Targeting Metabolism as a Novel Therapeutic

Approach to Autoimmunity, Inflammation,

and Transplantation
This information is current as Ian A. Bettencourt and Jonathan D. Powell
of June 4, 2020. J Immunol 2017; 198:999-1005; ;
doi: 10.4049/jimmunol.1601318
http://www.jimmunol.org/content/198/3/999

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References This article cites 69 articles, 30 of which you can access for free at:
http://www.jimmunol.org/content/198/3/999.full#ref-list-1

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 The Journal of
Brief Reviews Immunology
Targeting Metabolism as a Novel Therapeutic Approach to
Autoimmunity, Inflammation, and Transplantation
Ian A. Bettencourt and Jonathan D. Powell
Immune cell activation and differentiation occurs concur- The particular metabolism of lymphocytes differs at each
rently with metabolic reprogramming. This ensures that stage of development and has been extensively detailed else-
activated cells generate the energy and substrates neces- where (2–5). In brief, naive lymphocytes resemble many of
sary to perform their specified function. Likewise, the the somatic cells in the body and progress through metabolic
metabolic programs among different cells of the immune pathways in a textbook fashion, relying on glycolysis and
system vary. By targeting different metabolic pathways, subsequent TCA cycling to produce a maximum amount of
these differences allow for selective regulation of immune ATP (2). However, upon activation, there is a dramatic shift
responses. Further, the relative susceptibility of cells to a in the metabolism of lymphocytes. Similar to the Warburg
metabolic inhibitor is dictated by their metabolic de- effect, which was first observed by the biochemist Otto

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Warburg in cancer cells (6), there is a tremendous increase in
mands; cellular selectivity is based on demand. There-
glycolysis, even in the presence of abundant oxygen (7). This
fore, where differences exist in metabolic pathways
aerobic glycolysis seems counterintuitive but is actually a
between healthy and pathogenic cells, there is opportu- metabolic program undertaken by the cell that prioritizes the
nity for selective regulation with agents lacking intrinsic early generation of biosynthetic intermediates, which are
specificity. There are now a host of studies demonstrat- necessary for activation, proliferation, and effector function.
ing how inhibitors of metabolism (e.g., glycolysis, gluta- This metabolic change is facilitated by the upregulation of
mine metabolism, and fatty acid oxidation) can regulate several key transporters, enzymes, and signaling pathways (8,
immune responses and treat immune-mediated patho- 9). Effector cells also have differences in their metabolism
genesis. In this brief review we detail how inhibitors between different subsets, with Th1, Th2, and Th17 tending
of metabolism can be employed to regulate immune to be more glycolytic, whereas regulatory T cells (Tregs) rely
responses in both autoimmunity and transplantation. The more on lipid metabolism (8). These subset differences pro-
Journal of Immunology, 2017, 198: 999–1005. vide another opportunity for differential regulation, based on
the select needs of the particular subset. Different effector

I
n the past decade, the field of immunology has been subsets also have different signaling pathways, such as dif-
characterized by a marked increase in our understanding ferential mTOR complex I or II requirements for Th1/Th17
of genetic and signaling programs that define immune or Th2 cells (10, 11), or increased AMP kinase (AMPK)
cells. More recently, it has become clear that a key component activation in Tregs (8), further expanding the potential for
of immune cell regulation and function is the concomitant selective manipulation of cellular processes based upon their
reprogramming of metabolic pathways (1). The metabolism of differential metabolic demands.
a naive lymphocyte is different from that of a memory cell The transition from effector cell to memory cell involves
and is different from that of an effector (and indeed, even further metabolic changes. Memory cells are more reliant on
effector subsets have great differences in their metabolic fatty acid oxidation and have increased mitochondrial mass
profiles) (2). These differences offer promising opportunities (12, 13). This increase in mitochondria is coupled with the
for selective regulation of immune subsets. Furthermore, re- increase in spare respiratory capacity (13). From a metabolic
cent studies suggest that even metabolic inhibitors that lack perspective, memory cells are fueled to last. Furthermore,
intrinsic specificity can be made to affect only a select subset these metabolic changes allow the memory T cell to rapidly
of cells based on the metabolic demands of those cells. This expand and to take on an effector function upon restim-
principle of cellular selectivity based upon cellular demand ulation (14). From this overview of naive, effector, and
underlies a great deal of metabolic therapy and is broadly memory T cell metabolism, a picture emerges whereby selec-
applicable to a number of different cells and disease types. tively regulating metabolic pathways can lead to the fine-tuned

Department of Oncology, Bloomberg-Kimmel Institute for Cancer Immunotherapy, Abbreviations used in this article: AMPK, AMP kinase; BMT, bone marrow transplan-
The Sidney-Kimmel Comprehensive Cancer Research Center, Johns Hopkins University tation; DC, dendritic cell; DCA, dichloroacetate; 2DG, 2-deoxy-glucose; DON, 6-diazo-5-
School of Medicine, Baltimore, MD 21231 oxo-L-norleucine; GVHD, graft-versus-host disease; PDH, pyruvate dehydrogenase; PDHK,
PDH kinase; PKM2, pyruvate kinase M2; ROS, reactive oxygen species; SLE, systemic lupus
Received for publication August 2, 2016. Accepted for publication September 20, 2016.
erythematosus; Treg, regulatory T cell.
This work was supported by National Institutes of Health Grants AI072677, AI77610,
and AI09148. Copyright Ó 2017 by The American Association of Immunologists, Inc. 0022-1767/17/$30.00
Address correspondence and reprint requests to Dr. Jonathan D. Powell, Johns Hopkins
University School of Medicine, CRB1 Room 443, 1650 Orleans Street, Baltimore, MD
21231. E-mail address: [email protected]

www.jimmunol.org/cgi/doi/10.4049/jimmunol.1601318
1000 BRIEF REVIEWS: TARGETING METABOLISM TO REGULATE IMMUNE RESPONSES

regulation of immune function. In this brief review, we will Another metabolite that increases upon stimulation is
highlight several instructive examples of how the differential succinate. The increase in glutamine metabolism that ac-
metabolism of innate and adaptive immune cells is beginning companies aerobic glycolysis paradoxically increases the suc-
to be exploited therapeutically. cinate present in macrophages after stimulation, even though
flux through the TCA cycle is decreased (18). Succinate sta-
Targeting signaling by targeting metabolites in innate and adaptive bilizes HIF-1a, which leads to increased production of IL-1b.
immune cells Inhibition of glycolysis with 2DG prevents this increase in
The shift in the metabolism of innate immune cells upon succinate upon stimulation and leads to a decrease in IL-1b
activation is similar yet distinct from that which occurs in the production, as detailed later (19). Recently, an important role
adaptive immune system (2, 15). This is advantageous, be- for itaconate in regulating macrophage inflammation has been
cause it provides opportunities for both concurrent and dif- demonstrated (34). Itaconate has a regulatory role in macro-
ferential regulation of the two arms of the immune response. phage metabolism and acts by competitive inhibition of
Upon activation of macrophages and dendritic cells (DCs) in succinate dehydrogenase (35). In this model, itaconate en-
an inflammatory context, there is a shift from the quiescent dogenously produced by Irg1 has been shown to inhibit
state to a Warburg phenotype that is similar to that of succinate dehydrogenase, which leads to a block in the TCA
activated lymphocytes (16, 17). This is accompanied by a cycle and a subsequent increase in succinate accumulation in
decrease in the flux through the TCA cycle (18, 19). How- LPS-stimulated macrophages. Alternatively, in IRG12/2 cells
ever, the goal of this shift in metabolism is not to support there is an increase in HIF-1a concurrent with a relative
proliferation. Rather, such metabolic changes support full decrease in succinate (34). Such findings demonstrate an ad-

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activation and cytokine production (20), as well as other ditional link of the HIF-1a–IL-1b axis to the efficiency and
important host defense functions, such as phagocytosis (21). directionality of the electron transport chain.
DCs require a shift to aerobic glycolysis to mature and be- Acetate also plays a role in guiding cellular differentiation
come capable of presenting Ag and activating lymphocytes and function. Acetate is increased systemically upon bacterial
(17, 18, 22). When hexokinase, an enzyme involved in the infection (36). When memory CD8 T cells that were initially
first step of glycolysis, is inhibited by treatment with the small primed in increased acetate are restimulated, they are able to
molecule inhibitor 2-deoxy-glucose (2DG), macrophages mount a more rapid response and have a more dramatic
stimulated with LPS display mitigated production of IL-1b increase in glycolysis upon restimulation. In addition, adoptive
(19, 23). Underlining the specificity of this metabolic ap- transfer of CD8 memory cells that were initially simulated in
proach, targeting hexokinase with 2DG can selectively block acetate is more protective against Listeria challenge (36).
IL-1b production whereas not altering the transcription of Facilitating the metabolic shift that occurs upon activation,
TNF-a (19). cells of the innate immune system undergo transcriptional and
In addition to the shift to aerobic glycolysis, innate cells signaling pathway changes that dramatically alter their be-
undergo a number of other metabolic changes, which are havior. One such transcriptional change (that was mentioned
potential targets for metabolic therapies. The manipulation of earlier) is an increase in HIF-1a upon the induction of aerobic
these metabolites takes on an added importance because many glycolysis. This increase in HIF-1a occurs under normal ox-
metabolites also function as signaling molecules, the alteration ygen tension, is promoted by mTOR signaling, and is nec-
of which can have profound effects on the downstream im- essary for cytokine production upon activation (19, 37).
mune response. In this context, metabolites are not simply the Corresponding to the increased mTOR signaling after acti-
end product of metabolism, but also can alter cell function by vation, there is a decrease in AMPK signaling in innate im-
differentially signaling separate biochemical and molecular mune cells upon LPS stimulation. However, metformin
pathways. treatment activates the AMPK signaling pathway, and this
The production of NO is sustained by the increased gly- activation is sufficient to decrease IL-1b production, as well as
colysis after activation (24) and is required for activation- increase the production of IL-10 (28). In addition to acti-
induced inhibition of oxidative phosphorylation (25). In vating AMPK, metformin also inhibits electron transport
addition, reactive oxygen species (ROS) are associated with chain complex I (38). Interestingly, the ability of metformin
priming the NLRP3 inflammasome (26). Treatment with to promote a shift to a more immunosuppressive cytokine
metformin, a diabetes drug that activates AMPK (27), can profile is also found in rotenone, which also inhibits electron
decrease the production of ROS as a mechanism for modu- transport chain complex I (28).
lating immune responses (28). ROS are also key for T cell As is the case for the various subsets of effector T cells, M1
activation, because lymphocytes that are genetically incapable and M2 macrophages also have different metabolic demands.
of producing mitochondrial ROS cannot activate NFAT Transcriptional differences between the classically defined M1
translocation to the nucleus or produce IL-2 (29). Another and M2 cells also have important metabolic consequences. The
metabolite in flux is citrate, which is pumped out of the alternatively activated M2 macrophages have a metabolism
mitochondria and can serve as a substrate for histone acety- somewhat similar to Tregs with oxidative phosphorylation
lation, and thereby facilitate the epigenetic activation of genes providing their energy, as opposed to aerobic glycolysis (39). In
crucial to metabolic pathways (30, 31). Histone acetylation addition, M2 macrophages have less inducible NO synthase
has recently been shown to be important in the IL-4–induced expression (leading to decreased NO production), increased
polarization of M2 macrophages and is tightly controlled by AMPK activity, and less HIF-1a (15). Further, it has been
ATP citrate lyase (32). Cytoplasmic citrate can also be used as proposed that an IL-4–mediated increase in PGC-1b is the
a substrate for lipid biogenesis and the production of ROS or driver of the oxidative phosphorylation that characterizes the
NO (33). metabolism of M2 macrophages (39). This metabolic and
The Journal of Immunology 1001

signaling phenotype is in contrast with the metabolic changes possibility exists that these small molecules that prevent the
that occur in more proinflammatory innate immune cells, and activity of PKM2 could be beneficial in treating autoimmune
provides potential differences with which the balance between inflammatory diseases. Although there has been less focus on
macrophage subtypes can be manipulated. the intervention of innate immune metabolism in treating
Parallel analysis of transcriptional and metabolomics data has autoimmunity and destructive inflammation, this is a field
provided further insight into the metabolic circuitry of acti- ripe for further exploration.
vated macrophages. Using a combined metabolic and tran-
scriptional analysis, termed CoMBI-T, Jha and colleagues (40) Targeting metabolism in bone marrow transplantation
were able to simultaneously examine the interplay between In addition to their role in protective immunity, T lymphocytes
metabolites and the enzymes involved in pathways that use or make an important contribution to disease pathogenesis in
generate them. This approach revealed strikingly different a variety of autoimmune conditions. Normally, T cell meta-
metabolic profiles in M1 and M2 macrophages. In the M1 bolism, upon activation, involves a rapid increase in aerobic
macrophages, the conversion of isocitrate to a-ketoglutarate glycolysis (along with a concurrent transcriptional/translational
was specifically found to be deficient, because of decreased increase in the machinery involved in these processes) and an
transcription of the enzyme responsible for that reaction, increase in the uptake of glutamine to replenish the TCA cycle to
isocitrate dehydrogenase (Idh1). Decreased a-ketoglutarate derive anaplerotic substrates from that pathway (2). Also, ac-
production in M1 macrophages requires that citric acid serve tivated T cells display increased shunting of carbons into al-
as a precursor for itaconate and fatty acid synthesis (40). Irg1, ternative metabolic circuits, such as the pentose phosphate
as discussed earlier, is one of the most strongly upregulated pathway (46). However, in a number of autoimmune diseases,

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transcripts in M1 macrophages as identified by CoMBI-T this metabolism is disrupted. In the case of graft-versus-host
analysis, thus leading to increased levels of itaconate in M1- disease (GVHD) after bone marrow transplantation (BMT),
activated macrophages. Dimethyl itaconate administration T cell metabolism is remarkably shifted. The immune response
was able to partially reverse tissue injury in a cardiac in GVHD is characterized by a constant encounter between the
ischemia-reperfusion model, in which damage is caused in activated lymphocytes and their target tissue. This constant,
part by hypoxia-induced ROS production (41). Dimethyl high level of Ag engagement appears to lead to a different
itaconate pretreatment was also shown to decrease ROS metabolism in the pathogenic donor cells. Their high re-
production in bone marrow–derived macrophages, as well quirement for ATP means they cannot subsist on oxidative
diminish inflammatory cytokine production and inflamma- glycolysis alone, and therefore such cells are forced to find an
some activation (34). In contrast, M2 macrophages require alternate source of fuel. This can be provided by the oxidation
glutamine metabolism. The generation of UDP-GlcNAc was of fatty acids (47). When examining the metabolic tracing of
found to be highly dependent on glutamine, because labeled 13
C-labeled glutamine, glucose, and palmitate in T cells
nitrogen from glutamine made up more than half of the from a mouse model of GVHD after allotransplant, it was
nitrogen in UDP-GlcNAc after just 4 h. Glutamine depri- found that glutamine uptake and incorporation into RNA (as
vation dramatically decreased M2 generation, leading to ribose) and fatty acids (as palmitate) are markedly increased as
downregulation specifically in M2 signature gene transcrip- compared with T cells from naive mice. This is in contrast with
tion. This includes downregulation of CCL22, the secretion the results of labeled glucose tracer incorporation, which shows
of which was also dramatically reduced in glutamine-free no difference between ribose or palmitate incorporation, and
media (40). However, glutamine concentration had no im- the use of a palmitate tracer, which demonstrates decreased
pact on M1 polarization as measured by inducible NO syn- incorporation across the board in diseased mice (48). This
thase expression (40). Furthermore, it has been shown that indicates that fatty acids are preferentially being catabolized for
glutamine deficiency actually increases the production of oxidative phosphorylation, whereas glutamine is being used as
TNF-a, while protecting LPS-stimulated macrophages from an anabolic substrate, and hints at an alternative metabolism
lipid toxicity (42). that is specific to pathogenic lymphocytes in GVHD, partic-
In addition to metabolites altering macrophage polarization, ularly one that is reliant on lipid oxidation for the vast ATP
enzymatic differences can shift the balance between M1 and needs of chronically activated cells. These differences in terms
M2 macrophages. Pyruvate kinase M2 (PKM2) is transcrip- of metabolic demands and reprogramming suggest that meta-
tionally upregulated upon LPS stimulation of bone marrow– bolic therapy might be able to selectively inhibit activation of
derived macrophages and can form a dimer that is enzymat- the GVHD-inducing cells.
ically inactive, but can travel to the nucleus and induce Analysis of competing pathways (Fig. 1) indicates that
transcription of glycolytic genes by interacting with HIF-1a metabolic therapy specifically targeting fatty acid metabolism
(43). Small molecules DASA-58 and TEPP-46 force PKM2 (required to meet the increased demand for ATP) with eto-
into a tetrameric conformation (44), which is incapable of moxir would be ideal and could selectively inhibit the per-
promoting HIF-1a transcription, leading to a decrease in IL- sistently activated GVHD-inducing lymphocytes. However,
1b production after LPS stimulation (45). Furthermore, great care must be taken to avoid disturbing the proliferation
treatment with TEPP-46 decreases M1 macrophage polari- of nonpathogenic donor cells. In a mouse model of bone
zation after LPS stimulation, and both DASA-58 and TEPP-46 marrow allotransplant, proliferating bone marrow cells
dramatically decrease activation-induced glycolysis. TEPP-46 reconstituting the immune system of a lethally irradiated
administration leads to decreased IL-1b production and in- syngeneic host undergo a dramatically different metabolic
creased bacterial loads in the spleen and liver of mice infected program than the pathogenic cells, with the healthy cells re-
with Salmonella typhimurium, because of decreased cellular lying more on glycolysis than oxidative phosphorylation (47).
killing of bacteria (45). Although deleterious in this case, the Small-molecule inhibitors of the F1F0 ATPase, such as BZ423
1002 BRIEF REVIEWS: TARGETING METABOLISM TO REGULATE IMMUNE RESPONSES

Targeting metabolism in solid organ transplantation

In the case of solid organ transplantation, metabolic therapy has
also been employed. However, in this scenario, the metabolic
demands of the effector cells promoting graft rejection are
somewhat different from those observed in BMT, and thus the
antimetabolic targeting strategy is different (53). For solid organ
transplant, it appears that there is far less reliance on lipid
metabolism for the generation of ATP, and rejecting cells appear
to employ aerobic glycolysis (54). This may be due to the fact
that, unlike in GVHD, where the donor pathogenic lymphocytes
are persistently being activated by host Ag, in the setting of solid
organ transplant, the host pathogenic lymphocytes have less fre-
quent encounters with alloantigen. As such, CD4 T cell activa-
tion in the setting of solid organ transplant more closely
resembles the classical metabolic shift that is seen during the
normal activation of lymphocytes (2). To this end, it was found
FIGURE 1. Summary of metabolic pathways vital for T cells responses that inhibiting glycolysis with 2DG combined with metformin,
(black) and drugs that inhibit these pathways (green). The particular condition
an inhibitor of complex I of the electron transport chain (38), can
of autoimmune inflammation the drug has been tested in is in blue.
substantially decrease the glycolysis of an activated T cell, and by

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extension its cytokine production and proliferation (55). When
and LyC-31138, have demonstrated promise as a metabolic these two drugs are combined with 6-diazo-5-oxo-L-norleucine
therapy for GVHD (47, 48). These drugs prevent the produc-
(DON), a glutamine analogue that broadly inhibits glutamine
tion of ATP, as well as increase the mitochondrial polarization of
uptake and metabolism (56–58), and thus its ability to replenish
the pathogenically activated lymphocytes. In allotransplant BMT
the TCA cycle, it is possible to more completely abrogate the
models of GVHD, these have been shown to rapidly induce
immune response. In the transplant setting, these three drugs can
apoptosis in the pathogenic cell population and significantly
be combined with great effect. Triple therapy with 2DG, met-
decrease cytokine production, leading to decreased GVHD
formin, and DON was capable of suppressing the proliferation of
clinical score and increased survival (47, 48). These ATPase
pathogenic CD4 and CD8 effector T cells and was able to
inhibitors act by inducing caspase-regulated apoptosis in the
markedly inhibit completely MHC-mismatched allograft rejec-
pathogenic cells (47). Importantly, these agents are specific for
the pathogenic cells and their rapid requirement for ATP pro- tion in models of both skin and heart transplantation. Further-
duction, and thus do not effect immunological reconstitution of more, due to the fact that Tregs are more reliant on lipid
the graft (47). Another therapeutic strategy is targeting fatty acid metabolism, the triple therapy inhibited the CD4 effector re-
oxidation with etomoxir, an agent that blocks lipid metabolism sponse, but actually promoted the generation of Ag-specific Tregs
at CPT1 (49). After allotransplant, 2 wk of etomoxir treatment (55). That is, the metabolic therapy did not lead to the wholesale
was able to decrease clinical GVHD scores from 10 d to a inhibition of immune responses but rather, based on differential
month after the end of treatment. Etomoxir administration was metabolism, selectively inhibited effector responses while pro-
successively able to reduce the proliferation and promote the moting Treg responses. Given these properties, current studies are
apoptosis of GVHD-inducing CD8 T cells that have divided under way to combine metabolic therapy with tolerance-inducing
numerous times while undivided cells were unaffected (50). This therapy (e.g., costimulatory blockade) to try to promote long-
is advantageous, because the highly divided cells were found to term tolerance in the absence of long-term immunosuppression.
be the pathogenic cell population (47). Targeting fatty acid Furthermore, these studies suggest a potentially broader
metabolism is a therapeutic strategy that does not impact other principle in terms of targeting metabolism as a means of regu-
cells of the immune system, such as DCs or naive T cells, and lating immune responses. It is somewhat striking that, despite the
does not inhibit graft reconstitution (50). fact that the metabolic inhibitors employed target metabolic
Despite these impressive results treating GVHD by blocking pathways found in all cells, the combination therapy in the setting
lipid metabolism, others have found that the pathogenic T cells in of transplant rejection had a robust therapeutic index (55). That
GVHD behave metabolically as normally activated T cells. That is, although activated effector cells mediating graft rejection were
is, it has more recently been reported that pathogenic T cells in sensitive to metabolic inhibition, resting immune cells and other
GVHD increase both their glycolytic and oxidative phosphor- healthy tissues were relatively unaffected. Indeed, at higher doses,
ylation rates, while decreasing their uptake and oxidation of fatty triple therapy might inhibit proliferating gut epithelial cells or
acids (51). Furthermore, inhibition of glycolysis with 3-PO, a result in bone marrow suppression (59, 60). However, for the
specific inhibitor of PFKB3 (52), improved survival and de- purpose of preventing allograft rejection, triple metabolic ther-
creased GVHD clinical scores. This improvement was not seen apy readily inhibited effector cells without significant side effects.
with 2DG, because it was too toxic for the prolonged treatment These observations point to cellular selectivity based upon de-
necessary (51). It remains to be determined whether the differ- mand. That is, relatively nonspecific inhibitors can exert cellular
ences in observed metabolic phenotypes (reliance on lipid oxi- selectivity by differentially affecting cells that necessitate the
dation versus glycolysis) in these studies of GVHD reflect subtle greatest and/or extraordinary demand for the particular meta-
differences between the models with regard to pathogenesis. bolic pathway (Table I).
Most likely both processes will turn out to be playing a role in Manipulating the balance between regulatory and effector
the GVHD-inducing cells. T cell metabolism is an effective strategy for the treatment of
The Journal of Immunology 1003

autoimmune inflammation. Pyruvate dehydrogenase (PDH)

inhibition by PDH kinase (PDHK) promotes the conversion

Gatza et al. (47)Glick et al. (48)

of pyruvate to lactate over the canonical progression of py-

Byersdorfer et al. (50)

ruvate to acetyl-CoA (61). When PDHK1 is inhibited by the

Gerriets et al. (63)

Yin et al. (65, 69)

Yin et al. (65, 69)

Lee et al. (55)

Lee et al. (55)

Lee et al. (55)

addition of dichloroacetate (DCA) (62) in vitro, it has a

References
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of Th17 cells, while promoting the generation of T regula-
tory cells (63). This is likely due to differences in Pdhk1
expression in the different cell types, because Th17 have
higher Pdhk1 expression levels than Tregs. Therefore, when
DCA was used to treat the Th17-driven model of autoim-
mune inflammation, experimental autoimmune encephalitis,
it was found that the inhibition of PDHK significantly de-
creased disease scores and progression. Disease alleviation

(in combination with 2DG and DON)

Prolong graft survival (in combination

Prolong graft survival (in combination

Decrease clinical score and pathogenic

Decrease clinical score while preserving

Prolong graft survival (in combination

Decrease clinical score while preserving
normal immune function unaffected

normal immune function unaffected

Decrease clinical score while leaving

Decrease clinical score while leaving

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with DON and metformin)

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Tregs
Effect
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TLR2 agonist PAM, as well as bacterial pathogens that are
dependent on TLR2 signaling to induce a response (64).
Knockdown of PDHK1 increases the expression of M2
signature genes at early time points after activation and in-
creases the oxidative respiration that preferentially leads to
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macrophages do not require fatty acid metabolism until later

For each drug, its target, the autoimmune inflammation on which the drug was tested, its effect, and the literature reference are listed.
after activation (64).

Experimental autoimmune
Solid organ transplant

Solid organ transplant

Solid organ transplant
Targeting metabolism in systemic lupus erythematosus

BMT GVHD
BMT GVHD
Disease Model

encephalitis
Another condition of pathogenic T cell activation that has
SLE

SLE
been targeted with metabolic therapy is systemic lupus
erythematosus (SLE). Similar to GVHD after BMT, in the
case of SLE there is a constant, persistent encounter between
the pathogenic lymphocyte (the pathogenesis of SLE is
chiefly reliant on CD4 T cells) and its target tissue (65). As a
result, pathogenic T cells take on a chronically activated
phenotype, and thus have dramatically different metabolic
needs than healthy tissue (66). Similar to pathogenic T cells
in GVHD, and in contrast with the lymphocytes activated
Electron transport chain (complex I)

under normal conditions or in the case of solid organ

Glutamine uptake and metabolism

Pyruvate branch point (PDHK1)

transplant, CD4 T cells in SLE meet their energetic needs

Lipid metabolism (CPT1a)
Glycolysis (hexokinase)

mostly through oxidative phosphorylation. Tracer experi-

Summary of significant works described in this article

Pathway Targeted

ments that use 13C-uniformly-labeled glucose found more

ATP synthase

oxidation to CO2 in a NZB/W mouse model of lupus, with

no differences in glycolysis or pentose phosphate pathway
activity (65). This augmented reliance on oxidative phos-
phorylation is coupled to increased mitochondrial polari-
zation and mass in the T cells of SLE patients, which is
caused in part by decreased mitochondrial autophagy (67).
This phenotype can be partially reversed by treatment with
3-PEHPC, a geranylgeranyl transferase inhibitor, which is
also sufficient to decrease autoantibody formation and lu-
pus nephritis in both NZB/W and MRL/lpr mouse models
2-Deoxy-D-glucose

BZ423/LyC31138

of lupus (68).
Drug

Further studies have attempted to more fully characterize

Metformin

the metabolism of SLE lymphocytes. Using a triple congenic

Etomoxir
DON

mouse model of lupus, CD4 T cells were analyzed for

DCA
Table I.

metabolic activity ex vivo and found them to have increased

basal metabolism before the onset of disease, including both
1004 BRIEF REVIEWS: TARGETING METABOLISM TO REGULATE IMMUNE RESPONSES

glycolysis, as determined by extracellular acidification rate, and Disclosures

oxidative metabolism, as determined by oxygen consumption J.D.P. is the founder of Dracen Pharmaceuticals. I.A.B. has no financial con-
rate (69). Predisease cells had decreased spare respiratory ca- flicts of interest.
pacity as compared with wild type controls, and although they
produced ATP at the same rate, predisease cells had a lower
ATP charge, indicating increased energy use (69). To gain
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