collectively, IL-34 may have important
3.2.7 Immune response roles in orchestrating the innate and adaptive immune responses via
Inflammation is a vital biological process that enables the host to regulating cytokine/chemokine expression and rendering M𝝓s into
develop a protective response to injury, pathogen, cancer, or immune distinct phenotypes.
BAGHDADI ET AL . 11

4 PATHOLOGICAL ROLES OF IL-34 Sjogren’s syndrome is a chronic inflammatory autoimmune disease


characterized by the disturbance of cytokine networks and the pres-
Despite its selective expression in the skin and brain in the steady ence of focal B and T cell infiltration. The pathogenesis of Sjogren’s
state, accumulating evidence has unveiled important roles of IL-34 syndrome is considered to be multifactorial, and epithelial cells of
in various pathological conditions.12 In each disease, IL-34 can tell the salivary glands are suggested to play important pathological roles
different stories depending on the cellular origin, the molecular and represented by the massive secretion of several pro-inflammatory
cellular components in the surrounding microenvironment, in addition cytokines in the histopathological lesions. In clinical samples from
to the availability and expression magnitude of receptors and regu- patients with Sjogren’s syndrome, Cicca et al. observed an increased
lators related to IL-34 such as CSF-1R, PTP-𝜁 , and syndecan-1. The expression of IL-34 in infiltrating mononuclear cells and ductal epithe-
expression of IL-34 is accompanied by disease severity and progression lial cells in the inflamed salivary glands. The increased expression of
in some cases, but can also show beneficial effects in others. Accord- IL-34 was found to be associated with increased expression of pro-
ingly, the role of IL-34 in disease is complex, controversial, and highly inflammatory cytokines, such as TNF-𝛼, IL-1𝛽, IL-17, and IL-23p19.
context-dependent. Here, we summarize the major pathological roles Importantly, IL-34 expression was accompanied by the expansion of
of IL-34 described in the literature. pro-inflammatory CD14Bright CD16+ monocytes in the inflamed sali-
vary glands; an observation supported experimentally by in vitro
evidence. Thus, IL-34 is suggested to involved in the pathogenesis of
4.1 Autoimmune diseases
salivary gland inflammation in Sjogren’s syndrome.46
The pathological roles of IL-34 in autoimmune disorders have been SLE is a heterogeneous multisystemic autoimmune inflammatory
evaluated in several diseases such as RA, Sjogren syndrome, SLE, psori- disease characterized by polyclonal activation of T and B lymphocytes,
asis, and psoriatic arthritis. RA is a chronic autoimmune disease of the production of auto-antibodies, and formation of immune complexes
joints characterized by synovial inflammation and hyperplasia result- that result in tissue and organ damage. Two separate studies by Wang
ing in progressive cartilage and bone destruction. Pro-inflammatory et al. and Xie et al. have found elevated levels of serum IL-34 in SLE
cytokines are fundamental to the pathophysiology of RA. Numer- patients and correlates with the accumulation of the related clinical
ous studies have unveiled the pathologic role of IL-34 in RA as a features.44,45 The role of IL-34 in SLE is supported by evidence from
downstream effector of pro-inflammatory cytokines, contributing experimental animal models. In comparative transcriptional profiling
importantly to inflammation and bone erosion.26–42 Elevated levels of of 3 murine models of SLE nephritis has revealed unique and shared
IL-34 can be detected in the blood, synovial fluids, and synovial tissues regulatory networks, and IL-34 was one of the factors shared between
of RA patients. At the cellular level, IL-34 expression can be detected these 3 models, showing enhanced expression in the SLE kidney
in a wide range of cells, including synoviocytes, multinucleated giant nephritis.43 The pathological function of IL-34 SLE in addition to other
cells, and M𝝓s in the synovial lining layer, and endothelial cells, autoimmune disorders remains to be explored in future works.
inflammatory cells, and fibroblasts in the sublinig layer of synovial
tissues.26 Evidence from in vitro experiments has shown that pro-
4.2 Inflammation
inflammatory cytokines, including TNF-𝛼, IL-1𝛽, IL-6, and IL-17, can
induce the expression of IL-34 in osteoblasts and synovial fibroblasts The involvement of IL-34 in inflammation has been suggested by the
via JNK- and NF-𝜅B-mediated mechanisms.26,28,133 Functionally, evidence that showed induced expression of IL-34 in a wide range
IL-34 contributes to the pathophysiology of RA via multiple molecular of cells upon exposure to various inflammatory stimuli that activate
and cellular mechanisms: (1) IL-34 mediates a positive feedback loop NF-𝜅B such as pro-inflammatory cytokines, PAMPs, and chemical
that results in an enhanced expression of pro-inflammatory cytokines stressors.11,12 Specific inhibitors of NF-𝜅B can sufficiently reduce
such as IL-6 and IL-17,36,40–42 (2) promotes migration of PBMCs that IL-34 expression after stimulation, indicating that NF-𝜅B regulates
showed enhanced expression of IL-17,41 (3) enhances proliferation IL-34 expression in stimulated cells.133,134 Since NF-𝜅B is a master
and differentiation of M𝝓s, which serve as a predominant infiltrating regulator of the inflammatory signaling pathway, IL-34 is expected to
cell type in the inflamed synovia that promotes inflammation by be correlated with various inflammatory conditions. Consistent with
enriching the environment with pro-inflammatory factors,26 and this, an enhanced expression of IL-34 has been reported in several
(4) supports RANKL-induced osteoclastogenesis resulting in bone pathological conditions accompanied by inflammation such as inflam-
erosions.27 Additionally, IL-34 induces STAT3 activation and miRNA- matory bowel disease,51,52 coronary artery disease,48,53,61 chronic
21 increment in synovial fibroblast, resulting in increased resistance apical periodontitis,60 obesity,78 chronic liver disease in NAFLD,57 and
of fibroblast to apoptosis and enhanced IL-6 expression, which in turns lesions of the salivary glands.46,63 Importantly, IL-34 was suggested
contribute to Th17 production.36 A recent study by Galligan et al. have to be involved in the pathological complications of these chronic
suggested a novel role of IL-34 in simulating fibrocyte proliferation conditions, such as renal dysfunction in chronic heart failure,61 liver
and activating during arthritis, thereby contributing to both onset fibrosis in NAFLD,57 and insulin resistance and T2DM in obesity.78,80
and systemic spread of the disease in a murine model of collagen- In 2 separate studies by Zwicker et al. and Franzè et al., IL-34 was
induced arthritis (Fig. 4A).39 Using the same model, IL-34 was found identified as a novel modulator of human and experimental inflam-
to aggravate disease severity by enhancing levels of pro-inflammatory matory bowel disease, which importantly sustains inflammatory path-
cytokines such as IL-6, IL-17, and TNF-𝛼.39,42 ways in the gut. IL-34 expression was increased at both mRNA and
12 BAGHDADI ET AL .

IL-1β
A IL-6
Synovial
B
PAMPs TNFα
TNFα IL-17 Fibroblast
Osteoblast Colon epithelium

IL-34
NF-Kβ↑

Synovial PBMCs
Fibroblast IL-34
Fibrocyte PBMCs Macrophage

Proliferation
STAT3 Activation Colon
Migration Cytokines/chemokines
miR-21 Increment epithelium
IL-17
Proliferation ERK1/2
Proliferation IL-1β
IL-6
IL-8
Survival MCP1
IL-17 cells↑ CCL2 IL-6 TNFα
Onset

Damage
CSF-1R
C D
Neuron • Survival
• Tumor growth
• Metastasis Cancer cell
IL-34 • Stemness
• Therapeutic
resistance IL-34

IL-34 IL-34
IL-34
CSF-1R
CSF-1R CSF-1R
Endothelial
Neuron Microglia
cells
Claudin-5, Occludin Osteoclasts
CREB BBB integrity IDE, HO-1 Monocytes Endothelial cells
Survival Chronic
TGFβ recruitment
Activation
• Survival
• Tumor growth Angiogenesis
Neuroprotection • Metastasis Bone destruction
Pro-inflammation • Stemness
cytokines • Therapeutic
Neuroinflammation Necrotic factors resistance

F I G U R E 4 Pathological roles of IL-34. The role of IL-34 in disease is complex, controversial, and highly context-dependent. Via complex networks
that involve different cells and molecules, IL-34 exhibits various pathological roles such as in RA (A), inflammatory bowel disease (B), neurological
disorders (C), and cancer (D). In most cases, enhanced expression of IL-34 is accompanied by disease severity and progression

protein levels in the inflamed colon of patients with Crohn’s disease ulcerative colitis animal model, have suggested a new method based
and ulcerative colitis. Stimulation with the pro-inflammatory cytokine on combining between mRNA expression analysis and effects of
TNF-𝛼 significantly induced the expression of IL-34 in colon epithe- cytokines, chemokines, and growth factors described in the literature
lial cells via an NF-𝜅B-mediated mechanism. On the other hand, stim- to get a better understanding of the inflammatory processes in disease.
ulation of colon epithelial cells with IL-34 enhances the expression In this model, IL-34 was suggested to induce Th2-drive inflammation,
of pro-inflammatory cytokines and chemokines such as TNF-𝛼, IL-6, which may result in activation of the inflammatory remodeling condi-
and CCL20 through an ERK-dependent mechanism. Thus, IL-34 is sug- tion. This inflammatory condition might be responsible for fibrosis and
gested to mediate a positive feedback loop that results in the amplifica- epithelial hyperplasia in patients with ulcerative colitis.59
tion of the inflammatory circuit by enriching the inflammation loci with In addition to inflammatory bowel disease, a crucial pathologic role
pro-inflammatory cytokines and enhancing the infiltration of inflam- of IL-34 has been described in kidney inflammation. During kidney
matory lymphocytes (Fig. 4B).51,52,140 A recent study by Zwicker et al. injuries, M𝝓s play critical roles in the regulation of inflammatory
has described the expression of IL-34 receptors in the gut. CSF-1R response to injury, which can be beneficial leading to kidney repair,
and PTP-𝜁 were detectable at the protein level in both immune cells or harmful resulting in kidney destruction. While tubular cell-derived
and intestinal epithelial cells. The expression of PTP-𝜁 was high in the CSF-1 is required for kidney repair, Baek et al. have identified tubular
colon but weak in PBMCs and monocytes/M𝝓s. CSF-1R showed high cell-derived IL-34 as a critical inflammatory mediator that contributes
expression in monocytes/M𝝓s but was also detectable in intestinal to kidney injury. Studies on Il34LacZ/LacZ mice showed that IL-34
epithelial cells. Importantly, PBMCs and monocytes responded differ- expression could be detected in renal tubule cells.5,6 In a murine model
entially to IL-34 and CSF-1 stimulation with altered expression of pro- of ischemia-reperfusion kidney injury, IL-34 expression raised rapidly
inflammatory cytokines and chemokines. Taken together, the patholog- in tubular epithelial cells during the acute phase and promoted tubule
ical roles of IL-34 during inflammation is suggested to be importantly destruction by infiltrating M𝝓s and neutrophils in the inflamed kidney.
impacted by the cellular expression patterns of the related recep- Upon chronicity, IL-34 worsens chronic kidney disease by 2 distinct
tors, CSF-1R and PTP-𝜁 .139 Recently, a brilliant study by Jodeleit et al. mechanisms: (1) enhanced intrarenal M𝝓 infiltration and (2) elevated
that validates the disease network in the NOD-SCID IL2r𝛾 null NSG proliferation of bone marrow-derived myeloid cells, which increases
BAGHDADI ET AL . 13

circulating monocytes and neutrophils that are recruited by several thereby boosting their ability to promote type I collagen expression
chemokines induced by IL-34 in the injured kidney. Thus, IL-34 was by hepatic stellate cells.66 The pathological involvement of IL-34 in
suggested to promote persistent ischemia-incited acute kidney injury the infection-associated cytokine network can also be observed in
and worsens the subsequent chronic kidney disease.49,55 influenza A virus (IAV) infection. Yu et al. described the induction of IL-
34 expression by IL-22 in IAV-infected PBMCs. Upon secretion; IL-34
seems to mediate a negative feedback loop that inhibits IL-22 produc-
4.3 Infections
tion, indicating an essential role of IL-34 in regulating the inflammatory
Dysregulation of cytokines and chemokines expression occurs during cascade during immune response against IAV.71
viral infections and importantly contribute to modulating viral repli- On the other hand, IL-34 has beneficial effects in the context of
cation, persistence, and disease progression. The second appearance other viral and bacterial infections. For example, Cheng et al. described
of IL-34 in the literature was in an interesting study by Covaleda et al. the ability of IL-34 to repress HBV replication in HBV-infected hep-
that described for the first time a pathological potential of IL-34 in atocytes in vitro and in vivo when administrated intravenously into
viral infections. In a model of EIAV infection, monocyte-derived M𝝓s HBV transgenic mice.73 On the contrast, Wang et al. showed recently
showed enhanced expression of IL-34 upon EIAV infection, which that serum IL-34 is elevated in HBV patients and correlates with
was selectively dependent on the existence of the viral protein, S2. biomarkers of liver inflammation and fibrosis in patients with chronic
Macrophages are the natural target for EIAV replication. In addition HBV.76 In an infection model of the ranavirus FV3 in Xenopus lae-
to their roles as viral reservoirs, infected M𝝓s serve as vehicles that vis, Grayfer et al. showed that IL-34-derived M𝝓s exhibited potent in
enable the virus to reach different tissues and organs. Considering the vitro antiviral activity represented by robust gene expression of Arg-
biological importance of IL-34 in promoting the formation and prolif- 1, ROS, NADPH oxidase, and type I IFN. Consistent with these antivi-
eration of monocyte/M𝝓 lineage in the bone marrow, EIAV-induced ral activities, IL-34 administration significantly prolonged survival of
IL-34 may help to promote a suitable cellular environment that is likely FV3-infected tadpoles.117,119 More recently, Lin et al. have described
to enhance viral replication and dissemination.64 HIV, a retrovirus an enhanced expression of IL-34 during sepsis in patients and murine
closely related to EIAV, depends on M𝝓s at the early phase for estab- models. Interestingly, treatment with IL-34 helped to protect mice
lishing the HIV infection. Similarly, M𝝓s enhance HIV production and against polymicrobial sepsis, while IL-34 neutralization worsens sur-
dissemination to other cells and tissues and aid viral persistence by vival. Intraperitoneal administration of IL-34 was found to induce the
serving as a long-lived cellular reservoir of HIV in several tissues. Chi- expression of several cytokines and chemokines that recruit M𝝓s and
hara et al. provided evidence of the potential involvement of IL-34 in neutrophils such as IL-6, TNF𝛼, CXCL1, and CCL2. Thus, IL-34 may help
HIV infection by showing that HIV-1 replication is tended to be higher as an immunotherapeutic adjuvant to ameliorate survival and bacterial
in IL-34-differentiated M𝝓s due to the strong activation of MAPK clearance in sepsis.74 Additionally, Xu et al. suggested the importance
signaling pathway downstream of CSF-1R.108 Therefore, it is reason- of IL-34 in inducing immune tolerance to harmless commensal fungus
able to suspect that IL-34 supports the development and maintenance such as Candida albicans. Upon stimulation with heat-killed candida,
of HIV-M𝝓 reservoirs through CSF-1R signaling. Later, Gerngross IL-34 suppresses TNF-𝛼 production in M1-polarized M𝝓s by down-
et al. showed robust IL-34 expression in brain parenchyma of SIV- regulating the expression of 2 critical PPRs: dectin-1 and TLR2. Thus,
infected rhesus macaques. Importantly, in vitro stimulation with IL-34 the constitutive expression of IL-34 in the mucosal and dermal skin may
enhanced HIV-1 production in microglia and expanded IL-10+ mono- play a role in maintaining immune tolerance toward commensal colo-
cytes via a CSF-1R-mediated mechanism. Thus, IL-34 may contribute nizing microorganisms.70
to HIV-associated neuropathogenesis by maintaining alternative M𝝓 In addition to viral and bacterial infections, several studies have
polarization and providing critical pro-survival signaling that protects suggested the involvement of IL-34 in parasite and bacterial infec-
infected M𝝓/microglia from apoptosis.67,68,108 Similar involvement of tions, such as in gilthead sea bream (Sparus aurata) infected with
microglia in CNS infections was suggested in other models. In a murine Enteromyxum leei,65 grouper infected with C. irritans,69 and large
model of neuro-invasive West Nile virus infection, Vasek et al. showed yellow croaker (Larimichthys crocea) infected with Vibrio anguillarum
that Il34−/− mice with fewer microglial cells were protected from bacterium.75 As described above, IL-34 expression can be induced in
West Nile virus-induced synaptic terminal loss.72 Accordingly, IL-34 various cells following PAMPs stimulation, which indicates an impor-
may probably contribute to the neurocognitive impairment in patients tant role of IL-34 in the regulation of innate immune response against
recovering from neuro-invasive disease in West Nile virus infection. infectious pathogens. However, the biological outcome of IL-34, favor-
In the context of HCV infection, IL-34 acts as a pro-fibrotic factor able or unfavorable, seems to be controversial and depend on the infec-
associated with chronicity. Preisser et al. showed that IL-34 is secreted tious pathogen, site, and phase of infection.
by HCV-infected hepatocytes, and play important roles in the recruit-
ment and differentiation of monocytes into pro-fibrogenic M𝝓s, which
4.4 Neurologic disorders
(1) promote type I collagen secretion by hepatic stellate cells, (2) favor
the survival of hepatic stellate cells by decreasing NK cell-mediated Microglia can be activated by various triggering factors, such as in
cytotoxic activity, and (3) enrich injured sites with inflammatory cells injury, infection, or neurodegeneration. Depending on the type of
via the expression of various cytokines and chemokines. Furthermore, stimuli and cues at the surrounding microenvironment, microglia can
IL-34-M𝝓s response to IL-13 by decreased expression of MMP-1, exhibit distinct activation phenotypes and may exert both beneficial
14 BAGHDADI ET AL .

and detrimental effects. IL-34 is suggested to provide potent neuro- 4.5 Cancer
protection by the modulation of microglial functions.81,82 Studies on
In the tumor microenvironment, CSF-1R regulates the function
microglial activation have indicated that in contrast to CSF-1, IL-34
and survival of tumor-associated M𝝓s (TAMs), which play crucial
results in an anti-inflammatory reparative phenotype in rodent and
roles in tumor growth, invasion, metastasis, angiogenesis, immune
human microglia.91 Given that both IL-34 and CSF-1 are expressed
suppression, and therapeutic resistance.141 Thus, the CSF-1R axis has
in the brain, a decrease in IL-34 expression is expected to result in
gained the most attention in recent cancer immunotherapeutic strate-
an imbalance in CSF-1R signaling within the brain resulting in neu-
gies, and various approaches that target this axis are currently under
roinflammation. On the other hand, chronic activation of microglia
clinical development.142–144 As a ligand of CSF-1R, several studies
by IL-34 is suggested to be accompanied with overactivation of
have focused on the role of IL-34 in cancer, showing pro-tumorigenic
myeloid cell-specific transcription factors such as PU.1 and C/EBP-
functions of IL-34 in the tumor microenvironment via multiple effects
𝛼, which enhances the expression of pro-inflammatory cytokines
on both cancer cells and myeloid cells (Fig. 4D).
and promotes neuroinflammation in chronic stages of neurological
When cancer cells are threatened such as in chemotherapy, internal
disorders (Fig. 4C).91
cascades of survival signaling are triggered to protect against cell
Several studies have unveiled the pathological involvement of IL-
death and defend against future insults. In this regard, accumulating
34 in several neurological disorders. The abnormal accumulation of
evidence has unveiled the importance of IL-34:CSF-1R axis in cancer
oA𝛽 plays critical roles in the pathogenesis of Alzheimer’s disease.
chemoresistance. CSF-1R is expressed in a subset of cancer cells or
Given that IL-34 selectively enhances the neuroprotective effects
can be induced upon exposure to chemotherapeutic agents.95,100,102
of microglia to attenuate oA𝛽 neurotoxicity, IL-34 is suggested to
Similarly, IL-34 is expressed in various types of cancer cells and can be
be pathologically involved in Alzheimer’s disease. Using human brain
induced by chemotherapy treatment.95–106 In an autocrine fashion,
clinical samples, Walker et al. have shown that IL-34 expression is
cancer cell-derived IL-34 induces strong activation of ERK1/2 and AKT
decreased in the inferior temporal gyrus in some cohorts of patients
downstream of CSF-1R, thus providing CSF-1R-expressing cancer cells
with Alzheimer’s disease.91 An interesting observation by Zhang et al.
with a critical survival signaling that help them to survive under strict
has suggested that vitamin D is capable of inducing IL-34 expres-
chemotherapeutic conditions, such as in pemetrexed-treated pleural
sion in neural cells. Consistent with this, a specific binding site for
malignant mesothelioma cells,95 doxorubicin- or cisplatin-treated
vitamin D receptor was identified within the core promoter of IL-34
lung cancer cells,100 and oxaliplatin-treated colon cancer cells.102
gene.93 Vitamin D supplementation is considered as a novel approach
Moreover, in addition to intracellular signals, the release of extracel-
to treat Alzheimer’s disease. Thus, IL-34 may provide a mechanistic
lular signals provides a way to recruit adjacent cells into an amplified
explanation of the beneficial effects of vitamin D for patients with
protective program. During cancer progression, IL-34 serves as a pow-
Alzheimer’s disease.
erful tool to reprogram M𝝓s into tumor-promoting M𝝓s in primary
Prion diseases are progressive neurodegenerative disorders caused
tumors. In solid tumors, TAMs are the most abundant immuno-
by transmissible pathogenic agents characterized by their ability to
suppressive leukocytes in the tumor microenvironment, and their
induce abnormal folding of specific normal cellular proteins called
high intensity is correlated with poor prognosis. TAMs have an M2-
prion proteins. Striking activation of microglia is frequently observed
polarized phenotype that enables them to regulate immune responses,
in prion diseases, which is suggested to play protective roles in prion
favor angiogenesis and promote tumor progression, invasion, and
pathogenesis. Consistent with this, Zhu et al. have found in a murine
metastasis.141 Early studies on the biology of IL-34 have shown
model of prion disease that the deficiency of microglia in Il34−/− mice
that IL-34-derived M𝝓s exhibit most of the phenotypic (CD14high
resulted in more astrogliosis and a significant acceleration of prion
CD163high IL-10high IL-12low CD86low ) and functional characteristics
disease progression. The scarcity of microglia at early stages of prion
(low T cell costimulatory properties, suppression of activated effector
infection or poorly understood defects in microglial functions was sug-
T cell responses) of TAMs.123 Consistent with this, embryonic stem
gested to play a role in determining disease progression.88 In this
cells-derived IL-34 contributes to polarizing bone marrow-derived
regard, it is of great interest to examine the expression levels of IL-34
M𝝓s into M2-like M𝝓s that exhibit most tumor-associated M𝝓s
in the context of prion diseases.
phenotypic and functional features, showing increased levels of
Huntingtin’s disease is an inherited neurodegeneration disorder
Arg-1, Tie-2, and TNF-𝛼 and contribute to angiogenesis and teratoma
caused by the accumulation of the abnormal protein mHTTx1. In an
progression.145 Additionally, IL-34-derived M𝝓s favor switching mem-
interesting study by Khoshnan et al., mHTTx1 was shown to create
ory T cells into Th17 cells via constitutive expression of membrane
a stressed neuronal environment that activates IKK𝛽, which in turn
IL-1𝛼. Membrane IL-1𝛼 is involved in several processes, including
promotes the aggregation of mHTTx1 and subsequent induction of
inflammation and antitumor immunity. Additionally, membrane IL-
procaspase-3 and IL-34. In turn, increased IL-34 secretion may ini-
1𝛼 exhibits pro-inflammatory and pro-angiogenetic properties and
tially signal to microglia to express neuroprotective factors and main-
increases tumor growth and metastasis. The constitutive expression
tain survival. However, chronic activation by IL-34 may lead instead to
of membrane IL-1𝛼 in IL-34-modified M𝝓s allows them to maintain
pathological activation of microglia that shows enhanced production
locally restrained and smoldering inflammation, which is required for
of inflammatory cytokines and necrotic factors, resulting in neuronal
angiogenesis and metastasis.135 Consistent with these backgrounds,
degradation and death via non-cell autonomous interactions.89
several studies have proved the ability of IL-34 to increase frequencies
BAGHDADI ET AL . 15

of M2-polarized TAMs with enhanced pro-tumorigenic functions Hiyoshi et al. have described a role of CSF-1R mutations in hereditary
contributing importantly to tumor growth, angiogenesis, metastasis, diffuse leukoencephalopathy.148 It is also of great interest to evaluate
and therapeutic resistance.98–101 Furthermore, IL-34 is secreted the impact of CSF-1R mutations in IL-34- or CSF-1-expressing tumors.
by cholangiocarcinoma stem-like subsets and educates TAMs in a Collectively, the favorable/unfavorable impact of IL-34 expression
way that helps to shape tumor-supportive immune niche.104 More at the tumor microenvironment can be determined by receptors and
recently, Han et al. have suggested the potential involvement of IL-34 regulators expressed by the cellular components in addition to the
in resistance to immunotherapy. In a clinical case of a patient with molecular components available at the tumor microenvironment and
melanoma that acquired resistance to anti-PD-1 immunotherapy, involved in the signaling network of IL-34.
IL-34 showed enhanced expression in metastatic refractory melanoma
compared to melanoma from primary sites, which correlates positively
with increased infiltration of CD163+ TAMs, which have high potential
5 IL-34 FROM BENCH TO BEDSIDE
to suppress effective antitumor immune responses.106 In addition
to TAMs, CSF-1R expression can be detected on tumor-associated
5.1 IL-34 as a therapeutic tool
dendritic cells, tumor-associated neutrophils, and myeloid-derived
suppressor cells. Thus, it is of great interest to evaluate the impact of Based on its biological characteristics, IL-34 may show therapeutic
IL-34 on these myeloid cells within the tumor microenvironment. benefits in disease treatment. In inflammation, IL-34 may help to
The crosstalk between IL-34 and other molecular and cellular com- attenuate inflammation and promote resolution by suppressing inflam-
ponents of the tumor microenvironment plays important roles in matory cytokines production and accelerating the formation of
tumor progression at primary sites or in distant metastasis. For exam- immunosuppressive immune cells such as M2-polarized M𝝓s and Tregs
ple, IL-34 is secreted by hepatocellular carcinoma cells and enhances at the inflammation loci. In infection, IL-34 may also help to control dis-
the production of TGF-𝛽1 by TAMs. In turn, TAMs-derived TGF- ease progressions such as in HBV infection and sepsis. As suggested
𝛽1 enhances IL-34 production in hepatocellular carcinoma cells by by Cheng et al., treatment of HBV transgenic mice (HBV-Tg C57BL/6)
suppressing the expression of a microRNA (miR-28-5p) that nega- with IL-34 was effective to reduce serum levels of HBV DNA, suggest-
tively regulates IL-34 expression. The resulting IL-34-TGF-𝛽-mi-R-28- ing a rationale for the use of IL-34 in HBV treatment.73 Additionally, Lin
5p feedback loop was suggested to modulate hepatocellular carci- et al. showed that IL-34 administration improved survival and bacterial
noma metastasis.101 Additionally, IL-34 was found to be produced by clearance in a mouse model of polymicrobial sepsis.74
giant cell tumors of bone and suggested to play a key pathogenic role In transplantation, IL-34 can importantly contribute to immunosup-
in RANKL-induced osteoclastogenesis by enriching the microenviron- pression and immunotolerance required for graft survival. In a car-
ment with bone-resorbing osteoclasts.94 Finally, IL-34 showed high diac allograft model in rats, Bézie et al. described a novel role of IL-34
expression in some patients with brain metastasis of breast cancers, in promoting allograft tolerance by the induction of CD8+ and CD4+
where it may induce a phenotypic shift in resident microglia.97 Tregs and inhibition of alloantibody production.136 Similarly, Zhao et al.
IL-34 is expressed in various types of cancer, as suggested by found that IL-34 was effective to inhibit acute rejection and prolong
data from public databases such as PrognoScan and Human Protein the recipients’ survival by altering the polarization of Kupffer cells
Atlas.146,147 The expression magnitude of IL-34 differs between can- polarization into an M2-phenotype in a liver transplantation model in
cers from various histological backgrounds and varies among patients rats.125 Additionally, IL-34 can be used as an ex vivo cytokine for the
from high, weak to absent. As suggested by its potent pro-tumorigenic generation of immunosuppressive immune cells that can be utilized as
functions, high expression of IL-34 correlates with poor prognosis adjuvant cell therapy to prolong survival of implanted grafts. In this
of cancer patients, such as in brain and lung cancers.146,147 Impor- regard, PSCs have obtained a great interest in cell-based regenerative
tantly, IL-34 showed enhanced expression in advanced stages (III and therapies due to their capacity to differentiate into various cells that
IV) compared to early stages (I and II) in a cohort of lung cancer help to replenish cells lost in various conditions. To avoid immune rejec-
patients, suggesting a correlation between IL-34 expression and tumor tion of PSCs-derived grafts, PSCs-derived immunoregulatory cells can
progression.105 On the contrast, high expression of IL-34 is favorable in importantly help to prolong survival of allografts derived from the
certain types of cancer, such as in some cohorts of patients with head same donor of PSCs.149,150 IL-34 has the potential to drive PSCs differ-
and neck cancers or breast cancers.146,147 Further studies are needed entiation into specific cell types such as microglial cells and can provide
to examine whether IL-34 may have beneficial effects in some cancers, a critical activation signal of CSF-1R for the generation of immuno-
and the related mechanisms. suppressive M2-polarized M𝝓s.123,128,129 Thus, IL-34 may be useful in
In addition to CSF-1R, IL-34 exerts physiological and pathologi- the field of regenerative medicine in 2 ways: (1) generation of grafts
cal functions via other receptors and regulators such as PTP-𝜁 and and (2) induction of allograft tolerance directly in patients, or by the
syndecan-1.21,22 IL-34 inhibits proliferation, motility, and clonogenic- ex vivo generation of immunoregulatory cells that suppress allograft
ity in the human glioblastoma cell line U251 via a PTP-𝜁 -mediated immune responses.
mechanism.21 Additionally, IL-34 significantly increases the migra- IL-34 is physiologically essential for the development, maintenance,
tion of the human acute leukemia cell line THP-1 via a syndecan-1- and proper functioning of Langerhans cells and microglia in the skin
mediated mechanism.22 Interestingly, IL-34 can induce the differenti- and brain, respectively.5,6 In animal studies, the deficiency of IL-34
ation of CSF-1R-expressing leukemia cells into monocyte-like cells.96 shows no remarkable changes at the steady state but has a signifi-
16 BAGHDADI ET AL .

cant impact on pathological conditions such as inflammation and viral in cancer therapy. Depleting or repolarizing TAMs showed promis-
infection.5,6 Obviously, IL-34 may have therapeutic benefits to restore ing effects in preclinical models.141 As an important factor that
critical physiological functions required for homeostasis at sites of increases TAMs frequencies and enhances their pro-tumorigenic
expression. Consistent with this, a correlation between reduced IL- functions, targeting IL-34 has a therapeutic potential in TAMs-
34 expression and disease severity can be observed in the context targeting strategies.98,100,101,104,106 Furthermore, since cancer cells
of atopic dermatitis and some cohorts in patients with Alzheimer’s rely on IL-34-activated signaling pathways for their survival under
disease.50,91 In atopic dermatitis, IL-34 may act as a negative reg- chemotherapeutic conditions, targeting IL-34 may help to sensi-
ulator that inhibits the propagation of the inflammatory cascades tize therapeutic-resistant cancer cells to cancer therapy such in
toward the development of active skin lesions.50 In neurological disor- chemoresistant lung cancers, colon cancers, and malignant pleural
ders, IL-34 has therapeutic potential by restoring blood–brain barrier mesotheliomas.95,100,102 Finally, neutralizing IL-34 may show thera-
integrity, enhancing neuroprotective functions of microglia, and pro- peutic benefits in controlling tumor growth, cancer-induced osteoclas-
moting neuro-recovery in damaged neurons.81–86 Consistent with this, togenesis, suppressing angiogenesis, and inhibiting cancer cell invasion
the intracerebroventricular administration of IL-34 was effective to and metastasis.
ameliorate impairment of associative learning and reduced oA𝛽 levels In neurological disorders, the removal of microglia appeared to
through up-regulation of IDE and HO-1 in APP/PS1 transgenic mouse have beneficial effects in some neurodegenerative disease models,
model that resembles Alzheimer’s disease.81 These functions of IL- such as in stroke, cranial irradiation, toxin-induced neurotoxicity,
34 may give a clue for new therapeutic strategies in neuroinflamma- and amyotrophic lateral sclerosis. Indeed, most studies using CSF-
tory and neurodegenerative diseases such as multiple sclerosis and 1R inhibitors have demonstrated therapeutic benefits of microglial
Alzheimer’s disease. removal from rodent brains.91 Accordingly, targeting IL-34 may serve
as an attractive therapeutic strategy for the treatment of these disor-
ders. IL-34 also enhances the anti-inflammatory effects of microglia
5.2 IL-34 as a therapeutic target
and thus may have therapeutic potential in treating neurodegenera-
On the contrast, targeting of IL-34 may show therapeutic benefits tive diseases that are aggravated by systemic inflammation, such as in
in other diseases. In chronic inflammatory conditions such as inflam- Parkinson disease.90
matory bowel disease, the blockade of IL-34 may help to attenuate
inflammation by suppressing the expression of inflammatory factors,
including TNF-𝛼, IL-6, and CCL20.51,52,140 In mucosal explants isolated 6 CONCLUDING REMARKS
from patients with inflammatory bowel disease, Franzè et al. found that
IL-34 neutralization was sufficient to reduce TNF-𝛼 and IL-6.51 As an In the literature, IL-34 is described as the CSF-1 “twin” cytokine.4 Both
important factor that mediates acute kidney injury and worsens subse- cytokines control the biology and function of mononuclear phagocytic
quent chronic kidney disease, targeting IL-34 in the kidney and circu- lineage similarly in vitro, but specifically in vivo.11,12 IL-34 shows a con-
lation was suggested by Baek et al. as a potential therapeutic strategy stitutive expression at both mRNA and protein levels in keratinocytes
in kidney injuries.49 In autoimmune diseases, neutralizing IL-34 is and neurons and can be induced in a wide range of cells by several
similarly expected to have multiple therapeutic effects in autoimmune stimuli. The molecular mechanisms that control IL-34 expression—
diseases such as RA, including (1) blocking of the inflammatory circle physiologically or pathologically—remain mostly unknown, and identi-
caused by cytokine storm such as IL-6 and IL-17,28,36,37 (2) reduction fying the responsible signaling pathways or transcription factors may
of pathogenic immune cell subsets such as Th17 cell,31,40,41 sensitizing help to open new opportunities in medicine. For example, considering
synovial fibroblasts to apoptosis,36 and (3) controlling bone erosion its pivotal roles in Langerhans cells maintenance and microglial neuro-
and cartilage destruction caused by excessive osteoclastogenesis.27 protective functions, utilizing low-molecule compounds or stimulators
In Sjogren’s syndrome, targeting of IL-34 was suggested as promis- that induce IL-34 expression may have therapeutic potential in the skin
ing immunotherapy that may help to suppress the expansion of and neurological disorders. On the other hand, targeting IL-34 by neu-
pro-inflammatory CD14bright CD16+ monocytes in the inflamed tralizing Abs or specific inhibitors that suppress IL-34 expression in the
salivary glands.46 cellular targets may help to control other diseases such as RA, inflam-
IL-34 shows favorable effects on controlling viral diseases such as matory bowel disease, and cancer.
HBV.73 On the opposite, the IL-34 blockade can exert therapeutic The deficiency of Il34 gene showed no remarkable effects in knock-
effects in other viral infections. For example, neutralizing IL-34 may out mice in the steady states, in contrast to Csr1r- or Csf1-deficient
help to reduce profibrotic M𝝓s that cause liver fibrosis in the context mice.5,6 Thus, targeting IL-34-based strategies can be expected to
of HCV infection,66 suppress viral replication such as in HIV,108 and be accompanied by fewer side effects compared to CSF-1R or CSF-1
block the inflammatory cascade in IAV.71 Furthermore, IL-34 may serve blockade. However, Il34-deficient mice showed impaired responses
as an attractive target for eliminating long-lived M𝝓 reservoirs of HIV to skin antigens and viral infections of the CNS.5,6 Accordingly, IL-34
infection in the brain as well as other tissues.67,68 targeting should be carefully considered in patients with skin or neuro-
In cancer, IL-34 neutralizing can potentially contribute to effec- logical disorders. On the other hand, IL-34 may serve as a therapeutic
tive antitumor responses by multiple mechanisms. In recent years, tool in certain conditions. However, considering its critical roles in
TAMs have increasingly become recognized as an attractive target osteoclastogenesis and immunosuppression, therapeutic strategies
BAGHDADI ET AL . 17

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AUTHORSHIP 2012;20:676–687.

M.B. and K.S. performed the literature review and drafted the paper. 16. Felix J, Elegheert J, Gutsche I, et al. Human IL-34 and CSF-1 estab-
Y.U. designed and generated illustrations. Y.U., N.Hama, T.K., N.Han, lish structurally similar extracellular assemblies with their common
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ACKNOWLEDGMENTS 18. Kryshtafovych A, Moult J, Bales P, et al. Challenging the state of the
This work was supported in part by Japan Agency for Medical art in protein structure prediction: highlights of experimental target
structures for the 10th Critical Assessment of Techniques for Protein
Research and Development AMED (K. S.), Japan Society for the Pro-
Structure Prediction Experiment CASP10. Proteins. 2014;2:26–42.
motion of Science (JSPS) Grant-in-Aid for Young Scientists (grant no.
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18K15261, M.B.), and Joint Research Program of Institute for Genetic
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Medicine, Hokkaido University (The Liason Laboratory in the Center 2015;23:1621–1631.
for Infection-Associated Cancer). Figures and illustrations were pro- 20. Ségaliny AI, Brion R, Brulin B, et al. IL-34 and M-CSF form a novel het-
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