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Nat Rev Rheumatol. Author manuscript; available in PMC 2018 May 01.
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Published in final edited form as:

Nat Rev Rheumatol. 2017 May ; 13(5): 313–320. doi:10.1038/nrrheum.2017.54.

Fine tuning of immunometabolism for the treatment of rheumatic

diseases
Jillian P. Rhoads,
Division of Molecular Pathology, Department of Pathology, Microbiology, and Immunology,
Vanderbilt University Medical Center, 1161 21st Avenue South, Nashville, Tennessee 37232, USA

Amy S. Major, and

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Division of Molecular Pathology, Department of Pathology, Microbiology, and Immunology,

Vanderbilt University Medical Center; the Division of Rheumatology and Immunology, Department
of Medicine, Vanderbilt University Medical Center; and the Vanderbilt Center for Immunobiology,
Vanderbilt University School of Medicine, 1161 21st Avenue South, Nashville, Tennessee 37232,
USA

Department for Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee
37232, USA

Jeffrey C. Rathmell
Division of Molecular Pathology, Department of Pathology, Microbiology, and Immunology, and the
Vanderbilt Center for Immunobiology, Vanderbilt University School of Medicine, 1161 21st Avenue
South, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA
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Abstract
All immune cells depend on specific and efficient metabolic pathways to mount an appropriate
response. Over the past decade, the field of immunometabolism has expanded our understanding
of the various means by which cells modulate metabolism to achieve the effector functions
necessary to fight infection or maintain homeostasis. Harnessing these metabolic pathways to
manipulate inappropriate immune responses as a therapeutic strategy in cancer and autoimmunity
has received increasing scrutiny by the scientific community. Fine tuning immunometabolism to
provide the desired response, or prevent a deleterious response, is an attractive alternative to
chemotherapy or overt immunosuppression. The various metabolic pathways used by immune
cells in rheumatoid arthritis, systemic lupus erythematosus and osteoarthritis offer numerous
opportunities for selective targeting of specific immune cell subsets to manipulate cellular
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metabolism for therapeutic benefit in these rheumatologic diseases.

Correspondence to J.C.R. [Link]@[Link].

Author contributions
All authors researched the data for the article, provided a substantial contribution to discussions of the content and contributed to
writing the article and to review and/or editing of the manuscript before submission.
Competing interests statement
The authors declare no competing interests.
 Rhoads et al. Page 2

Inflammatory and autoimmune diseases are driven by the activation and effector functions of
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both innate and adaptive immune cells. In addition to neutrophils and other cells involved in
acute inflammation, macrophages and dendritic cells are activated to promote T and B
lymphocyte responses in rheumatologic diseases such as systemic lupus erythematosus
(SLE)1 and rheumatoid arthritis (RA)2. Osteoarthritis (OA), although generally considered
non-inflammatory, can present with an inflammatory phenotype and the inflammatory
processes involved in this disease are increasingly recognized3. In each of these diseases,
inflammatory cytokines stimulate immune cells4 or monocyte-to-osteoclast differentiation to
promote autoimmunity or bone resorption and degradation5,6. Although these rheumatologic
diseases have unique characteristics, in each setting haematopoietic cells must be stimulated
to gain effector functions and differentiate. The signalling and gene expression changes that
accompany these cellular activation and differentiation events have been well studied, but it
is now apparent that the metabolism of disease-effector cells is also tightly regulated6–9.
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Each inflammatory cell, and even anti-inflammatory cell, undergoes metabolic

reprogramming upon activation and these changes are essential for disease. Therefore,
targeting the metabolic pathways involved offers a new avenue for potential treatment of
rheumatologic diseases. Because immunological functions are associated with specific
metabolic programmes, this approach affords the particularly attractive possibility that
inhibiting the appropriate pathway could lead to selective, cell-specific blockade. In this
Perspectives article, we discuss the various metabolic pathways used by immune cells to
attain optimal responses and explore the possibility and key principles of manipulating these
pathways for therapeutic benefit in rheumatologic diseases, with a focus on RA, SLE and
OA.

Cellular metabolic reprogramming

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Activation of immune cells leads to changes in metabolic pathways

Resting lymphocytes, macrophages and dendritic cells all use catabolic metabolic pathways
that switch to anabolic programmes after activation by antigens, cytokines or stimulation of
innate pattern-recognition receptors by pathogen-associated or damage-associated molecular
patterns (PAMPs and DAMPs, respectively)7. This switch supports resting cell survival and
immune surveillance as well as growth and effector function of stimulated cells. Resting T
cells take up glucose, amino acids and lipids at a low rate and flux these fuels through
glycolysis, glutaminolysis and fatty acid oxidation to maximize mitochondrial oxidative
metabolism7. This mode of metabolism generates maximal ATP and is associated with a
long T cell lifespan10–13. Given the need to maintain osmolarity through the sodium–
potassium ATPase and the energy demands of rapid chemotaxis and cytoskeletal
remodelling during this surveillance mode of resting lymphocytes14, it is not surprising that
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metabolism in resting immune cells is programmed to actively support the most efficient
ATP-generating processes.

Lymphocyte stimulation leads to abrupt changes in metabolic pathways in these cells.

Stimulation of T cells through the T cell receptor in conjunction with co-stimulation leads to
a sharp increase in glycolysis and glutaminolysis15–17 (FIG. 1). Simultaneously, activated T
cells decrease mitochondrial fatty acid oxidation in order to conserve lipids for new

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membrane synthesis18,19. Co-stimulatory signals have key roles in this transition; CD28
augments glucose uptake and glycolysis in activated T cells16, whereas inhibitory receptors,
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such as cytotoxic T-lymphocyte protein 4 (CTLA4) and programmed cell death protein 1
(PD-1), can decrease glycolysis and instead promote mitochondrial fatty acid
oxidation15,20–22. In part, these regulators act through control of signalling via phosphatidyl-
inositol 3-kinase (PI3K), AKT and mechanistic target of rapamycin (mTOR)23. Resting B
cells undergo a similar metabolic shift upon activation. Stimulation of B cells through
antigen receptors or Toll-like receptors (TLRs) leads to upregulation of the glucose
transporter GLUT1 and glycolysis24,25. As in T cells, this metabolic reprogramming is
dependent on mTOR signalling, as deficiency of regulatory-associated protein of mTOR
(RAPTOR) and mTOR complex I (mTORC1) or alteration of the PI3K pathway disrupts B
cell development and activation, and can impair class-switching in germinal centres26–28.
Ultimately, as an immune response ceases, memory lymphocytes revert to oxidative
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pathways that are essential to enabling persistence of memory and robust secondary
responses10,12. Memory lymphocytes can, however, retain enhanced metabolic features that
facilitate rapid and strong secondary responses29,30.

Dendritic cells and macrophages differ from lymphocytes in that proliferation is not as
important a cellular goal following activation. The ability to mature and gain effector
function (including the differentiation of monocytes into osteoclasts) is, however, essential
for these cells. Macrophages and dendritic cells are activated in response to PAMPs and
DAMPs, including TLRs, and this activation increases glycolysis to promote inflammatory
function and maturation31–35. TLR signalling through serine/threonine-protein kinase TBK1
leads to AKT activation and mTORC1 signalling to promote this glycolytic switch36–38.
Increased glycolysis both promotes inflammation and can enhance ‘trained immunity’, a
process that, although not specific in the same way as adaptive immune responses, can lead
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to improved secondary innate responses32,39. In addition to enabling enhanced biosynthesis

of effector molecules and cytokines, this metabolic reprogramming supports the growth of
essential cell structures, such as the endoplasmic reticulum and Golgi37, which have critical
roles in the cell biology of effector function.

Metabolic programmes are specific for immune cell subsets and functions
A critical aspect of the metabolic reprogramming events described above is that they are not
uniform in a given cell type, but instead utilize specific pathways that are essential for
particular cell subsets and functions (FIG. 1). This specificity was first demonstrated in
classical ‘M1’ macrophages and alternatively activated ‘M2’ macrophages, in which
activation with IL-4 led to a peroxisome proliferator-activated receptor γ co-activator 1-β
(PGC1β)-dependent increase in oxidative metabolism that contrasted with the more
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glycolytic metabolism of macrophages activated by IFNγ and the TLR4 ligand

lipopolysaccharide40. Indeed, these metabolic pathways were linked to the functions of the
cells, as promoting increased glucose uptake by GLUT1 expression enhanced
proinflammatory macrophage activity35, whereas promoting mitochondrial lipid oxidative
pathways stimulated anti-inflammatory macrophage function40,41.

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Although OA is characterized by subchondral sclerosis42, inflammation and innate

immunity can contribute substantially to disease pathogenesis3. The differentiation of
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monocytes/macrophages into osteoclasts that contribute to inflammation in OA also depends

on specific metabolic programmes. In particular, hypoxia and the hypoxia-inducible factors
HIF-1α and HIF-2α promote osteoclast differentiation43,44. Increased lactic acid, which can
suppress glycolysis, also promotes generation of osteoclasts45. Together, these findings
support the model that different macrophage-derived subsets have distinct metabolic
programmes that promote, and are intimately linked to, cell function and fate.

Subsequent to these early studies in macrophages, T cell subsets were also found to utilize
distinct metabolic programmes46, with particular differences noted between regulatory T
(Treg) cells and CD4+ effector subsets, including type 1 T helper (TH1), TH2, and TH17
cells19,46,47. Effector T cells are largely glycolytic downstream of mTOR signals48 that
differentially affect specific CD4 subsets through mTORC1 or mTORC2 (REF. 49), whereas
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Treg cells preferentially utilize a mitochondrial oxidative metabolism consisting of lipid and
pyruvate oxidation19,46,47. Indeed, whereas lipid synthesis is required for TH17 cells, and
overproduction of lipids can lead to T cell phenotypes associated with autoimmunity50, lipid
oxidation promotes Treg cell differentiation51. This alternative metabolic programme is
regulated by the Treg cell transcription factor FOXP3 (REFS 52,53) as well as by PGC1α
and hSIRT3 (also known as NAD-dependent protein deacetylase sirtuin-3, mitochondrial)54.
In vivo, effector T cells depend on GLUT1 (REF. 55) as well as the amino acid transporters
solute carrier family 1 member 5 (SLC1A5, also known as ASCT2 or neutral amino acid
transporter B(0))56 and solute carrier family 7 member 5 (SLC7A5, also known as large
neutral amino acids transporter small subunit 1 or LAT1)57, whereas Treg cells can function
independently of these transporters55–57. Treg cells can, however, initiate glycolysis, in a
manner dependent on mTORC1 activation for proliferation58–60 following activating or
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inflammatory signals52. Increased glycolysis in Treg cells augmented proliferation but also
reduced the suppressive capacity of these cells52. This switch between maximal Treg cell
proliferation or suppressive capacity was controlled in part by the PI3K–AKT–mTORC1
pathway, and constitutive activation of AKT or mTORC1 led to accumulation of poorly
suppressive Treg with low phenotypic stability52,61–63. Tight regulation of mTOR activity is
thus required for Treg cell function. In other CD4+ T cell subsets, such as T follicular helper
cells, metabolism seems to be more balanced and relies on both glycolysis and oxidative
phosphorylation64,65. Metabolism in macrophages and dendritic cells is also regulated by
mTORC1 and mTORC2 signalling66,67. In particular, signalling through mTORC1 can
promote glycolysis, which can enhance M1 macrophage activation35,41,66, whereas M2
macrophages utilize oxidative metabolism that is regulated by signal transducer and activator
of transcription 6 (STAT6) and PGC1β40. Inhibition of mTOR kinase can, therefore, alter
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macrophage metabolism and might affect macrophage subsets.

Immunometabolism in disease
Chronic encounters with autoantigens and inflammatory signals can sharply alter
immunometabolism in ways that differ from the response to acute stimulation. Indeed,
chronic viral infections diminished glucose metabolism in T cells68. Alterations in

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immunometabolism in inflammatory diseases reveals insight into disease processes and

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potential therapeutic targets.

Systemic lupus erythematosus

Metabolomics analyses of sera from patients with SLE have revealed a variety of
considerable alterations in metabolites and metabolic pathways that correlate with disease
activity and manifestations69–71. Although serum metabolites can be affected by multiple
cell types and tissues, several metabolic pathways have been shown to differ between T cells
of healthy individuals and patients with SLE, and between healthy and lupus-prone animals.
Mitochondrial glucose oxidation can be increased72 and mitochondria have been shown to
be hyperpolarized in chronically activated T cells in SLE73,74. Persistent mitochondrial
hyperpolarization leads to production of reactive oxygen species (ROS), which can sensitize
T cells to necrosis, leading to the release of self-antigens and perpetuation of the
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autoimmune response75. The Sle1c locus conferred chronic CD4+ T cell activation in the
NZB mouse model of lupus76. This locus can be further divided, and the Sle1c2
susceptibility locus contains only two genes, one of which, Esrrg, encodes oestrogen-related
receptor γ (ERRγ), a nuclear receptor that regulates oxidative phosphorylation and
mitochondrial function. Studies by Perry et al. in CD4+ T cells from mice expressing the
Sle1c2 locus showed decreased mitochondrial mass and chronic mitochondrial
hyperpolarization compared with wild-type CD4+ T cells77. Interestingly, B6.Sle1c2 CD4+
T cells produced more IFNγ than controls. Increased proliferation and activation of
B6.Sle1c2 CD4+ T cells could be attributable to decreased expression of ERRγ — in breast
cancer cells, a decrease in levels of ERRγ led the cells to undergo aerobic glycolysis and
expend ATP78. Although Perry et al.77 did not demonstrate that decreased Essrg expression
in Sle1c2 CD4+ T cells, or the effects of this decrease on mitochondrial function, were
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directly responsible for increased TH1 skewing, studies have shown that increased glycolysis
due to overexpression of GLUT1 in CD4+ T cells increases IFNγ production16. Most
importantly, the studies in B6.Sle1c2 mice further confirm a role for mitochondrial
metabolism in rheumatologic diseases and suggest that altered T cell metabolism is, in part,
genetically programmed.

In addition to changes in glucose metabolism, CD4+ T cells from patients with SLE also
display defects in lipid metabolism. T cells from these patients show increased levels of
glycosphingolipids and cholesterol, as well as increased expression of the nuclear receptor
oxysterols receptor LXRβ (also known as liver X receptor β), which has a role in cellular
lipid metabolism and trafficking79,80. Treatment of CD4+ T cells from patients with SLE
with an LXR antagonist led to decreased glycosphingolipid production, and blockade of
glycosphingolipid biosynthesis in these cells restored normal T cell function50.
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Whole-body metabolism can also be affected in SLE, which could influence autoimmunity.
Although the underlying mechanisms are poorly understood, patients with SLE had
significantly elevated fasting levels of insulin, indicating a predilection for insulin resistance
and metabolic disease81. This phenomenon was recapitulated in a mouse model of lupus
whereby B6.Sle1.Sle2.Sle3 mice spontaneously developed glucose intolerance without
being fed a high-fat diet82. Whereas immune dysfunction might contribute directly to the

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sequelae of metabolic syndrome, such as atherosclerosis83, altered metabolic hormones and

lipids can also modulate immunity, promoting B cell dysfunction82 and effector T cell
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differentiation and function84–86.

Rheumatoid arthritis
Chronic stimulation and the synovial microenvironment alters T cell metabolism in RA. T
cells of patients with RA have reduced expression of 6-phosphofructo 2-kinase/fructose-2,
6-bisphosphatase 3 (PFKFB3)87. This enzyme is a key regulator of fructose-2, 6-
bisphospate, the allosteric activator of phospho fructokinase, and lower PFKFB3 will lower
glycolysis while increasing flux to the pentose phosphate pathway and generation of
NADPH7,87. Elevated NADPH can neutralize ROS, which, although damaging at high
concentrations, are otherwise essential to promote T cell activation88. Indeed, restoration of
T cell ROS could suppress synovial inflammation89. In addition to direct changes in T cells,
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the hypoxic environment in the RA synovium90 creates a situation similar to the chronic
mitochondrial hyper-polarization seen in SLE. The formation of the synovial pannus
restricts the availability of oxygen to infiltrating immune cells, which might contribute to
altered glucose and mitochondrial metabolism90.

Osteoarthritis
Altered metabolism contributes to OA but the underlying mechanisms are less firmly
established than in SLE or RA. Nevertheless, increased glucose uptake, as determined
by 18F-fluorodeoxyglucose PET imaging, correlated with OA progression91. The hypoxic
environment of the OA synovium might promote osteoclast differentiation and function9.
Furthermore, metabolic syndrome can exacerbate OA92, and advanced glycation end
products (AGEs) can activate the AGE-specific receptor (RAGE) to impair osteoblast growth
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and function and promote receptor activator of NF-κB ligand (RANKL, also known as TNF
ligand superfamily member 11) and osteoclastogenesis92,93. Indeed, chondrocyte-
synthesized RANKL might promote bone destruction in OA94. The role for mitochondria in
osteoclast differentiation was established by genetic deletion of a component of electron
transport complex I, Ndufs4, in mice. Deletion of Ndufs4 led to greater differentiation of
precursor cells into macrophages rather than osteoclasts95, supporting a model in which
mitochondrial oxidative metabolism promotes osteoclastogenesis. This balance is
complicated, with oxidative metabolism seemingly important for osteoclast differentiation
and glycolysis seemingly important for bone resorption96.

Targeting immunometabolism
Rationale for targeting immunometabo-lism in rheumatologic diseases
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Given the metabolic changes associated with immune cell activation and function, as well as
the altered metabolism of T cells, macrophages and dendritic cells in rheumatologic
diseases, a key question is to what extent is it possible to target metabolism with new
therapies? The observation of aerobic glycolysis (the Warburg effect) in cancer cells has led
to cell metabolism being considered an attractive potential target for cancer treatment for a
number of years97. However, the effects of strategies directly inhibiting metabolic pathways
have been disappointing or generally modest97. One very important difference between

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successful cancer therapies and successful therapies to control inflammatory diseases is that
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cancer cells must be fully eliminated, whereas simply halting effector function would be
sufficient in immunologic diseases. When targeting immunometabolism in autoimmunity,
therefore, blocking a metabolic pathway to the extent that apoptosis is induced is not
necessary98. Rather, it is essential only to impair a pathway sufficiently so as to alter specific
cell functions. A variety of pathways could, in principle, be targeted to modulate an immune
response. Effector T cells, for example, require high rates of glycolysis and amino acid
uptake, whereas Treg cells are less dependent on or can even be independent of these
pathways55–57. Therefore, it is reasonable to hypothesize that inhibition or modulation of
glycolytic pathways could shift the balance of effector and regulatory T cell subsets to
provide a favourable outcome in autoimmune disorders. Each of these pathways has multiple
metabolic steps and specific enzymes or nutrient transporters amenable to pharmacologic
intervention.
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Principles of targeting immunometabolism in rheumatologic diseases

Several key principles will dictate approaches to pharmacologic modulation of
immunometabolism in rheumatologic diseases (BOX 1). For example, unlike kinase
signalling pathways, metabolic pathways are not generally amplificatory and weak inhibitors
might be most useful. With kinases, the potential for exponential expansion of signalling
cascades typically makes it essential to inhibit the vast majority of kinase activity to elicit a
functional effect. Metabolic pathways, by contrast, are limited by the levels of metabolites
and conservation of mass. Thus, modest inhibition of a kinase might achieve little, but
modest inhibition of a metabolic pathway could have a strong effect. This paradigm is
evident in the action of metformin, a weak inhibitor of mitochondrial electron transport
complex I99 that can nonetheless leads to multiple effects that modify cell function and
survival, including reducing TH17 cells and osteoclasts in a model of RA100 and promoting
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Treg cell differentiation46,100. It stands to reason that this treatment strategy would also be
beneficial in other autoimmune disorders characterized by effector T cell dysregulation, such
as SLE. Additionally, specificity of a therapeutic approach targeting metabolic pathways can
arise not only from restricted expression of the target, but from the dependence of specific
cell populations on specific metabolic pathways. Ideally, a pharmacologic target would be
selectively expressed only in the target cell type. However, an equivalent outcome can be
achieved if the drug target is only essential in a specific population of cells. This seems to be
the case for many potential targets in immunometabolism. Such a strategy could be
employed by inhibiting HIF-1α to block the development of TH17 cells and promote Treg
cell differentiation in RA and OA. HIF-1α is specifically required for glycolysis in TH17
cells, and does not play a part in other T cell subsets. Thus, although fundamental metabolic
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pathways might be shared, the selective reliance of immune cell subsets or populations on
specific metabolic programmes renders those cell populations susceptible to inhibition.

Several strategies might be used to modulate immunometabolism in rheumatologic diseases.

In addition to targeting key metabolic regulatory signalling pathways, such as the mTOR
pathway48,49, or direct inhibition of metabolic events, such as nutrient uptake or enzyme
function, metabolic pathways could be modulated at bifurcation points in order to shift
metabolic flux from one pathway to another. Pyruvate metabolism might provide such a

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target. Two of the major fates of pyruvate are conversion to lactate by lactate dehydrogenase
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(LDH) or uptake into mitochondria to generate acetyl-CoA for oxidation by pyruvate

dehydrogenase (PDH). Inflammatory effector T cells favour pyruvate conversion to lactate,
whereas Treg cells favour pyruvate oxidation19. The flux of pyruvate towards lactate or
acetyl-CoA can be regulated by PDH kinase (PDHK) phosphorylation and the inhibition of
PDH. Thus, effector T cells utilize PDHK to maintain LDH-mediated conversion of
pyruvate to lactate. Inhibition of PDHK relieves PDH inhibition to promote pyruvate
conversion to acetyl-CoA and impairs effector T cell function while promoting Treg cell
differentiation. This strategy has shown promise in relieving inflammation and promoting
Treg cells in models of disease including collagen-induced arthritis101, asthma102,
alloreactivity103 and experimental autoimmune encephalitis (EAE)19.

Immunometabolic therapeutic targets

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There are many potential targets from which to choose to modulate autoimmunity and
improve rheumatologic disease outcomes. Some metabolic processes are already targeted by
standard of care treatments for these diseases. Methotrexate, for instance, has many modes
of action, including potential inhibition of Janus kinase (JAK)– STAT signalling104.
Inhibition of one-carbon metabolism (a network of pathways involved in amino acid
metabolism and nucleotide synthesis) by methotrexate might also have important inhibitory
functions on cell growth, redox balance and epigenetics105. Other key areas could also
provide focal points for new drug development (FIG. 2); indeed, several examples now exist
in which pharmacologic targeting of metabolism has had protective effects against immune-
mediated diseases. In an important proof-of-principle study, inhibition of T cell metabolic
pathways protected lupus-prone mice from disease: Yin et al. showed that treatment with the
non-metabolizable glucose analogue 2-deoxy-D-glucose (2-DG) plus metformin reversed
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cytokine and autoantibody production in an animal model of lupus106. Furthermore, in vitro

production of IFNγ by T cells from patients with SLE was normalized by metformin
treatment. The combination of 2-DG and metformin would suppress both glycolysis and
mitochondrial metabolism. The extent to which such dual metabolic inhibition might be
broadly necessary in the treatment of rheumatologic diseases is unclear, but the metabolic
plasticity of T cells might require this approach.

Beyond combinations of 2-DG and metformin, targeting amino acid metabolism could prove
a promising approach. One potential therapeutic strategy is inhibition of glutamine uptake
and metabolism. Glutamine is a non-essential amino acid that is used at high rates to support
anabolic metabolism and its uptake is rapidly increased during T cell activation via the
transporter SLC1A5 (REFS 56,107). Importantly, SLC1A5 deficiency attenuates TH1 and
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TH17 responses and prevents the onset of EAE in experimental mouse models56. The amino
acid transporter SLC7A5 is also essential for T cell activation57 by supporting amino acid
uptake essential for mTORC1 activity. Given the wide role of amino acids in anabolic
metabolism and intracellular signalling, mechanisms that regulate these pathways are
promising targets for modulation of immune cell function in inflammatory diseases.
Strategies to suppress glycolysis, mitochondrial metabolism and amino acid metabolism
could have far-reaching applications beyond autoimmunity. A 2015 study demonstrated that
the combination of 2-DG and metformin, with the addition of an inhibitor of glutamine

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metabolism, reduced rejection of skin allografts or heart transplants in mice whereas the
individual treatments had minimal effects108.
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Regulation of ROS is also critical for immunological function88, and mitochondrial ROS
production could be a target. Indeed, the F1F0-ATPase inhibitor Bz-423 (REF. 109) does not
block ATP production but rather leads to increased ROS and can protect against lupus and
graft-versus-host disease in animal models, in part by inducing lymphocyte apoptosis110,111.
PDHK1 can also regulate mitochondrial ROS via regulation of pyruvate flux into the TCA
cycle. Indeed, inhibition of PDHK1 led to increased ROS that promoted Treg cells and could
protect from EAE19. In addition, the mitochondrial ROS scavenger MitoQ reduced
mitochondrial anti-viral signalling (MAVS) activation and attenuated IFNγ production32,112.

A number of other metabolic events have promise as targets in rheumatologic diseases.

Given the role of hypoxia in RA and OA, targeting the stability of HIF-1α or HIF-2α and
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the hypoxic response might offer protection from multiple aspects of joint inflammation113.
Similarly, modulators of glycolysis, such as PFKFB3 (REF. 114) or LDH115, can suppress T
cell activation or regulate IFNγ production. With these approaches, direct inhibition of a
central carbon glucose metabolism pathway raises concerns of broad toxicity. However, in
the studies discussed above the effects in vivo were surprisingly modest. This outcome is
probably due to the partial inhibitory effect of each of these strategies and the selective
dependence on those pathways of metabolically active inflammatory cells.

Challenges and future directions

Immunometabolism offers the opportunity to selectively target specific immune cell subsets
by modifying the metabolic pathways essential for their function. This concept represents a
paradigm shift away from targeting specific signalling pathways that might be active in a
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wide range of cells. However, a concern is that although only selected cells might require
high fluxes through specific metabolic pathways, the extent to which other cell types might
also activate and periodically rely on those same pathways remains unclear. Adverse effects
of putative metabolic therapies are, therefore, critical challenges. This is particularly true for
chronic diseases, which can require long-term treatment. Proliferative or metabolic tissues,
such as the gut, liver, muscle and β cells, could be especially sensitive.

Despite these concerns, metabolic pathways are already being targeted, including by
standard-of-care therapies, and some metabolic therapies are already standard of care. Other
therapies certainly have metabolic implications that might contribute to their mechanisms of
action. Methotrexate, for example, inhibits one-carbon metabolism yet is standard-of-care
treatment for RA. Also, metabolic changes following inhibition of mTOR signalling
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certainly contribute to immune suppression48. A potential benefit of targeting

immunometabolism to modulate immunity is that the selective use of pathways by effector
or regulatory T cells or macrophages may enable short-term treatments to shift immune cell
populations and provide durable protection from inflammation and disease. Thus, a short
therapy period could provide benefit and reduce the potential for adverse effects. The
immunometabolism field is rapidly evolving and our increasing knowledge of the metabolic
pathways that promote effector and regulatory immune cell differentiation or the generation

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of osteoclasts might now provide rational strategies to exploit the metabolic requirements of
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each subset.

Acknowledgments
The authors would like to thank members of the Rathmell and Major labs for their contributions and intellectual
input. The authors’ work is supported by the Alliance for Lupus Research (J.C.R.), NIH National Institute of
Diabetes and Digestive and Kidney Diseases grant R01DK105550 (J.C.R.), the Lupus Research Alliance (A.S.M.),
U.S. Department of Veterans Affairs Merit Award I0BX002968 (A.S.M.) and NIH National Heart, Lung, and Blood
Institute grant F31 HL128040 (J.P.R.).

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Box 1
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Key principles in immunometabolism pharmacology

Specificity
A critical goal in targeting any pathway is specificity for a population of cells that drives
the disease phenotype. Because metabolic pathways are, in principle, shared between all
cells, target specificity is a concern when developing new therapies. However, despite
potentially shared expression of enzymes, specificity arises from the requirements of
immune cells to maintain high metabolic fluxes through specific pathways to elicit
specific functions.

Redundancy
Typically, multiple isoforms of each enzyme or multiple transporters for each nutrient
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exist. Only specific cell populations rely on a given enzyme isoform or transporter, so
inhibition of these proteins will affect only that particular population of cells.

Plasticity
Metabolic pathways can adapt to shifts in nutrient availability. Thus, blockade of a
specific pathway can simply elicit plasticity and many cells can adjust to bypass the
block or to utilize a different pathway. However, these changes in the cellular metabolic
programme can modify the function of immune cells. A shift in pathways that might be
insufficient to induce apoptosis or block proliferation might nevertheless shift the fate of
a T cell or macrophage to reduce or modify inflammatory function.

Partial inhibition
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Because metabolic pathways are limited by conservation of mass and, unlike kinase
signalling cascades, do not generally amplify, a partial inhibition can lead to a large
functional effect.

Durability of response
Concerns of adverse effects will be reduced if the fate of immune cells is shifted so as to
elicit durable responses to time-limited or episodic treatment.
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Figure 1. Metabolic reprogramming of immune cell populations matches immunological function

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Naive T cells, resting B cells and macrophages utilize a catabolic and oxidative metabolic
programme. After stimulation via antigen receptor with co-stimulation or through pattern-
recognition receptors such as Toll-like receptors (TLRs), these immune cells undergo
metabolic reprogramming. Effector lymphocytes or inflammatory macrophages induce an
anabolic meta bolic programme with highly increased nutrient uptake for glycolysis and
glutamine metabolism. Regulatory cells or alternatively activated macrophages, by contrast,
primarily utilize a programme of lipid and pyruvate oxidation. These programmes are

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important to the function of each subset; if the cellular metabolism does not match the cell
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fate, immune cells will fail to gain appropriate functional capacity. BCR, B cell receptor;
CTLA-4, cytotoxic T lymphocyte protein 4; HIF, hypoxia-inducible factor; mTOR,
mechanistic target of rapamycin; PD-1, programmed cell death protein 1; PGCla,
peroxisome proliferator-activated receptor γ co-activator 1-α; TCR, T cell receptor; Treg
cell, regulatory T cell.
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Figure 2. Metabolic processes to target in the treatment of rheumatologic diseases

Metabolic areas and key current or potential targets for drugs to modify immunometabolism
and shift immune cell subsets and fate are indicated. 2-DG, 2-deoxy-d-glucose; ASCT2,
solute carrier family 1 member 5; DCA, dichloroacetate; ETC, electron transport chain;
GLUT1, glucose transporter 1; HIF-1α, hypoxia-inducible factor 1α; HK, hexokinase;
LDHA, lactate dehydrogenase A; mTORC, mechanistic target of rapamycin complex;
PDHK1, pyruvate dehydrogenase kinase 1; PFKFB3. 6-Phosphofructo 2-kinase/
fructose-2,6-bisphosphatase 3.
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