Immunological Medicine

ISSN: (Print) 2578-5826 (Online) Journal homepage: https://www.tandfonline.com/loi/timm20

Basic mechanism of immune system activation by

mitochondria

Yukiko Iwasaki, Yusuke Takeshima & Keishi Fujio

To cite this article: Yukiko Iwasaki, Yusuke Takeshima & Keishi Fujio (2020) Basic mechanism
of immune system activation by mitochondria, Immunological Medicine, 43:4, 142-147, DOI:
10.1080/25785826.2020.1756609

To link to this article: https://doi.org/10.1080/25785826.2020.1756609

© 2020 The Author(s). Published by Informa

UK Limited, trading as Taylor & Francis
Group on behalf of the Japanese Society of
Clinical Immunology.

Published online: 12 May 2020.

Submit your article to this journal

Article views: 5887

View related articles

View Crossmark data

Citing articles: 14 View citing articles

Full Terms & Conditions of access and use can be found at

https://www.tandfonline.com/action/journalInformation?journalCode=timm20
IMMUNOLOGICAL MEDICINE
2020, VOL. 43, NO. 4, 142–147
https://doi.org/10.1080/25785826.2020.1756609

REVIEW ARTICLE

Basic mechanism of immune system activation by mitochondria

Yukiko Iwasaki, Yusuke Takeshima and Keishi Fujio
Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

ABSTRACT ARTICLE HISTORY

Almost 160 years after the discovery of mitochondria, they are known for their production of Received 19 March 2020
energy and are called “the powerhouse of the cell”. Recently, immune-metabolism has been Accepted 8 April 2020
revealed as a key factor controlling immune cell proliferation and differentiation. Resting
KEYWORDS
lymphocytes generate energy through oxidative phosphorylation and fatty acid oxidation,
Mitochondrial dysfunction;
whereas activated lymphocytes rapidly shift to glycolysis. Oxidative phosphorylation mtDNA; OXPHOS; mtROS;
(OXPHOS) as well as mitochondrial reactive oxygen species (mtROS) generated through the autoimmune diseases
electron transport chain (ETC) are involved in many immune cell functions. Moreover, mito-
chondria are dynamic organelles that can provide immunogenic molecules, such as mito-
chondrial DNA (mtDNA) resulting in innate immune system activation. Here, we describe the
role of mitochondria in immune system regulation, highlighting metabolism-dependent and
other immunogenic aspects.

1. Introduction There is accumulating evidence that mitochon-

In the Warburg effect, cancer cells shift from oxida-
tive phosphorylation towards aerobic glycolysis.
Immune-metabolism refers to the processes control-
ling immune cell differentiation, proliferation and
function. In clinical settings, insights into metabolic
regulation of autoimmune diseases have been accu-
mulating. Inhibition of mammalian target of rapamy-
cin (mTOR), a key protein kinase regulating cellular
metabolism and cell growth, was reported to be
effective in the treatment of systemic lupus erythema-
tosus [1]. Mitochondria are the main energy producer
of cells through the process of oxidative phosphoryl-
ation (OXPHOS). They also function as biosynthetic
centers and balance redox signaling [2]. In a genome-
wide association study (GWAS), several single nucleo-
tide polymorphisms (SNPs) related to mitochondria
were associated with systemic lupus erythematosus,
suggesting the importance of mitochondrial function
in SLE pathogenesis [3]. Mitochondrial dysfunctions,
including increased production of reactive oxygen
species (ROS) and decreased respiration were
reported in untreated skeletal muscles of dermato-
myositis (DM) patients [4]. Interferon (IFN) b, a
type I IFN, induced ROS in human myotubes and it
reportedly contributed to mitochondrial dysfunction.
In Sjӧgren’s syndrome (SS), a relation between mito-
chondrial dysfunction and oxidative stress was postu-
lated in its pathogenesis [5].
dria are a hub of the immune system [6]. In this
review, we discuss the importance of mitochondrial
functions in autoimmune diseases from the point of
view of immunogenicity and immune-metabolism.
2. Mitochondria as activators of the
immune system
Mitochondria are the source of damage-associated
molecular patterns (DAMPs). Immunogenicity of
mitochondria can be partly explained by the fact
that they originated through endosymbiosis accom-
panied by gene transfer from the endosymbiont
to the host. The hypomethylated CpG motif of
mitochondrial DNA (mtDNA) is thought to be a
remnant of engulfed bacteria and they are immuno-
genic. In addition to mtDNA, mitochondria produce
several DAMPs, such as ATP, succinate, cardiolipin,
N-formyl peptides and transcriptional factor A
(TFAM). In concordance with impaired mitochon-
drial quality, these molecules are recognized by pat-
tern recognition receptors (PRRs) and activate the
immune system.　Nine kinds of anti-mitochondrial
antibodies (AMA), M1 to M9, have been character-
ized. AMA-M2, -M4, -M8, and -M9 classes were
described in primary biliary cholangitis (PBC) and
AMA-M1, -M3 and -M5 classes were detected in
SLE patients. The molecular target of M1 is known

CONTACT Yukiko Iwasaki yunyan-todai@umin.ac.jp Department of Allergy and Rheumatology, Graduate School of Medicine, The University of
Tokyo, Tokyo, Japan
ß 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group on behalf of the Japanese Society of Clinical Immunology.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits
unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

to be cardiolipin, which exists within the inner
mitochondrial membrane [7].
2.1. Nlrp3 inflammasome activation by
mitochondrial components
The inflammasome, the immune surveillance system
of cells, consists of high molecular weight protein
complexes composed of PRR-containing pyrin and a
caspase recruitment and activation domain, an
adaptor protein apoptosis-related speck-like protein
(ASC) and the effector protease caspase-1. Assembly
of the inflammasome complex occurs in response to
pathogen- or damage-associated molecular patterns.
PRRs have several subgroups, such as toll-like recep-
tors (TLRs), C-type lectin receptors (CLRs), RIG-I
like receptor (RLR), AIM2-like receptor (ALR) and
nucleotide-binding oligomerization domain-like
receptors (NLRs). Among the NLRs, nucleotide
oligomerization domain-like (NOD-like) receptor
family pyrin domain 3 (NLRP3) is the most exten-
sively studied and is a multiprotein platform whose
activation leads to caspase-1-dependent secretion of
proinflammatory cytokines, such as interleukin-1b
(IL-1b) and IL-18. Mitochondria play a pivotal
role in NLRP3 inflammasome activation.
Mitochondrion-derived molecules, mitochondrial
ROS (mtROS), oxidized mtDNA and cardiolipin,
contribute to NLRP3 inflammasome activation [8].
Mitochondrial antiviral signaling protein (MAVS),
which is involved in regulating the production of
type I IFN, associates with NLRP3, thereby recruit-
ing NLRP3 to mitochondria [9]. Recently, Pim-1, a
serine/threonine kinase, was revealed to regulate the
NLRP3 inflammasome in podocytes of lupus neph-
ritis [10]. Moreover, NLRP3 inflammasome activa-
tion plays a crucial role in the pathogenesis of
rheumatoid arthritis (RA), systemic sclerosis (SSc)
and inflammatory bowel diseases (IBD) [11]. In
these autoimmune diseases, mitochondrial compo-
nents might play a crucial role in their pathophysi-
ology through activating NLRP3 inflammasome.
2.2. Microparticles containing mitochondrial
components detected as foreign antigens
Mitochondrial components such as mtDNA can
move to the cytosol through mitochondrial perme-
ability transition pores (mPTP) and act as intracellu-
lar antigens [12]. It remains unclear how
mitochondria-derived components are detected as
foreign antigens. Generally, cells rearrange the cyto-
skeleton and package intracellular components into
small vesicles and secrete them into the circulation.
These microparticles (MPs) are 100–1000 nm in
diameter, larger than exosomes. MPs carry a wide
IMMUNOLOGICAL MEDICINE 143
variety of cytoplasmic and nuclear components,
including DNA and RNA. Large MPs (approxi-
mately 3000 nm) containing mitochondrial mole-
cules (mitoMPs) can be elevated in the blood and
are associated with major SLE features in SLE
patients. This indicates mitoMPs play an important
role in SLE pathogenesis [13].
2.3. Toll-like receptor (TLR) 9 and cGAS-STING
signaling activated by mtDNA
Toll-like receptor (TLR) 9 is one of the PRRs that
recognizes unmethylated CpG DNA originating
from bacteria, viruses or mtDNA. mitoMPs trans-
ported to endosomes are detected by TLR9 and sub-
sequently induce the production of proinflammatory
cytokines through MyD88-NF-jB signaling or type I
IFNs in plasmacytoid dendritic cells (pDCs). In add-
ition, mtROS and mtDNA induce the formation of
neutrophil extracellular traps (NETs), and a TLR9
antagonist was reported to prevent NETosis in
human neutrophils [14]. NETs are also important
for SLE pathogenesis by releasing nuclear antigens
outside of cells.
DNA released to the cytosol is detected by cyclic
GMP-AMP synthase (cGAS) that is linked to stimu-
lator of interferon genes (STING), a DNA sensor in
the cytosol. It induces the expression of IFN-b and
IFN-stimulated genes through IFN regulatory factor
3 (IRF3) phosphorylation. mtDNA can also induce
type I IFN production through the cGAS/STING
pathway [15] and oxidized mtDNA is associated
with SLE pathogenesis through type I IFN induction
in a cGAS/STING dependent manner [16]. In add-
ition, STING-gain-of-function mutations induced
IFN-b1 in vitro [17]. The STING mutations discov-
ered in patients with lupus-like syndromes and
autoinflammatory disease are called STING-associ-
ated vasculopathy with onset in infancy (SAVI).
3. Metabolic regulation by mitochondria in
immune cells
Mitochondria have fundamental roles in regulating
metabolic pathways through glucose oxidation as
well as the biosynthesis of fatty acids, amino acids
and hormones. Tight control of mitochondrial func-
tions and dynamics is critical for maintaining
homeostasis of the immune system. Historically,
metabolic regulation of immune cells has been
extensively investigated in CD4 T cells and mono-
cytes. The regulation of metabolism in other
immune cell subsets is important for their survival,
proliferation and activation [3,18]. In addition,
mtROS predominantly produced by OXPHOS and
the electron transport chain (ETC) can regulate
144 Y. IWASAKI ET AL.
diverse environmental and pathological stimuli.
Excessive production of ROS is observed in various
disease conditions including autoimmune diseases.
3.1. Activation and functional changes of
immune cells by regulating metabolism
Metabolic regulation in monocytes/macrophages has
long been investigated. M1 macrophages, inflamma-
tory macrophages, depend on glycolysis for the pro-
duction of ATP. The induction of nicotinamide
adenine dinucleotide phosphate (NADPH) synthesis
is achieved through the pentose phosphate pathway
(PPP). ROS is produced through catabolizing
NADPH by NADPH oxidase functions, and it pre-
vents infection. M2 macrophages, which contribute
to tissue repair and release the anti-inflammatory
cytokine IL-10, reportedly depend on OXPHOS and
fatty acid oxidation to produce energy [19].　
In activated CD4þ T cells, the metabolic shifts
from OXPHOS to aerobic glycolysis, the PPP and
glutaminolysis have been investigated in detail [20].
Overexpression of glucose transporter type 1
(GLUT1), the expression of which is upregulated by
T-cell receptor (TCR) stimulation under hypoxia,
causes an autoimmune phenotype in mice
[21,22].　 Sanroque mice (Roquinsan/san) present a
lupus-like phenotype because of Inducible
Costimulator (ICOS) overexpression. In this setting,
metformin, an ETC inhibitor, suppresses Th17 cell
differentiation and promotes regulatory T cell
(Treg) differentiation. It also prevents germinal cen-
ter B cell (GCB) and plasma cell differentiation
through activation of the AMP-activated protein
kinase (AMPK)-mTOR pathway [23]. Tregs are
necessary for the maintenance of immuno-tolerance
and homeostasis. The suppressive function of Tregs
in mice was shown to be impaired by the deficiency
of mitochondrial complex III, 1 of the 5 protein
complexes in the inner mitochondrial membrane,
the main source of ATP in a cell [24]. Mice lacking
complex III in Tregs displayed a loss of T cell-sup-
pression capacity without altering Treg proliferation
and survival. Increased DNA methylation and the
metabolites 2-hydroxyglutarate (2-HG) and succin-
ate in these Tregs inhibited the ten-eleven transloca-
tion (TET) family of DNA demethylases.
Mitochondrial complex III in Tregs was critical for
maintaining immune regulatory gene expression and
suppressive function.
Unlike T lymphocytes, in B cells both OXPHOS
and aerobic glycolysis are upregulated during cell
activation. The importance of metabolic regulation
of B cells was suggested by the following observa-
tions. First, in B cells deficient for TNF receptor-
associated factor 3 (TRAF3), which is a negative
regulator of multiple B cell functions, there is an
increased survival rate due to upregulated expres-
sion of Glut1 and hexokinase 2 (Hk2). The latter
phosphorylates glucose to produce glucose-6-phos-
phate (G6P) in the first step of glucose metabolism
[25]. Moreover, in our own transcriptomic analysis
of immune cell subsets in peripheral blood mono-
nuclear cells, the OXPHOS signature in memory B
cells appears to be a key player in SLE pathogenesis
(unpublished data). B cells chronically stimulated by
B-cell activating factor, a member of the tumor
necrosis factor family (BAFF), an important cyto-
kine for SLE pathogenesis, were metabolically
reprogrammed, resulting in upregulated glycolysis
and enhanced antibody production [26]. Moreover,
the survival of long-lived plasma cells relies on
pyruvate imported into mitochondria [27].
In activated dendritic cells, glucose uptake and
lactate production are elevated through glycolysis, as
observed in M1 macrophage. However, metabolites
from glycolysis are utilized for fatty acids synthesis
and ATP production, a process dependent on
OXPHOS [28]. Plasmacytoid dendritic cells (pDCs),
the main type I IFN-producing cells, are important
for SLE pathogenesis and are known to be metabol-
ically reprogrammed by an autocrine type I IFN
receptor-dependent pathway. Such autocrine type I
IFN signaling is characterized by increased fatty acid
oxidation (FAO) and OXPHOS for full pDC activa-
tion [29], suggesting that the inhibition of FAO and
OXPHOS might allow the amelioration of type I
IFN-related diseases, such as SLE.
3.2. Immune system affected by mitochondrial
reactive oxygen species (mtROS)
Mitochondria have a key role in oxygen metabolism
and are the major contributor to ROS formation.
ROS are important to many physiological processes,
such as aging, cancer and type 2 diabetes mellitus
[5,30,31]. mtROS in peripheral blood mononuclear
cells from SLE patients induced mitochondrial anti-
viral signaling (MAVS) oligomerization resulting in
the induction of type I IFN [32]. Mitochondrial
hyperpolarization and elevated mtROS production
have been observed in T cells from SLE patients
[33]. mito TEMPO, the mitochondria-targeted
superoxide dismutase mimetic with superoxide scav-
enging properties, was able to prevent inflamma-
some-dependent IL-1b production in human
macrophages, suggesting the importance of mtROS
in macrophage activation [34]. In B cells, mtROS
promoted class switch recombination and sup-
pressed plasma cell differentiation by attenuating
heme synthesis [35]. mtROS provides signals for
 IMMUNOLOGICAL MEDICINE 145

various cell fate/state determinations and functions
as regulators of the immune system.
4. Concluding remarks
Mitochondria are critical organelles that regulate the
immune system. That is, they regulate signaling
pathways and cell fate in both innate and adaptive
immune cells through their control of metabolic
states as well as mtROS production. Mitochondria
are also a source of immunogenicity following their
loss of integrity. Mitochondrial dysfunction can acti-
vate NLRP3 inflammasomes in immune cells [36]
and NLRP3 activation is important for pathogenesis
and development of autoimmune diseases (Figure 1
and Table 1). Metabolic regulation in each immune
cell subset reviewed in this article is summarized in
Table 2.

Figure 1. Mitochondrial regulation on immune system. Figures were prepared using BioRender (http://www.biorender.com)
and modified from Sack [37].

Table 1. Role of mitochondrial components in immune responses and related autoimmune diseases.
Mitochondrial components Reported roles in immune responses Related autoimmune diseases
mtDNA secreted as DAMPs detected by TLR9, Inducers of NETs, NLRP3 SLE, SAVI(STING mutation)
mitoMPs, inflammasome activationa, & Activation of cGAS/
oxidized mtDNA STING pathway.
mtROS NLRP3 inflammasome activation, Inducers of NETs, MAVS SLE (especially T cells), Dermatomyositis,
oligomerization, Macrophage activation, Promotion of class Sjӧgren syndrome
switch recombination and suppression on plasma cell
differentiation.
ATP, succinate, cardiolipin, DAMPs produced by mitochondria.
TFAM
Cardiolipin NLRP3 inflammasome activation.
MAVS Recruite NLRP3 inflammasome to mitochondria.
Pim-1 Important for preserving mitochondrial morphology, related Lupus nephritis
to NLRP3 inflammasome activation.
a
NLRP3 inflammasome activation is also related to RA, SSc, and IBD.

Table 2. Metabolic regulation in immune cell subsets.

Immune cell type Reported metabolic regulation Related experimental reports
CD4þ T cell Shift from OXPHOS to aerobic glycolysis, PPP, and glutaminolysis Overexpression of Glut1 causes an
on activation. autoimmune phenotype in mice.
Th17 cell ETC is important for differentiation. Metformin, ETC inhibitor, suppresses its
differentiation in Sanroque mice.
Treg ETC complex III is critical for regulatory gene expression,
suppressive function.
B cells Both OXPHOS and aerobic glycolysis upregulated on activation. Upregulation of Glut1 and Hk2 contributes to
its survival rate.
GCB and plasma cell ETC is important for their differentiations. Metformin prevents their differentiations
through activation of AMPK/mTOR pathway.
Long-lived plasma cell Survival dependence on pyruvate imported to mitochondria.
M1 macrophage Aerobic glycolysis-dependent energy (ATP) production. NADPH
synthesis through PPP is important for their ROS production.
M2 macrophage OXPHOS and fatty acid oxidation (FAO)-dependent production
of ATP.
Dendritic cell Upregulated aerobic glycolysis on activation. Metabolites
produced through glycolysis are utilized for FAO and
ATP production.
pDC Activation is dependent on increased FAO and OXPHOS induced
by autocrine IFN signaling.
146 Y. IWASAKI ET AL.
It is notable that the precise mechanism underly-
ing the cross-talk between metabolic regulation and
ROS production in mitochondria remains unclear.
Moreover, the approaches to analyzing the mutual
metabolic regulation among various immune cell
subsets remain a challenge for future research.
Finally, it will be necessary to investigate the contri-
butions of mitochondria to immune system regula-
tion by using purified human immune cell samples
to fully understand the mechanisms underlying vari-
ous human autoimmune diseases.
Disclosure statement
No potential conflict of interest was reported by
the author(s).
References
[1] Lai Z-W, Hanczko R, Bonilla E, et al. N -acetylcys-
teine reduces disease activity by blocking mamma-
lian target of rapamycin in T cells from systemic
lupus erythematosus patients: a randomized, dou-
ble-blind, placebo-controlled trial. Arthritis
Rheum. 2012;64(9):2937–2946.
[2] Spinelli JB, Haigis MC. The multifaceted contribu-
tions of mitochondria to cellular metabolism. Nat
Cell Biol. 2018;20(7):745–754.
[3] Takeshima Y, Iwasaki Y, Fujio K, et al.
Metabolism as a key regulator in the pathogenesis
of systemic lupus erythematosus. Semin. Arthritis
Rheum. 2019;48(6):1142–1145.
[4] Meyer A, Laverny G, Allenbach Y, et al. IFN-
b-induced reactive oxygen species and mitochon-
drial damage contribute to muscle impairment and
inflammation maintenance in dermatomyositis.
Acta Neuropathol. 2017;134(4):655–666.
[5] Pagano G, Castello G, Pallard o FV. Sjøgren’s syn-
drome-associated oxidative stress and mitochon-
drial dysfunction: Prospects for chemoprevention
trials. Free Radic. Res. 2013;47(2):71–73.
[6] Breda C. N d S, Davanzo GG, Basso PJ, et al.
Mitochondria as central hub of the immune sys-
tem. Redox Biol. 2019;26:101255.
[7] Becker Y, et al. Anti-mitochondrial autoantibodies
in systemic lupus erythematosus and their associ-
ation with disease manifestations. Sci Rep. 2019;9:
1–16.
[8] Liu Q, Zhang D, Hu D, et al. The role of mito-
chondria in NLRP3 inflammasome activation. Mol
Immunol. 2018;103:115–124.
[9] Park S, Juliana C, Hong S, et al. The mitochon-
drial antiviral protein MAVS associates with
NLRP3 and regulates its inflammasome activity. JI.
2013;191(8):4358–4366.
[10] Fu R, Xia Y, Li M, et al. Pim-1 as a therapeutic
target in lupus nephritis. Arthritis Rheumatol.
2019;71(8):1308–1318.
[11] Shen H-H, Yang Y-X, Meng X, et al. NLRP3: a
promising therapeutic target for autoimmune dis-
eases. Autoimmun Rev. 2018;17(7):694–702.
[12] Bernardi P, Rasola A, Forte M, et al. The mito-
chondrial permeability transition pore: channel
formation by F-ATP synthase, integration in signal
transduction, and role in pathophysiology. Physiol
Rev. 2015;95(4):1111–1155.
[13] Mobarrez F, Fuzzi E, Gunnarsson I, et al.
Microparticles in the blood of patients with SLE:
size, content of mitochondria and role in circulat-
ing immune complexes. J. Autoimmun. 2019;102:
142–149.
[14] Itagaki K, Kaczmarek E, Lee YT, et al.
Mitochondrial DNA released by trauma induces
neutrophil extracellular traps. PLoS One. 2015;
10(3):e0120549.
[15] West AP, Shadel GS. Mitochondrial DNA in
innate immune responses and inflammatory path-
ology. Nat Rev Immunol. 2017;17(6):363–375.
[16] Lood C, Blanco LP, Purmalek MM, et al.
Neutrophil extracellular traps enriched in oxidized
mitochondrial DNA are interferogenic and con-
tribute to lupus-like disease. Nat Med. 2016;22:
146–153.
[17] Liu Y, Jesus AA, Marrero B, et al. Activated
STING in a vascular and pulmonary syndrome. N
Engl J Med. 2014;371(6):507–518.
[18] Lightfoot YL, Blanco LP, Kaplan MJ. Metabolic
abnormalities and oxidative stress in lupus. Curr
Opin Rheumatol. 2017;29(5):442–449.
[19] Kelly B, O’Neill LA. Metabolic reprogramming in
macrophages and dendritic cells in innate immun-
ity. Cell Res. 2015;25(7):771–784.
[20] Maciolek JA, Alex Pasternak J, Wilson HL.
Metabolism of activated T lymphocytes. Curr.
Opin. Immunol. 2014;27:60–74.
[21] Jacobs SR, Herman CE, MacIver NJ, et al. Glucose
uptake is limiting in T cell activation and requires
CD28-mediated Akt-dependent and independent
pathways. J Immunol. 2008;180(7):4476–4486.
[22] Cretenet G, Clerc I, Matias M, et al. Cell surface
Glut1 levels distinguish human CD4 and CD8 T
lymphocyte subsets with distinct effector functions.
Sci Rep. 2016;6:24129.
[23] Lee S-Y, Moon S-J, Kim E-K, et al. Metformin
suppresses systemic autoimmunity in Roquin san/
san mice through inhibiting B cell differentiation
into plasma cells via regulation of AMPK/mTOR/
STAT3. JI. 2017;198(7):2661–2670.
[24] Weinberg SE, Singer BD, Steinert EM, et al.
Mitochondrial complex III is essential for suppres-
sive function of regulatory T cells. Nature. 2019;
565(7740):495–499.
[25] Liu YH, et al. Quantitative PPARc expression
affects the balance between tolerance and immun-
ity. Sci. Rep. 2016;6:1–13.
[26] Caro-Maldonado A, Wang R, Nichols AG, et al.
Metabolic reprogramming is required for antibody
production that is suppressed in anergic but exag-
gerated in chronically BAFF-exposed B cells. JI.
2014;192(8):3626–3636.
[27] Lam WY, Becker AM, Kennerly KM, et al.
Mitochondrial pyruvate import promotes long-
term survival of antibody-secreting plasma cells.
Immunity. 2016;45(1):60–73.
[28] Everts B, Amiel E, Huang SC, et al. TLR-driven
early glycolytic reprogramming via the kinases
TBK1-IKKe supports the anabolic demands of
dendritic cell activation. Nat Immunol. 2014;15:
323–332.
[29] Wu D, Sanin DE, Everts B, et al. Type 1 interfer-
ons induce changes in core metabolism that are

critical for immune function. Immunity. 2016;
44(6):1325–1336.
[30] Reuter S, Gupta SC, Chaturvedi MM, et al.
Oxidative stress, inflammation, and cancer: how
are they linked? Free Radic. Biol. Med. 2010;
49(11):1603–1616.
[31] Elmarakby AA, Sullivan JC. Relationship between
oxidative stress and inflammatory cytokines in dia-
betic nephropathy. Cardiovasc. Ther. 2012;30(1):
49–59.
[32] Buskiewicz IA, Montgomery T, Yasewicz EC, et al.
Reactive oxygen species induce virus-independent
MAVS oligomerization in systemic lupus erythe-
matosus. Sci Signal. 2016;9(456):ra115–ra115.
[33] Gergely P, Niland B, Gonchoroff N, et al.
Persistent mitochondrial hyperpolarization,
increased reactive oxygen intermediate production,
IMMUNOLOGICAL MEDICINE 147
and cytoplasmic alkalinization characterize altered
IL-10 signaling in patients with systemic lupus
erythematosus. J Immunol. 2002;169(2):1092–1101.
[34] Traba J, Kwarteng-Siaw M, Okoli TC, et al.
Fasting and refeeding differentially regulate NLRP3
inflammasome activation in human subjects. J Clin
Invest. 2015;125(12):4592–4600.
[35] Jang K-J, Mano H, Aoki K, et al. Mitochondrial
function provides instructive signals for activation-
induced B-cell fates. Nat Commun. 2015;6:6750.
[36] Sadatomi D, Nakashioya K, Mamiya S, et al.
Mitochondrial function is required for extracellular
ATP-induced NLRP3 inflammasome activation. J.
Biochem. 2017;161:503–512.
[37] Sack MN. Mitochondrial fidelity and metabolic
agility control immune cell fate and function. J
Clin Invest. 2018;128:3651–3661.