Fimmu 13 780839

REVIEW
published: 26 January 2022

doi: 10.3389/fimmu.2022.780839
Modulation of Macrophage
Immunometabolism: A New
Approach to Fight Infections
Thierry Gauthier and Wanjun Chen *
Mucosal Immunology Section, National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health
(NIH), Bethesda, MD, United States
Macrophages are essential innate immune cells that contribute to host defense during
infection. An important feature of macrophages is their ability to respond to extracellular
cues and to adopt different phenotypes and functions in response to these stimuli. The
evidence accumulated in the last decade has highlighted the crucial role of metabolic
reprogramming during macrophage activation in infectious context. Thus, understanding
and manipulation of macrophage immunometabolism during infection could be of interest
to develop therapeutic strategies. In this review, we focus on 5 major metabolic pathways
including glycolysis, pentose phosphate pathway, fatty acid oxidation and synthesis,
Edited by: tricarboxylic acid cycle and amino acid metabolism and discuss how they sustain and
Jan Fric,
regulate macrophage immune function in response to parasitic, bacterial and viral
International Clinical Research Center
(FNUSA-ICRC), Czechia infections as well as trained immunity. At the end, we assess whether some drugs
Reviewed by: including those used in clinic and in development can target macrophage
Frederick J. Sheedy, immunometabolism for potential therapy during infection with an emphasis on SARS-
Trinity College Dublin, Ireland
Mireille Laforge,
CoV2 infection.
U1141 Neuroprotection du cerveau en
Keywords: macrophage, immunometabolism, infections, SARS – CoV – 2, therapeutics
développement (INSERM), France
*Correspondence:
Wanjun Chen
[email protected] INTRODUCTION
Specialty section: Macrophages are professional phagocytes patrolling most of the tissues, helping to maintain
This article was submitted to homeostasis and contributing to the first line of defense against pathogens (1). They are notably
Molecular Innate Immunity, characterized by a high plasticity and ability to change their phenotype in response to different
a section of the journal environmental stimuli (2). Macrophages derive either from an embryonic origin (deriving from the
Frontiers in Immunology
yolk-sac or the liver and maintained throughout the life by self-renewal) or originate from monocyte
Received: 21 September 2021 precursors (differentiating in the tissue after their infiltration) (3). Macrophages notably counter
Accepted: 07 January 2022 invading pathogens by recognizing defined pathogen associated molecular patterns (also known as
Published: 26 January 2022
PAMP) by a system of pathogen recognition receptors (PRR). Different classes of PRR have been so far
Citation: described: the ALR (for Absent in melanoma 2 (AIM2)-like receptors) the CLR (for C-type lectin
Gauthier T and Chen W (2022)
receptors), the NLR (for NOD-like receptors), the RLR (for RIG-I-like receptors), the TLR (for Toll-
Modulation of Macrophage
Immunometabolism: A New Approach
like receptors) and the cGAS (cyclic GMP–AMP Synthase)-STING (Stimulator of Interferon Genes)
to Fight Infections. signaling (4, 5). ALR are composed of AIM2 and IFI16 (Interferon (IFN)-Inducible protein 16) which
Front. Immunol. 13:780839. can sense cytosolic and nuclear DNA by assembling inflammasomes (6, 7). RLR are composed of RIG-
doi: 10.3389/fimmu.2022.780839 I (Retinoic acid-inducible gene I), MDA-5 (Melanoma differentiation factor-5) and LGP-2
Frontiers in Immunology | www.frontiersin.org 1 January 2022 | Volume 13 | Article 780839

Gauthier and Chen Macrophage Immunometabolism and Infection
(Laboratory of genetics and physiology-2) which detect viral RNA the primary source of energy. Once entering the cells through its
and DNA. NOD1 (Nucleotide-binding oligomerization domain- transporters, glucose is broken down by glycolysis. Along all
containing protein 1) and 2 belong to the NLR and recognize gram these different steps, glycolysis can be diverted to provide
positive and negative bacteria. TLR are the best described family of metabolites for the PPP pathway or the generation of amino
PRR and 10 members belong to this family in human (TLR1 to 10) acids, but its primary fate will be to enter the TCA cycle and
and 12 in mice (TLR1 to 13 except TLR 10). They recognize a wide finally feed the OXPHOS to generate energy in the form of ATP.
variety of PAMP including bacterial, parasitic and viral ligands (4, While it has been thought for decades that the purpose of
8–10). Finally, the cGAS-STING pathway can recognize microbial metabolic pathways is to generate energy, it now appears that
and cytosolic DNA (11). While all these PRR trigger different producing intermediates metabolites is also important for
molecular signaling, they will lead to the generation of an innate cellular and molecular signaling (Figure 1). We will discuss in
immune response via the production of pro-inflammatory more detail the different steps of these five major pathways in the
molecules (cytokines, chemokines and DAMP (Damage next sections.
Associated Molecular Patterns). The PRR recognizing viral
PAMP will also trigger the secretion of type I interferon (IFN) The Glycolytic Pathway
which are crucial molecules in the antiviral response (4, 10, 12). In macrophages, glucose from the extracellular environment
These signaling cascades lead to the activation of different typically enters the cell through the glucose transporter
components of innate and adaptive immune responses, host cell GLUT1 (Glucose transporter 1) [encoded by the gene Slc2a1
metabolism and phagocytosis (13, 14). An important hallmark of (Solute Carrier 2a1)] to fulfill glycolysis (19, 20) (Figure 1).
macrophages is their plasticity in response to environmental cues. Glucose is further catalyzed by the Hexokinases (Hk1-4) which
During bacterial and viral infections, the PRR stimulation and the phosphorylates glucose into glucose-6-phosphate. The glucose-
pro-inflammatory micro-environment will enable macrophages to 6-phosphate then enters the glycolysis (through the form of
be activated toward a pro-inflammatory phenotype (also called fructose-6-phosphate) or the PPP (which will be discussed
classically activated macrophages or M1). On the other hand, a below). Fructose-6-phosphate can also be used by the
parasitic infection will result in the differentiation of alternatively phosphofructokinases (Pfkl, m, p) into glycolysis or diverted
activated macrophages, notably through the effects of IL-4 and IL- toward the hexosamine biosynthesis pathway. This pathway will
13 (also called anti-inflammatory phenotype, or M2). These lead to the generation of UDP-GlcNAc that is the substrate used
different polarized states will help the macrophages to sustain for the glycosylation reactions (O- and N-GlcNAcylation). A
their functions during homeostasis and in diseases, including downstream metabolite of glycolysis, the glyceraldehyde-3-
infections (15–17). Notably, a growing body of evidence show phosphate can also lead to the generation of glycerol-3-
that macrophages change their activation state through phosphate and the biosynthesis of diverse lipids. Another
reprogramming of the metabolism. These metabolic changes, possible break into the glycolysis is to enter the serine and
not only provide energy but also sustain changes in function glycine pathway from 3-phosphoglycerate. Serine can further
and phenotype (18). In this review, we will highlight the main be converted into folate to generate one-carbon units. The final
metabolic pathways and discuss how they regulate macrophages glycolytic enzyme is the pyruvate kinase (PKM1 and 2 are the
functions in response to different types of infections. We will also main isoforms in most tissues) which catalyzes the conversion of
assess how the innate immune memory of macrophages during phosphoenolpyruvate into pyruvate. Pyruvate is then converted
infections (called trained immunity) can be supported by changes into 2 major metabolites. The first one is lactate which is
in metabolism. Finally, we will envision the possibility of targeting generated by the lactate dehydrogenase (LDHA and B), and
macrophage immunometabolism as a possible therapeutic target finally exported to outside the cell, in a process that is called
to infections. aerobic glycolysis. While this process was originally described to
occur in cancer cells due to a defect in mitochondria, this aerobic
glycolysis clearly occurs during normal cellular processes in
MAIN METABOLIC PATHWAYS USED immune cells including macrophages. It appears that, despite
BY MACROPHAGES generating less adenosine triphosphate (ATP) per molecule of
glucose used, this mechanism can sustain a rapid activation of
Cell intrinsic metabolic changes are required in all cells to immune cells and preserve the redox balance through a tight
metabolize nutrients to help their survival, proliferation and control of the NADH levels. The second pathway is for the
differentiation. Five major pathways are used by macrophages to pyruvate to be oxidized in the mitochondria by the pyruvate
generate energy: i.e. the glycolysis, the tricarboxylic acid (TCA) dehydrogenase (PDH) which convert it into acetyl-coA to enter
cycle, the pentose-phosphate pathway (PPP), the fatty acid the TCA cycle (21–23).
metabolism [including the fatty acid oxidation (FAO) and the
fatty acid synthesis (FAS)] and the amino acid metabolism. In The TCA Cycle
addition to generating energy, macrophages also produce The TCA cycle (also called Krebs cycle or citrate cycle) occurs
intermediates metabolites that support their phenotype into the mitochondria (Figure 1). It is initiated with the
reprogramming in response to external stimuli. Interestingly, generation of acetyl-coA coming from three possible sources:
these diverse metabolic pathways are closely linked to each other the pyruvate from glycolysis, the fatty acyl-coA from fatty acids
and interconnected as described below. In most cells, glucose is and the acetate (either coming from acetate metabolism or

FIGURE 1 | Overview of the main metabolic pathways used by macrophages. There are 5 major pathways used by macrophages to provide energy in cells
including glycolysis, TCA (Tricarboxylic acid) cycle, PPP (Pentose phosphate pathway), FAS (Fatty acid synthesis) and FAO (Fatty acid oxidation) and amino
acid (Aa) metabolism. These pathways are highly interconnected and are tightly regulated in immune cells, including macrophages. ACLY, ATP citrate lyase;
ACO2, Aconitase 2; ATP, Adenosine triphosphate; CPT1, Carnitine palmitoyltransferase 1; CS, Citrate synthase; ENO, Enolase; FH, Fumarase; GAPDH,
Glyceraldehyde 3-phosphate dehydrogenase; GLUT1, Glucose transporter 1; HK, Hexokinase; GS, Glutamine synthetase; IDH, Isocitrate dehydrogenase;
IDO, Indoleamine 2,3-dioxygenase; LDHA, Lactate dehydrogenase; MCT1, Monocarboxylate transporter 1; MDH, Malate dehydrogenase; NO, Nitric oxide;
iNOS, inducible NO synthase; OAA, Oxaloacetate; OGDH, a-ketoglutarate dehydrogenase; OXPHOS, Oxidative phosphorylation; P, Phosphate; PDH,
Pyruvate dehydrogenase; PFK1,Phosphofructokinase 1; PGK1, Phosphoglycerate kinase 1; PGI, Phosphoglucoisomerase; PGM, Phosphoglycerate mutase;
PKM, Pyruvate kinase muscle isotype; PP, bisphosphate; SAM, S-Adenosyl methionine; SCS, Succinyl coenzyme A synthetase; SDH, Succinate
dehydrogenase; SLC, Solute carrier; TDO, Tryptophan 2,3-dioxygenase; TPI1, Triosephosphate isomerase 1.
extracellular uptake). The acetyl-coA will, in combination with indirectly, PFK and HK enzymes (25). The major products
oxaloacetate, generate citrate which will be further oxidized into generated by the TCA cycle are NADH and FADH2 which can
the TCA cycle. Citrate can also be exported to the cytosol to be transferred into the electron transport chain to support the
generate itaconate or to be hydrolyzed by ATP-citrate lyase oxidative phosphorylation (OXPHOS) and the efficient
(ACLY) in cytosolic acetyl-coA which will fuel the fatty acid generation of ATP (26).
and cholesterol synthesis (for the generation of new membranes)
or will contribute to protein acetylation (notably histone The Pentose Phosphate Pathway
acetylation) (24). Interestingly, cytosolic citrate can also exert a The glucose-6-phosphate (G6P) generated by hexokinases can be
negative feedback on glycolysis by inhibiting, directly or metabolized to enter the glycolysis or be directed into the PPP

(which occurs in the cytosol) (Figure 1). The PPP is divided into Serine is a central hub for cell metabolism. As described
2 phases; an oxidative phase which will give raise to the reduction previously, it can be converted from the glycolytic metabolite 3-
of NADP+ (Nicotinamide adenine dinucleotide phosphate) into PG (3-phosphoglycerate). The conversion of Serine to Glycine is
NADPH linked to the conversion of G6P into ribulose-5- an outcome of Serine generation which can later lead to
phosphate (R5P); a non-oxidative phase will generate ribose-5- production of glutathione. Serine is also a major source for the
phosphate. NADPH is an essential cofactor for the generation of one-carbon metabolism pathway which will serve as a building
antioxidants, ROS and NO, but also to generate lipids and block for S-adenosylmethionine (and the regulation of protein
nucleotides. The R5P is a precursor of nucleotides and amino methylation), nucleotides, NAD(P)H, and ATP. Finally, this
acids synthesis (27). NADPH can further be used by the Fatty pathway can also fuel the folate metabolism leading to the
acid synthase to promote the generation of fatty acids or by the production of purines (36).
enzyme NADPH oxidase 2 (NOX2) to generate reactive oxygen Another important amino acid in term of immunometabolism
species (ROS) ultimately leading to an oxidative burst (28, 29). is Arginine. Arginine can be produced by many different pathways
(including extracellular uptake and intracellular production) to
The Fatty Acid Metabolism support cell growth and proliferation (37). An important feature,
Fatty acid Oxidation (FAO) is the most efficient producer of in macrophages, is the ability of arginine to be catalyzed either by
energy for the cell since a single molecule of fatty acid can NOS (Nitric Oxide Synthase) to generate NO (Nitric oxide) and
generate as much as 100 molecules of ATP. The short chain fatty citrulline or to be catalyzed by Arginase 1 (Arg1) to ornithine and
acids can passively enter the mitochondria, while the medium urea (38). Of note, Arg1 has been long described to be expressed
and long chain fatty acids need to be imported by the ligation to by anti-inflammatory M2 macrophages while the expression of
coA, which is then exchanged by carnitine palmitoyltransferase iNOS has been demonstrated to be a marker of pro-inflammatory
1A (CPT-1A) upon mitochondrial transfer (Figure 1). The M1 macrophages (38).
carnitine conjugated to the fatty acid is then shuttled into the L-tryptophan is also an essential amino acid coming from
mitochondria and the carnitine is removed by the CPT2 to give a dietary intake. A small fraction of tryptophan is used to the
molecule of fatty acid acyl-coA. The oxidation of this fatty acid production of proteins and neurotransmitters; however, the major
will lead to produce large amounts of acetyl-coA, NADH and part is used to fuel the kynurenine pathway which give raise to
FADH2 which are used to augment the TCA cycle and the several metabolites. The first step of this reaction is the conversion
OXPHOS to generate ATP. of tryptophan into N-formylkynurenine, which is catalyzed by the
Fatty acid synthesis (FAS), on the other hand, uses precursors rate-limiting enzymes IDO1,2 (Indoleamine-2,3-dioxygenase 1 and
from the other metabolic pathways (glycolysis, TCA cycle and 2) and TDO (Tryptophan-2,3-dioxygenase) (39, 40). Interestingly, it
PPP) to generate lipids. Notably, the acetyl-coA is transformed appears that the tryptophan metabolism in macrophages promotes
into malonyl-coA by the acetyl-coA carboxylases. Seven immune tolerance by increasing the generation of M2 macrophages
molecules of malonyl-coA are then condensated to generate and by depleting extracellular tryptophan, thus modulating T cell
palmitate (the initial product of fatty acid synthesis) by the functions (41, 42).
enzyme Fatty Acid Synthase. Palmitate, a 16 carbons saturated While all these metabolic pathways are described as distinct
molecule, is then elongated and desaturated to generate fatty acid entities, they are highly interdependent and inter-regulated
of diverse size and degrees of saturation (30, 31). demonstrating a tight and complex regulation of cellular
metabolism. A good example of this complex regulation is the
The Amino Acid Metabolism kinase serine/threonine kinase mTOR (mammalian Target of
Amino acids availability is crucial for multiple aspects of cell Rapamycin). mTOR is composed of 2 different complexes
biological functions. Since there is a large number of different mTORC1 and 2 (mTOR Complex). mTOR activation has been
amino acids, there are different pathways leading to the widely demonstrated to be regulated by the level of amino acid in
utilization and generation of amino acids. They can be divided the cell but mTOR is also regulated by the levels of glucose,
into two categories: the essential amino acids which cannot be oxygen and DNA damage (43, 44). Downstream, mTOR can
synthesized by the human body (and therefore need to be taken regulate lipid synthesis or the PPP through SREBP (sterol
from nutrition) and the non-essential amin acids which can be responsive element binding protein) and the glycolysis through
synthesized by the body (32). the transcription factor Hif-1a (Hypoxia induced factor 1 alpha),
An important amino acid for the macrophage behavior is both of which can transcriptionally activate genes that encode
glutamine. Glutamine enters the cell through a diverse range of enzymes belonging to these pathways (45, 46).
Slc transporter including Slc1a5 (Solute carrier 1a5) and Slc3a2, Importantly, these different pathways are used by all mammalian
which are highly expressed in macrophages (33) (Figure 1). cells to generate energy and intermediate metabolites. However,
Glutamine can then contribute to the generation of nucleotides different cells can modulate the use of these pathways to adapt their
or UDP-GlcNac or enter the mitochondria to generate glutamate function, development, or proliferation. In the context of
(34). The glutamate can generate glutathione (which can help to macrophage immunology, it appears that, despite the fact they are
control the redox balance) or be converted into a-ketoglutarate long-lived non proliferative cells, pro- and anti-inflammatory
to enter the TCA cycle. The glutamate is also a donor for the macrophages use different pathways to meet their needs,
generation of many different amino acids (35). differentiate into M1 and M2 macrophages and perform their

function. More specifically, it has now been demonstrated that the (Peroxisome Proliferator-Activated Receptor gamma) (50,
pro-inflammatory M1 macrophages rely on an increased 52) (Figure 2).
dependency on glycolysis and PPP, while they remodel largely The up-regulation of FAO is a crucial feature of AAM (53,
their TCA cycle and depend less on OXPHOS to generate energy. 54). This is orchestrated by a STAT6-PPARg/PGC-1b signaling
This will allow them to sustain an inflammatory phenotype pathway, finally leading to the expression of specific markers of
(increased phagocytosis, production of pro-inflammatory AAM and their survival (53, 55, 56). The main source of fatty
cytokines and chemokines, NO and ROS production, and acids for IL4 treated macrophages is through uptake of fatty
enhanced bacterial killing). On the other hand, the anti- acids via the scavenger receptor CD36 or through the lysosomal
inflammatory M2 macrophages will use the TCA cycle, the FAO lipolysis via lysosomal acid lipase, which both sustain the
and the OXPHOS to generate energy, while relying less on expression of alternative markers (57). Interestingly, during
glycolysis. They will also promote the glutamine metabolism and H. polygyrus infection, the inhibition of lipolysis block AAM
arginase activity. This will promote the expression of M2 markers, differentiation and the elimination of the parasite in an IL4
the production of anti-inflammatory cytokines and their pro-repair setting (57). However, two recent publications challenged the
functions. Interestingly, it appears that other pro- or anti- previous findings demonstrating that FAO is indispensable for
inflammatory immune cells (for example Th1/TH17 versus Treg) AAM polarization. These publications demonstrated that the
use similar pathways than macrophages to sustain their pro- genetic depletion of Cpt1a and Cpt2 does not inhibit the IL4
(glycolysis, PPP) and anti-inflammatory (TCA cycle, OXHPOS, induced polarization (58, 59). They also observed that the
FAO) phenotypes. This highlights the crucial role of the widely used FAO inhibitor etomoxir, at the doses commonly
microenvironmental cues to modulate immune cell metabolism used to inhibit FAO, inhibits IL4 polarization by targeting the
and functions (18, 47). We will now describe in details how CoA metabolism instead of the FAO (59). In fact, despite its
macrophages adapt their metabolic responses during different effect observed at low-dose (FAO inhibitor), a high dose of
types of infections. etomoxir can disrupt intracellular CoA homeostasis therefore
leading to block the IL4-induced polarization. The example of
etomoxir is of great interest for the field of immunometabolism.
In fact, many of the findings in this field rely on the use of
MACROPHAGE IMMUNOMETABOLISM inhibitor, some of which could have several off-targets, and
IN INFECTIONS tightly controlling the dose used when performing experiments
appears to be of crucial importance. This also highlights the
Role of Macrophage Immunometabolism necessity to confirm the findings observed by using inhibitors
During Parasitic Infection with other techniques like gene knock-down and to proceed
Parasitic infections such as helminths and protozoans represent a carefully in the interpretation of the results. The alternatively
major health concern in developing countries. According to the activated macrophages also increase glycolysis in response to
US Center for Disease Control and Prevention (CDC), malaria IL4 in a manner dependent on an AKT-mTORC2-IRF4
(caused by a protozoan named Plasmodium) is responsible for (Interferon regulatory factor 4) signaling pathway (60, 61).
the death of 600 000 people each year, mainly in sub-Saharan Interestingly, the loss of mTORC2 in macrophages during
Africa. Helminths, in the other side, could infect up to 1.5 billion helminth infection by H. polygyrus (Heligmosomoides
people worldwide and lead to diverse manifestations like polygyrus) lead to lose the AAM polarization and their ability
diarrhea, respiratory symptoms, asthma-like symptoms, as well to clear the infection (61). A possible outcome for this increased
as neurologic and motor disorders (16, 48, 49). glycolysis is to feed, together with glutamine, the hexosamine
biosynthetic pathway to promote protein glycosylation. In fact,
Macrophage Metabolism in Helminth the inhibition of this pathway with tunicamycin (an inhibitor of
Infection and IL-4 Dependent Polarization N-glycosylation) prevent the expression of some AAM markers
Helminths generate a type 2 immune response in the infected (54). Another outcome of this increased glycolysis is possibly to
organs, inducing the release of high levels of IL-4 and IL-13, fuel lipid synthesis, acetyl-coA production and TCA cycle (54,
which will instruct the macrophages to adopt an alternatively 62). The pool of acetyl-coA (notably coming from the cleavage
activated macrophages (50, 51). IL4 and IL13 can be produced by of cytosolic citrate from the enzyme ACLY which is activated in
T cells, innate lymphoid cells (ILC), basophils and eosinophils. an AKT-mTORC1 pathway) is used by macrophage in this
AAM express typical markers like RELMa (Resistin-like context to promote the histone acetylation of IL-4 inducible
molecule-alpha), VEGF (Vascular Endothelial Growth Factor), genes (60). However, some recent publications suggest that the
Arg1, YM1, IGF-1 (Insulin-like Growth Factor 1) or TGF-b link between glycolysis and AAM might be more complex. This
(Transforming Growth Factor Beta) which will help them to question has been raised because some publications
control parasite confinement in granulomas and their clearance, demonstrated that some inhibitors used to study the role of
as well as tissue repair and control of the immune response. In glycolysis (ACLY inhibitor and 2-DG) have a broader effect
addition, the transcription factors associated with this AAM than just inhibit their primary target (63). In fact, glucose
phenotype include STAT6 (Signal Transducer and Activator of depletion or galactose treatment, while affecting glycolysis,
Transcription 6), GATA3 (GATA binding protein 3) or PPARg does not affect the AAM polarization. In the meantime, 2-

FIGURE 2 | Phenotypic characteristics of pro- versus anti-inflammatory macrophages. Pro-inflammatory stimuli (like TLR ligands or pro-inflammatory cytokines) will
generate a pro-inflammatory response in macrophages, notably characterized by the production of pro-inflammatory cytokines, the expression of co-stimulatory
molecules and a Th1 response. On the other hand, anti-inflammatory stimuli (like IL4, IL13 or IL10) will promote a pro-repair phenotype in macrophages notably
caracterized by the production of anti-inflammatory and pro-resolutive factors and the generation of a Th2 response. In the context of infection, the generation of
pro-inflammatory macrophages will promote their killing activity but microbes will try to promote the generation of anti-inflammatory phenotype to escape these
responses. Anti-inflammatory macrophages, while promoting infections in general, will have a strong anti-helminth effect. Metabolically, the pro-inflammatory
macrophages use glycolysis and PPP to produce energy and have a broken TCA cycle. Instead, anti-inflammatory macrophages use the FAO and OXPHOS to
provide cellular energy. FAO, Fatty acid oxidation; IFN, Interferon; IL, Interleukin; LPS, Lipopolysaccharide; OXPHOS, Oxidative phosphorylation; NO, Nitric oxide;
PPP, Pentose phosphate pathway; TCA, Tricarboxylic acid; Th, T helper; TLR, Toll like receptor; TNFa, Tumor necrosis factor alpha.
DG, which can suppress both glycolysis and AAM polarization, and helminth infection remain unanswered. Firstly, how the
likely affect the AAM polarization by modulating the ATP glycolysis pathway is up-regulated during AAM; secondly, what
levels and the JAK-STAT6 signaling (64). Thus, several is the exact role of glycolysis during AAM polarization and how
questions about the role of glycolysis during IL-4 polarization it affects helminth infection; and finally, which metabolic

p a t h w a y t h e d i ff e r e n t g l y c o l y t i c m e t a b o l i t e s a r e cycle, AAM will use the glutaminolysis or the FAO. The

preferentially fueling. degradation of glutamine through glutaminolysis in IL-4
In the meantime, IL4 activation limits the use of the PPP in treated macrophages will generate a-ketoglutarate which will
macrophages by increasing the expression of the sedoheptulose promote the AAM polarization through 3 different mechanisms:
kinase CARKL (Carbohydrate kinase-like) that limits the 1) it is used to fuel the FAO; 2) it induces an epigenetic
production of sedoheptulose-7-phosphate, thus promoting an reprogramming demethylation of H3K27 on the promoters of
alternative activation (65). However, the mechanisms by which AAM-specific genes; 3) it favors PHD activity leading to the
the PPP interacts with the IL-4 polarization is not fully inhibition of NFkB pathway (66).
understood and needs to be further investigated. A crucial regulator of AAM polarization is the protein
IL4 treated macrophages generate ATP through an oxidative LAMTOR1 (Late endosomal/lysosomal adaptor and MAPK
TCA cycle coupled to OXPHOS (54) (Table 1). To fuel the TCA and mTOR activator 1). LAMTOR1 is a component of the
TABLE 1 | Metabolic changes induced during pathogen infections.
Pathogen Helminth Protozoa Bacteria Virus Trained

immunity
Glycolysis Increased glycolysis (possibly Depending on Increased glycolysis levels. Role is dependent on viral infection and Increased
to feed the TCA cycle or the the pathogen: Increased expression and/or timeline. Protective during RSV infection glycolysis through
Hexosamine pathway). L. infantum activation of most glycolytic genes and HIV-1 but detrimental during AKT-mTOR-
increases (GLUT1, HK1/2, GAPDH, PKM2…) norovirus and HIV-1 infections. HIF1a.
glycolysis while which promotes the production of
L. donovani pro-inflammatory cytokines
and L. (HMGB1, IL1b, IL6, TNFa…).
amazonensis
don’t. Support
the clearance of
T. cruzi.
PPP Limited use of PPP through Support the Increased PPP (notably through Role largely unknown. Might be Role unknown.
overexpression of CARKL. clearance of T. dowregulation of CARKL) which decreased during HIV-1 infection.
cruzi. support the inflammation.
FAO Up-regulation of FAO and Increased Role unknown. Cholesterol and FA import are increased Role unknown.
lysosomal lipolysis. FAO feed during T. cruzi which promote infection during HIV or
the TCA cycle. infection MHV-68 infections.
FAS Role unknown. Increased Possibly increased to sustain the Increased production of MUFA during Role unknown.
during T. cruzi inflammasome activation and IL1b/ TLR7/9 stimulation (decrease during
infection IL18 production. TLR3) which controls the expression of
pro-inflammatory genes.
TCA cycle/ TCA cycle intact and OXPHOS Depending on TCA cycle broken. Increase in citrate Altered TCA cycle and OXPHOS during Decreased
OXPHOS increased to generate energy. the pathogen: (which fuel PGE2, ROS and NO HIV infection. OXPHOS.
L. infantum production; also activates ACLY
switch from which promote LPS-induced gene
OXPHOS to expression), increase in itaconate
glycolysis while (which inhibits bacterial growth but
L. donovani limit inflammation) and increase in
and L. succinate (which stabilize HIF1a and
amazonensis promote pro-inflammatory gene
promote expression).
OXPHOS.
Aa Glutamine: feed the TCA cycle, Arginine is Glutamine is crucial for the Glutamine is a crucial source of energy Glutaminolysis is
metabolism promote anti-inflammatory depleted by production of NO and IL-1b through during HIV latent infection and has required for the
gene expression and inhibit the macrophages feeding of the TCA cycle. Serine is detrimental effect. IDO expression is induction of
NFkB pathway. Arginine: Arg1 to prevent also crucial for the production of increased during HIV and EBV infections trained immunity
expression highly increased. pathogen IL1b. The arginine metabolism is and its blockade lead to kill infected through control of
Tryptophan: expression of IDO growth during crucial for anti-bacterial response macrophages. Role of Arginine HIF-1a/KDM5
decreased and depletion of Leishmania (notably via the production of NO). metabolism is depending of the phase induction of TNFa
tryptophan. Lamtor1 is critical infections. The role of tryptophan is still unclear. infection and can be beneficial or and IL-6. The role
for expression of IL4 induced detrimental. mTOR is largely modulated of other Aa
markers. by viruses to promote cellular infection. remains unknown.
Aa, Amino acid; ACLY, ATP-citrate lyase; Arg1, Arginse 1; CARKL, Carbohydrate kinase-like; EBV, Epstein-Barr virus; FAO, Fatty acid oxidation; FAS, Fatty acid synthesis; GAPDH,
Glyceraldehyde 3-phosphate dehydrogenase; GLUT1, Glucose transporter 1; HIV, Human immunodeficiency virus; HIF1a, Hypoxia factor 1 alpha; HMGB1, High–mobility group box 1;
HK, Hexokinase; IDO, Indoleamine 2,3-dioxygenase; IL, Interleukin; KDM5, Lysine deacetylase 5; Lamtor1, Late endosomal/lysosomal adaptor and MAPK and mTOR activator 1; MHV-
68, Murine gammaherpesvirus-68; MUFA, Monounsaturated long chain fatty acid; mTOR, mammalian target of rapamycin; NFkB, Nuclear factor kappa B; NO, Nitric oxide; OXPHOS,
Oxidative phosphorylation; PGE2, Prostaglandin E2; PKM, Pyruvate kinase muscle isotype; PPP, Pentose phosphate pathway; ROS, Reactive oxygen species; RSV, Respiratory syncytial
virus; TCA, Tricarboxylic acid; TNFa, Tumor necrosis factor alpha.

mTORC1 complex which is necessary for the recruitment of AMPK (AMP-activated protein kinase) pathway. In this context,
mTORC1 to the lysosome in response to amino acid stimulation the deletion of SIRT1 or AMPK in mice led to promote parasite
(67). Importantly, macrophages deficient for LAMTOR1 or clearance (83). Interestingly, arginine, which is a crucial metabolite
depleted in amino acids in the media are completely unable to for the growth of Leishmania parasite, is depleted by macrophages
express the main IL-4 induced markers (e.g., Arginase I, (either through NO or polyamines). To counterbalance the
Mannose receptor, IL10 and RELMa) demonstrating a decisive depletion of arginine in infected macrophages, Leishmania
role of amino acids for the polarization (68). IL4 treated induces the overexpression of many arginine transporter. These
macrophages metabolize arginine to urea and ornithine via an findings demonstrate that the interaction between host and
increased expression of the Arg1 (69). Arg1 expression is pathogen metabolism is crucial to control the infection (84).
induced by a STAT6-Cebp/b (CCAAT-enhancer-binding During Trypanosoma cruzi infection, the glycolysis and
proteins beta) (70, 71). While Arg1 is one of the most used OXPHOS do not appear to be modulated in macrophages (82).
markers to define AAM, its exact role in macrophage However, FAO and lipids production are increased, and they
polarization remains largely unexplored. Some studies suggest promote the pathogen replication. This appears to be dependent
that, notably through the synthesis of polyamines, Arg1 might on the ability of T. cruzi to promote the expression of LDLR (Low
promote tissue repair during infections (72, 73). Downstream of Density Lipoprotein Receptor) therefore leading to the
arginine, the polyamine-eIF5-hypusine pathway regulates IL4 accumulation of LDL and cholesterol into the cells. However,
mediated polarization of macrophages and the blockade of this the exact downstream mechanisms remain to be elucidated (85,
pathway inhibits the protective effect of IL4 during H. polygyrus 86). Interestingly, IFN-g treatment of macrophages infected with
infection (74). On the other hand, the resistance to infection by T. cruzi support the up-regulation of a glycolysis-PPP axis
the helminth Trichuris muris is unaffected by the deletion of important for the production of ROS and NO and the clearance
Arg1 in macrophages suggesting more complex roles of arginine of the pathogen (87). T. brucei produces large amounts of
metabolism during helminth infection. In this context, indolepyruvate (a transamination product of tryptophan). This
macrophages treated by IL4 downregulate the expression of metabolite reduces the host level of HIF1a and the production of
IDO and promote the expression of the immunoregulatory IL1b as well as the glycolysis during LPS-induced inflammation
phenylalanine oxidase IL4L1 (IL4-induced gene 1) leading to (88). While the links between helminth infection and
the depletion of tryptophan (75, 76). However, the consequence macrophages start to be understood (mostly due to the study of
of this depletion is largely unexplored. One suggestion is that the IL4 treated macrophages), further mechanistic studies will be
depletion of tryptophan in the micro-environment remove a necessary to decipher how macrophages modulate their
source of energy used by helminths. metabolism to fight protozoa infection compared to how the
pathogen modulate their metabolism to favor its survival.
Macrophage Metabolism During
Protozoan Infection
Macrophages also play a crucial role in the immune responses to
protozoan infections. During protozoan infections, macrophage ROLE OF MACROPHAGE
polarization toward a pro-inflammatory phenotype will play a role IMMUNOMETABOLISM DURING
in the clearance of the pathogen. Macrophages will use the BACTERIAL INFECTION
respiratory burst and production of ROS (Reactive oxygen
species), NO (Nitric oxide) and pro-inflammatory cytokines During encounter of bacteria, macrophages are able to sense the
(TNFa, IL6, IFNg) as ways to kill the pathogen and initiate an pathogen through the system of PAMP-PRR. A well described
adaptive immune response if needed (77). Macrophages are PAMP is LPS that signals through TLR4. These stimuli will
responsible for the destruction of the parasites, yet paradoxically generate a pro-inflammatory phenotype of macrophages
also provide a way for parasite to replicate. In fact, protozoan typically characterized by their ability to kill pathogens and
could polarize macrophages toward an anti-inflammatory elicit an adaptive immune response via antigen presentation.
phenotype (similar to the one induced by IL4 during helminth The macrophages express high levels of co-stimulatory molecules
infection) to escape the killing by macrophages and favor their like CD40 (Cluster of differentiation 40), CD80, CD86, as well as
replication (78). Notably, the expression of Arg1, Mannose MHC-II (Major Histocompatibility Complex II) to perform
receptor (also called CD206) or PPARg in macrophages are antigen presentation. They also produce pro-inflammatory
detrimental to the host response during Leishmania infections cytokines such as TNFa, IL6, IL1b, IL12 and IL23 which will
(79–81). promote a TH1 (T helper 1) response leading to the production
At basal state, macrophage infection with L. donovani and of IFNg. The production of these cytokines will also further
L. amazonensis increases the OXPHOS levels, without affecting the polarize the macrophages toward a more pro-inflammatory
glycolysis, which is linked to an increase in the production of pro- profile through a positive feedback loop. Th1 cells, through
inflammatory cytokines and chemokines (82) (Table 1). During production of IFNg, will reinforce this pro-inflammatory
L. infantum infection, macrophages transiently increase aerobic polarization of macrophages notably by enhancing their ability
glycolysis which is followed by a later sustained increased in to clear the bacteria (via increased phagocytosis, autophagy,
OXPHOS through a SIRT1 (Sirtuin 1)-LKB1 (Liver kinase B1)- phagolysosomal maturation and promoting cytokines

production). In the meantime, the enhanced production of NO and macrophages from rheumatoid arthritis patients and a
and ROS will also provide mechanisms to enhance bacterial mouse model of arthritis. The activation of surface a-enolase
clearance. The expression of these factors is controlled by a trigger the production of inflammatory factors (TNFa, IL1b,
network of transcription factors including NFkB (Nuclear factor IFNg and PGE2) and could be detrimental for the pathology but
kappa B), STAT1 and 3, HIF1a or the IRFs (15, 23, 89). While could be beneficial during bacterial infection (97). Finally,
the principle of immunometabolism has been documented in PKM2, the major isoform of pyruvate kinases expressed in
many different contexts, the most well studied one is during the macrophages, is also up-regulated after LPS treatment.
bacterial infections associated with LPS stimulation (coupled or Interestingly, the activity of PKM2 is also regulated by its
not to IFNg stimuli) (Table 1). ability to dimerize or tetramerize (while other PK isoforms
It has been shown that macrophages treated by LPS+IFNg only exists as tetramers). PKM2 tetramer acts as a pyruvate
largely up-regulate their aerobic glycolysis to provide energy to kinase enzyme and therefore it regulates glycolysis, while the
the cell in a more efficient way (54). This increase is mediated by PKM2 dimer can exist in different localizations and has a
the glucose transporter GLUT1 which is up-regulated after moonlighting function (it can notably regulates the
bacterial stimuli. Interestingly, the deletion or up-regulation of mitochondria and ER functions or regulates gene expression in
Slc2a1 result in changes in the expression of many inflammatory the nucleus) (98). LPS induces the tetramerization of PKM2
genes (for example nos2, serpine1, mcp-1) (19, 20). The first step leading to decrease its nuclear localization and the expression of
of glycolysis is the generation of glucose-6-phosphate by the glycolytic and HIF-1a-induced genes. However, its dimerization
Hexokinases (and mostly in immune cells by HK1 and HK2). promotes the expression of pro-inflammatory genes. These
HK1 is regulated by mTORC1 and HK1-induced glycolysis is findings are also applicable in vivo since the activation of
necessary for the activation of the inflammasome (90). HK2 PKM2 decreases the inflammation and the bacterial load in a
exerts a similar effect through its localization in the model of LPS-sepsis and a model of Salmonella typhimurium
mitochondrial membrane. The release of HK2 from the outer infection (99). The knockdown or inhibition of PKM2 confirmed
membrane of the mitochondria is a sufficient event to trigger the that PKM2 is crucial for the inflammatory effect of LPS since it
activation of the NLRP3 inflammasome and the IL1b/IL18 also inhibits the NLRP3 and AIM2 inflammasomes activation,
production (91). The rate-limiting enzyme PFKL has been the HMGB1 (High–mobility group box 1) release and improves
identified as a negative regulator of the oxidative burst in the the survival of the mice in a model of LPS-induced septic shock
context of Staphylococcus aureus infection. When PFKL is (100, 101). Moreover, the inhibition of LDHA (the final step
deleted, glucose is diverted in the PPP rather than entering enzyme of glycolysis) might also protect cells against LPS
glycolysis and sustains the production of NADPH finally induction of pro-inflammatory genes (102). Finally, most of
leading to enhanced bactericidal activity through an the glycolytic enzymes are overexpressed after LPS treatment
unregulated respiratory burst (92). Another glycolytic enzyme, in a HIF-1a-dependent manner, suggesting the regulation of
aldolase can also play a role in macrophage immunometabolism. immune responses through glycolytic enzymes might be much
In fact, treatment of macrophages with itaconate, a well-known wider than previously thought and might also be tightly
anti-bacterial product which is a by-product of citrate and TCA regulated by the network of transcription factors expressed (47,
activity, induces the inhibition of aldolase during LPS 103). However, many of the findings obtained to prove the role of
stimulation and prevents the production of IL1b glycolysis in supporting inflammatory functions of LPS-treated
demonstrating that aldolase promotes the production of IL1b macrophages rely on the use of inhibitors that may possibly be
(93). Downstream of aldolase, LPS can also regulate GAPDH non-specific (e.g., 2-DG as it has been described before) or on the
through the malonylation of its lysine 213 which will regulate its deletion of transcription factors playing a broad role in the
activity and its binding to the TNFa mRNA, leading to an generation of proper immune response (e.g., HIF1a). Thus, it
enhance translation and cytokine production (94). Moreover, needs more studies and development of specific tools to target
macrophage treated with 4-Octyl itaconate modulates GAPDH glycolysis to fully understand the role of glycolysis in the
activity and glycolysis leading to a decrease in LPS-induced development of anti-bacterial responses.
inflammation in vitro and in a sepsis model (95). Another The increase in glycolysis in these cells is substantially
article linked GAPDH to an anti-inflammatory response in rerouted toward the PPP by downregulating the inhibitory
mice. In fact, treatment of LPS-induced sepsis mice with sedoheptulose kinase CARKL. This increase in PPP in turn
GAPDH lead to decrease inflammation and improve survival supports pro-inflammatory macrophage phenotype. It might
in a not fully understood mechanism suggesting that the promote NADPH production necessary for the NADPH
regulation of GAPDH might be a tight point of control for the oxidase and iNOS activity thus supporting an antibacterial
inflammatory response. However, in this study, the authors function (65, 104).
injected high levels (10 mg/kg) of GAPDH originated from While IL4 treated macrophages are not link to changes in the
rabbit muscle in a systemic manner suggesting that this effect TCA cycle, LPS-treated macrophages largely remodel their TCA
might not be relevant to decipher the physiological role of cycle through breaks at several key points of the cycle leading to
GAPDH in inflammation (96). a-enolase, which catalyzes the accumulation of citrate, succinate and itaconate (54, 104, 105).
conversion of 2-phosphoglycerate into phosphoenolpyruvate has Accumulation of citrate is due to a decreased expression of IDH
also been described to be expressed at the surface of monocytes (Isocitrate dehydrogenase) and increased expression of CIC

(Citrate carrier) (leading to its removal from the mitochondria) bacteria) also shifted the mitochondrial and glycolytic
(54, 106). Citrate can then be utilized to fuel the production of metabolism toward quiescence and induces a higher
PGE2 (Prostaglandin E2), NO and ROS (through increased FAS dependency of mitochondria to use exogenous fatty acid as a
and NADPH production) (106). Another crucial role of citrate is source of energy (119).
to promote histone acetylation via ACLY and the expression of Amino acids also have a role in the regulation of macrophages
LPS responsive genes (105–108). The next break occurs at the during bacterial infection. Glutamine is a crucial metabolite for
level of itaconate. Itaconate production is enhanced because of the production of NO as well as for IL1b (120, 121). Of note, a
the increased expression of IRG1 (Immune-Responsive Gene 1) similar phenomenon also occurs in macrophages activated by
(54, 109). Itaconate inhibits directly the growth of bacteria like BCG (122). Glutamine can feed the TCA cycle and is notably
Salmonella enterica and Mycobacterium tuberculosis (Mtb) by responsible for the increase of succinate observed after LPS
targeting the isocitrate lyase demonstrating a strong anti- treatment by inducing a GABA shunt. Inhibiting this
bacterial effect (109). Despite this effect, itaconate has an anti- glutamine-induced GABA shunt protects mice against LPS-
inflammatory effect on macrophage activation triggered by LPS induced sepsis and S. Typhymurium infection in mice (104).
+IFNg treatment by limiting the production of pro-inflammatory While the role of this metabolite is less described, serine is
factors including IL1b, IL6, IL12, NO or HIF1a. This occurs required for the optimal expression of IL1b gene and the
through different mechanisms that include the regulation of blockade of de novo serine synthesis improve survival in a
succinate oxidation (and the level of OXPHOS), the activation model of LPS-induced sepsis (123). The role of tryptophan
of a KEAP1 (Kelch-like ECH-associated protein 1)-NRF2 metabolism is more controversial. Studies have demonstrated
(Nuclear factor erythroid 2-related factor 2) pathway and the that LPS or IFNg can induce the expression of IDO and the
control of the ATF3 (Activating transcription factor 3)-IkBz degradation of tryptophan could have an anti-bacterial effect
(Nuclear factor of kappa light polypeptide gene enhancer in B- (47). However, another group reported that IL4L1 can block the
cells inhibitor zeta) (110, 111). The last break of TCA cycle in LPS effect in macrophages through induction of tryptophan
response to LPS occurs at the level of succinate. Succinate catabolism, suggesting that its exact role needs to be further
production is highly induced after LPS treatment in a studied (76). Finally, the arginine metabolism is another crucial
glutamine dependent manner, which stabilizes HIF-1a and the pathway to modulate the anti-bacterial response by regulating
expression of IL1b (104). Succinate can also promote this the balance between citrulline/NO (notably via iNOS) and the
pathway through the succinylation of PKM2 by SIRT5. Once levels of ornithine and urea (notably via ARG1) (38, 124). It also
PKM2 is succinylated it can form a heterodimer with HIF1a and appears that Mycobacterium tuberculosis regulates several amino
promote the expression of IL1b (112). Another mechanism by acid transporters and metabolic enzymes but the exact
which succinate can activate HIF1a is through its oxidation, mechanisms by which it affects the host response versus the
coupled with an increased mitochondrial potential membrane, bacterial survival remains to be elucidated (125).
which increases ROS production and thus the stability of HIF1a Despite the well described effect of LPS, other bacterial
(113). Interestingly, succinate can also promote inflammation infections have been described to modulate the host
through an autocrine and a paracrine manner via its release into metabolism. LPS has been widely used to study macrophage
the extracellular milieu and its sensing by the receptor immunometabolism because it is a simple way to mimic bacterial
GPR91 (114). infections and it shares functional similarities with other TLR
The role of fatty acid in macrophages treated by LPS is poorly ligands. However, it is a single product of gram-negative bacteria
understood. While the FAO seems to not be important for (and therefore does not mimic the possible effect of gram-
macrophage polarization, the fatty acid synthesis might play a positive bacteria) and it does not mimic the complex in vivo
role. In fact, LPS-treated macrophages increased their settings in which several TLR ligands and inflammatory
production of triglycerides which is associated with an increase mediators, as well as several types of bacteria, can modulate
in CD36 expression (115). The production of FA is regulated immunometabolism. Besides LPS, infection of human
through a UCP2 (Uncoupling Protein 2)-FASN (Fatty acid macrophages with Legionella Pneumophila induces aerobic
synthase) axis which can trigger the activation of the NLRP3 glycolysis and the inhibition of glycolysis by 2-DG reduces
inflammasome and the production of IL1b and IL18. The bacterial replication. The OXPHOS is however largely
regulation of this pathway improves the survival in a model of suppressed due to mitochondrial fragmentation through
polymicrobial sepsis (116). Salmonella infection promotes the accumulation of DNM1L (Dynamin 1 like) (126, 127).
expression of PPARd in macrophages. This will induce a switch L. Pneumophila also induces the production of itaconate by
from a glycolytic metabolism toward FA metabolism in host cells IRG1 which promotes the bacterial clearance as a host protective
and allow Salmonella to use the available glucose to promote its mechanism (128). Besides these effects, L. Pneumophila
replication (117). Mycobacterium tuberculosis, through an IFNg- modulates the expression of genes involved in lipid and amino
HIF1a axis, promotes the formation of lipid droplets. Lipid acid metabolism but more studies are needed to precisely define
droplets are not used by the bacteria for replication, but are the roles of these genes (129). During Mycobacterium
rather used by macrophages to promote the production of PGE2 tuberculosis infection, interstitial and alveolar macrophages
and LXB4 (Lipoxin B4) to support host defense (118). Live both have different roles and metabolism. In mice, interstitial
Mycobacterium tuberculosis (in contrast the dead or attenuated macrophages use the glycolysis to differentiate toward a pro-

inflammatory phenotype and control bacterial growth as well as from apoptosis (148). However, a previous study reported that
the mice survival. On the other hand, alveolar macrophages use HIV-I infection of macrophages decreased the glucose uptake
the fatty acid oxidation and are not able to control bacterial and the levels of several glycolytic intermediate (149). These
infection. Blocking glycolysis with 2-DG enhances bacterial discrepancies suggest that the timeline of infection as well as
replication while blocking FAO with etomoxir decreases other parameters like cell differentiation status (monocytes vs
bacterial replication (130–132). Interestingly, the control of macrophages) and the phenotype (pro- vs anti-inflammatory)
glycolysis in alveolar macrophages appear to be dependent on might play a part for the regulation of glycolysis into HIV-
miR-21 which controls the expression of PFKM and IL1b (133). infected macrophages and need to be further studied (150).
Finally, and similarly to other pathogens, Staphylococcus aureus During Dengue virus infection, the expression of GLUT1 and
has to ability to modulate the host metabolism which has been HK2 are increased as well as the level of early (from glucose to
recently reviewed recently (134–137). Another important glyceraldehyde 3 phosphate) glycolytic metabolites (G6P, F6P),
metabolic regulation of bacterial infection through metabolism while the levels of late (from glyceraldehyde 3 phosphate to
is that bacteria can reroute the macrophage metabolism to use pyruvate) glycolytic metabolites is increased at shorter time
nutrients for their own use which is nicely described elsewhere (10 h) and decreased later (48 h). Interestingly, glycolysis
and might be a key in the macrophage response to infections supports the viral replication and inhibition of glycolysis using
(138–141). oxamate (a competitive inhibitor of LDH) and 2-DG blocks the
viral replication (151). A similar phenomenon occurs during
murine norovirus infection (152). While the authors of these two
papers did not study further mechanisms, they hypothesized that
ROLE OF MACROPHAGE an increase in glycolysis could promote the generation of
IMMUNOMETABOLISM DURING biomolecules needed for their replication such as lipids, ATP
VIRAL INFECTION or NADH. The role of glycolysis during viral infection might be
virus dependent. In fact, during VSV (Vesicular stomatitis virus)
During viral infections, macrophages will elicit a pro- infection, glycolysis is increased through a type I IFN dependent
inflammatory response similar to what have been described pathway. The expression of several glycolytic enzymes is
during bacterial infection. Coupled to this, macrophages will increased in this context, and more particularly the expression
also start producing type I interferons (interferon alpha and of PFKFB3 which supports the viral phagocytosis and protects
beta). The sensing of ssRNA, dsRNA and unmethylated DNA the mice during RSV (Respiratory syncytial virus) infection
with CpG motifs via TLR3, 7 and 9, respectively, will trigger type in vivo (153). Finally, during SARS-CoV2 infection,
I interferon production by macrophages. The RLR family macrophages largely increase their glycolytic levels which
members will also recognize viral motifs and mediate the promotes the viral replication and the production of pro-
production of type I interferons (142). Type I interferons will inflammatory cytokines. Mechanistically, the infection induces
therefore signal through their receptors (Interferon-a/b receptor the production of mROS leading to the stabilization of HIF1a,
1 and 2) which will lead to the activation of the PI3K, MAPKs, thus promoting glycolysis. Interestingly, these changes in
STATs and IRF9 ultimately leading to the induction of the ISGs metabolism inhibit T cell responses and reduce epithelial cell
(Interferon Stimulated Genes). Theses ISGs include genes survival (154).
implicated in the mount of antiviral responses, inflammation, Little is known regarding the role of PPP during viral
pro- and anti-apoptotic molecules as well as regulation of infections in macrophages. A pioneer study underlined that
translation and RNA turnover. Type I interferons can be 6PG and S7P are decreased during HIV-1 infection and the
produced by a broad range of cells including macrophages, ratio NADP/NADPH is largely decreased (149). However, the
dendritic cells, epithelial cells, fibroblasts, as well as functional role of these changes in PPP remains unknown and
plasmacytoid dendritic cells (which is the primary source of will have to be further studied. Importantly, it has to be noted
interferons during viral infection). Type I interferon will that virus, similarly to what has been described above for
therefore signal in the abovementioned cells as well as in T bacteria, can hijack the host glycolysis (and metabolism in
and B cells (143, 144). Interestingly, while macrophages were not general) in an attempt to use these nutrients to sustain their
supposed to be the primarily source of type I interferon replication and survival in the host (155, 156).
producers, it clearly appears that they are able to control viral Similarly, the function of TCA cycle is poorly defined. During
infection through production of IFNa/b and are among the first HIV infection, the levels of the TCA cycle metabolites are
responders during viral infections (145, 146). unchanged (except for malate which is increased) (149).
The exact role of glycolysis during viral infection remains However, macrophages surviving HIV infection present an
unclear. First of all, the expression of GLUT1 is increased in altered TCA cycle and OXPHOS (157).
monocytes from HIV infected patients and is linked to an On the other hand, the activation of macrophages by viruses
increase in glucose uptake and the generation of pro- and their products largely remodels their lipid pool. The
inflammatory monocytes (147) (Table 1). HIV-I infection in stimulation of macrophages with TLR3, 7 and 9 agonists to
monocytes/macrophages also promotes the expression of HK1 mimic viral infection modulates the lipid composition of nearly
and its localization to the mitochondria thus protecting the cells all lipid classes. These changes largely occur through a MyD88

and TRIF signaling pathway and the interferon signaling is also a complex manner during viral infection. The activation of innate
requirement to these changes. Interestingly, the TLR3 and TLR7/ immune responses by viruses induces the production of NO by
9 signaling differentially modulate the fatty acid synthesis macrophages and other immune cells (176). But some viruses
respectively because of their use of the TRIF (TIR-domain- like the Sendai virus will try to limit the production of NO as a
containing adapter-inducing interferon-b) and MyD88 mechanism to escape host responses (177). In fact, while
(Myeloid differentiation primary response 88) signaling beneficial at first, a sustained production of NO over the time
pathways. While TLR3 stimulation decreased the generation of will lead to damage the host tissues and inhibits the Th1
saturated long chain fatty acid (SFA) and monounsaturated long responses (176); (178). Arginine, in the other hand, is a critical
chain fatty acid (MUFA), the TLR7/9 stimulations increased metabolite for the replication of viruses and the inhibition of
these levels. Mechanistically, the MyD88-NRF2 (Nuclear factor Arg1 reduces the viral replication and ability to infect the host
erythroid 2-related factor 2)/SREBP (Sterol regulatory element- cells (179). However, Arg1 might also promote the tissue repair
binding protein) axis induces the expression of stearoyl-CoA after viral infection [for an extensive review about the role of
desaturases 1 and 2 which negatively controls the inflammation arginine metabolism see (180)]. Finally, viruses can target mTOR
(Il1b, Il6 and Cxcl1 expression notably) through an increased to modulate the innate immune responses. For example,
production of these MUFAs (158). While this study was Vaccinia virus encode the protein F17 which as the ability to
performed using only TLR agonists, other publications in disrupt the mTOR complex in the Golgi which will block the
different cell types suggest that targeting fatty acid during activation of STING (Stimulator of interferon genes) and the
different types of viral infections might be a strategy to control generation of an interferon-mediated immune response (181,
viral replication (159–161). Type I interferons can also promote 182). Additionally, viruses can modulate mTORC1 to inhibit
the import of cholesterol and long chain fatty acid during murine host protein translation or promote the translation of their own
gammaherpesvirus-68 (MHV-68) infection (but also with HIV). mRNAs (183–185).
In this setting, blocking the lipid import protects from viral
infection through production of type I interferon in a STING-
dependent manner (162). Moreover, the infection of
macrophages by HIV impairs the cholesterol efflux through a ROLE OF MACROPHAGE
Nef (Negative regulatory factor)-ABCA1 (ATP-binding cassette IMMUNOMETABOLISM DURING
A1) pathway inducing the formation of foam cells. In the TRAINED IMMUNITY
meantime, the activation of TLR8 in macrophages by ssRNA
from HIV reinforces this foam cell phenotype through the The immune system is classically divided into two arms: the
production of TNFa (163, 164). Besides these effects, the innate immune system and the adaptive immune system.
cholesterol has also largely been demonstrated to be crucial for Scientists assumed for a long time that only the adaptive
the virus entry in the cell and the anti-viral response (165–168). immune system has an immunological memory, and that the
A growing number of evidence showed that SARS-CoV2 innate immune system was only able to sense pathogens in a
infection is linked to a reprogramming in lipid metabolism partially unspecific manner (through the PRR) which does not
with cholesterol playing a crucial role. Indeed, membranes rich last over the time. However, this concept has recently been
in cholesterol are a point of entry of SARS-CoV2 in the cells largely challenged. In fact, it appears that innate immune cells
(169). The enzyme cholesterol 25-hydroxylase (CH25H, do have an ability to develop a broad immunological memory
belonging to the ISGs) is highly induced during SARS-CoV2 that lasts over the time (and could even be antigen-specific in
infection and restricts viral infection by depleting cholesterol on some cases) (186, 187). These memory-like responses are now
the plasma membrane (170, 171). Moreover, SARS-CoV2 well known as trained immunity (188–190). Overall, trained
promotes the expression of several lipid synthesis modulators immunity will induce an enhanced inflammatory response in
(including SREBP1/2, CD36, PPARg or DGAT-1) leading to the response to secondary stimuli marked by the increased ability of
production of cholesterol and lipid droplets. Blockade of this monocytes to produce inflammatory cytokines (notably TNFa
pathway can decrease both the viral replication and the and IL6) trough sustained changes in metabolism. In human
inflammatory response induced by SARS-CoV2 (172, 173). monocytes, the stimulation with b-glucan followed by 7 days of
The modulation of amino acid uptake and production is also resting period leads to a decreased level of OXPHOS, increased
a crucial regulator during viral infections. The amino acid glucose consumption and lactate production (Table 1). An AKT-
glutamine is the main source of energy during HIV latent mTOR-HIF1a pathway is responsible for this increase in
infection along with glutamate and a-ketoglutarate and glycolysis and its blocking (either by pharmacological or
blocking the use of these metabolites induces the death of genetic inhibition) abrogates this trained immunity and is
latency infected macrophages (157). EBV (Epstein-Barr virus) protective in lethal models of C. albicans and S. aureus
and HIV infections both induce the expression of IDO in infections (191). Glutaminolysis is also required for the
macrophages in an IL6 and TNFa dependent manner thus induction of trained immunity through its ability to sustain the
inhibiting the activation of T cell activation. Inhibition of IDO production of fumarate which will modulate the stability of
eventually lead to the elimination of the macrophages infected by HIF1a and KDM5 (Lysine deacetylase 5) activity, thus
viruses (174, 175). The arginine metabolism is regulated in a promoting the epigenetic reprogramming at the promoter of

IL6 and TNFa (192). The cholesterol pathway is also linked to coronavirus 2) infection that leads to the development of
the induction of trained immunity through the induction of COVID-19 (Coronavirus disease 2019) and firstly appeared in
mevalonate production (192, 193). Mechanistically, mevalonate December 2019 in Wuhan, China. In fact, the development of
promotes the function of IGF1R (Insulin-like growth factor 1 potential therapeutics is critically needed since it already affected
receptor) and mTOR leading to subsequent epigenetic changes more than two hundred fifty million people worldwide and led to
(193). A similar glycolysis-AKT-mTOR-epigenetic pathway is 5,284,432 deaths (according to the daily WHO report on
also involved during BCG (Bacille Calmette-Guerin)-induced December 7th). As other viral infections, COVID-19 induces
trained immunity demonstrating that this pathway might be a the development of an immune response in which the innate
general process during different type of stimuli inducing trained immune cells (and notably macrophages) are the first line of
immunity (194). Interestingly, a similar phenomenon is observed defense (201). Several studies have been reported that the
in hematopoietic myeloid progenitors and increases the progression to severe forms of infection by COVID-19 (but
myelopoiesis (195). At the opposite of the concept of trained this also true for many viral and bacterial infections like the
immunity is the concept of immune tolerance (or development of sepsis) is associated with an overt and
immunoparalysis) which induced a persistent tolerance in dysregulated production of inflammatory factors like IL1b, IL6,
macrophages over the time, notably in response to LPS (186, TNFa, IFNg, GMCSF, CCL2, CCL3, CCL4, CXCL10 and many
189). Tolerant monocytes from sepsis patients show an impair others (202, 203). This cytokine release syndrome (or cytokine
levels of OXPHOS and glycolysis and IFNg can restore the storm) is responsible for damages during infections and more
metabolic defects through activation of mTOR (196). The state particularly into the lungs of patients of sepsis and COVID-19
of tolerance is induced by itaconate and b-glucan can revert this [also called Acute respiratory distress syndrome (ARDS)] and
state of tolerance by blocking the expression of Irg1 and plays a major role in the related deaths observed in patients with
increasing the expression of Sdh eventually reversing the severe conditions (204–207). Importantly, the monocyte/
immunoparalysis (197, 198). macrophage system is largely remodeled during acute SARS-
CoV2 infection with an increased proportion of inflammatory
monocyte infiltration in patients with severe condition and
macrophages harboring a highly pro-inflammatory phenotype
TARGETING MACROPHAGE (208, 209). Interestingly, a similar phenomenon occurs during
IMMUNOMETABOLISM AS A SARS-CoV infection (210, 211). As discussed before, many of
POTENTIAL THERAPEUTIC TARGET FOR these parameters are regulated by metabolism suggesting that
INFECTIONS: AN EMPHASIS targeting metabolism might be a therapeutic strategy to protect
ON COVID-19 against this overt inflammation during severe infections and
more particularly during COVID-19. Five drugs targeting
Macrophages have, for a long time, be considered potential metabolism are currently in use clinically to treat different
targets to control immune responses in a wide variety of diseases and could be used to prevent the cytokine storm:
diseases (199, 200). As new research shed light on the role of dimethylfumarate (DMF), metformin, methotrexate, rapamycin
immunometabolism in macrophages, it becomes clear that and dexamethasone (Table 2).
targeting the immunometabolism in macrophages can be a Firstly, DMF (a fumarate analog and NRF2 activator
therapeutic target during the development of many diseases currently used for the treatment of multiple sclerosis) notably
including infections. A current focus of research in the past inhibits NFkB, ERK (Extracellular-signal-regulated kinase) and
few months has been the development of drugs and vaccines for other signaling pathway. In macrophages, DMF will notably
the SARS-CoV-2 (Severe acute respiratory syndrome activates NRF2 to protect the cells from oxidative stress and
TABLE 2 | Potential therapeutic molecules for the treatment of infections.
Molecule Target Consequence
Already used in clinic

DMF NRF2-KEAP1, NFkB, ERK, GAPDH Decreases glycolysis and inflammation, promotes an anti-inflammatory phenotype.
Metformin Complex I of OXPHOS Inhibits ROS, ATP and IL1 b production, promotes IL-10 production.
Methotrexate AICAR (at low dose) Raises adenosine levels and activates AMPK. Decreases IL1b, IL6 and TNFa levels.
Rapamycin mTOR Promotes tolerance and controls glycolysis and inflammation.
Dexamethasone Multiple possible targets (including mTOR, NFkB…) Promotes tolerance. Increases OXPHOS and ROS levels. Antibacterial effect.
In development
2-DG Hexokinase Blocking of glycolysis. Decreases inflammatory responses.
TEPP-46 PKM2 Inhibits glycolysis, HIF1a and IL1b production
DMM SDH Inhibits HIF1a and IL1b production, promotes IL-10 and IL1RA production.
2-DG, 2-deoxyglucose; Aa, Amino acid; AICAR, Amido-imidazolecarbox-amido-ribonucleotide; DMF, Dimethylfumarate; DMM, Dimethylmalonate; Erk, Extracellular-signal-regulated
kinase; FAO, Fatty acid oxidation; FAS, Fatty acid synthesis; HIF1a, Hypoxia factor 1 alpha; HK, Hexokinase; HMG-CoA, b-hydroxy b-methylglutaryl-CoA; IL, Interleukin; KEAP1, Kelch-like
ECH-associated protein 1; mTOR, mammalian target of rapamycin; NFkB, Nuclear factor kappa B; NRF2, Nuclear factor erythroid 2-related factor 2; OXPHOS, Oxidative phosphorylation;
PKM, Pyruvate kinase muscle isotype; ROS, Reactive oxygen species; SDH, Succinate dehydrogenase; TNFa, Tumor necrosis factor alpha.

promote an anti-inflammatory phenotype (212). DMF also acts therapeutic efficacy to control the overt inflammation during
on glycolysis since it decreases the activity of GAPDH suggesting SARS-CoV2 infection (225–227). The effect of methotrexate on
therefore that DMF could be repurposed to modulate viral-induced inflammation has been or is currently being tested
immunometabolism during infectious diseases (213). Similarly in two cohorts of SARS-CoV2 and HIV patients and will
to DMF, 4-OI (an itaconate analog not used in clinic for the require further investigations (NCT01949116, NCT04352465).
moment) target the NRF2-KEAP1 pathway and might prevent Methotrexate is currently used as an anti-tumoral, anti-psoriatic
the cytokine storm during acute infections (214). These 2 analogs and anti-arthritic drug. However, due to its immunomodulatory
work by mimicking their respective metabolites suggesting that effects, methotrexate is associated to an increased level of
fumarate and itaconate modulation could be interesting targets infection in rheumatoid arthritis patients. Moreover, its use is
to dampen inflammation in infectious settings. Interestingly, a also linked to hepatotoxicity, pulmonary toxicity, nephrotoxicity,
recent report suggested that these 2 drugs might have a potent hematologic toxicity as well as gastrointestinal side effects and
antiviral and anti-inflammatory activity during COVID-19 carcinogenicity and 20-30% of patients have to stop the usage of
(DOI:10.21203/rs.3.rs-31855/v1, under review in Virology). this drug due to these side effects (which could remain for up to 5
Metformin is a first-line treatment for the treatment of type 2 years) therefore emphasizing the need of more research to
diabetes and metabolic disorders notably through a glucose determine its potential use to treat infections (228).
lowering effect. Interestingly, metformin has also an Another interesting target is to modulate mTOR by using the
immunomodulatory function. Both these functions depends on inhibitor rapamycin (or similar mTOR inhibitors like
the ability of metformin to activate AMPK. This occurs through everolimus, vistusertib or AZD8055). It has been demonstrated
the ability of metformin to inhibits the complex I of ETC which that rapamycin can protect mice against inflammation and death
controls the production of ATP and ROS. The blockade of ATP (through control of macrophages) in a model of CLP-induced
generation will lead to an increase in AMP or ADP/ATP ratio sepsis (229). Moreover, derivatives of rapamycin were shown to
which will consequently activate AMPK (215). Metformin is reduce the rate of infection to influenza in elderly in without side
known to suppress the production of IL1b and promotes the effects (230). These findings have led to the hypothesis that
production of IL10 in response to LPS (216). Interestingly, rapamycin might be a potential target to treat infections and
metformin has been used in the 1940’s as an antimalarial drug might be of great interest in severe forms of COVID-19 (231,
as well as to treat influenza and might show interesting properties 232). mTOR has also been hypothesized to be a therapeutic
in the treatment of M. tuberculosis and COVID-19 (217–220). target during Mtb, T cruzi or HIV infections (233–235) and the
Importantly, three recent studies have suggested that metformin safety and efficacy of sirolimus is currently being tested in a
could be used as a therapeutic during HIV, SARS-CoV2 and Mtb clinical trial as a Covid-19 treatment (NCT04461340). As an
infections (219, 221–223). In all pathologies, metformin use has immunosuppressant, blocking mTOR (notably with the use of
been linked to an improved survival in diabetes and obese patients. sirolimus) is linked to development of cancer (especially
Mechanistically, metformin reprograms the immunometabolism lymphoma and skin cancer), infections and other adverse
of CD4 and CD8 T cells which lead to a modulation of viral events including hyperglycemia and dyslipidemia (236).
replication and enhanced the immune responses. However, Finally, Dexamethasone, a synthetic glucocorticoid with anti-
whether macrophages can be targeted by metformin remains to inflammatory and immunosuppressive properties is widely used to
be studied (219, 223). Metformin has therefore be proposed to treat inflammatory conditions. Dexamethasone acts largely
possibly be a treatment for several bacterial, protozoal and viral through macrophages by decreasing their production of pro-
infections (https://doi.org/10.1002/dmrr.2975), and several clinical inflammatory factors (like CCL2, TNFa, COX-2…) (237–239).
trials to assess the use of metformin during HIV (NCT04500678, Dexamethasone is able to promote bacterial phagocytosis and
N C T0 2 3 8 3 5 6 3 , NCT02 65930 6, NCT049 30744 ) M tb killing by human macrophages in vitro and is protective in a
(NCT04930744) or SARS-CoV2 (NCT04510194) infections are model of LPS-sepsis (240, 241). A possible mechanism of action is
now ongoing. However, despite a relative good safety profile, also to increase the expression of OXPHOS genes and to promote
metformin is associated with several side effects (notably at the the production of ROS by macrophages finally leading to suppress
cutaneous and gastro-intestinal tract levels) and approximately 5% the T cell responses (242, 243). Interestingly, dexamethasone has
of the patients have to discontinue the treatment (224). recently been determined to be the first drug to save lives in the
At high dose, the methotrexate is an inhibitor of the DHFR SARS-CoV2 infection. The RECOVERY trial enrolled 2100
(Dihydrofolase reductase) which will block the downstream patients treated with low to intermediate doses of dexamethasone
inhibitors of the folate pathway eventually leading to the (6 mg per day for 10 days) compared to patients receiving standard
inhibition of nucleotide synthesis. At lower dose, methotrexate care. The survival rate was improved by 30% in patients receiving
is inhibiting AICAR (Amido-imidazolecarbox-amido- invasive ventilation and by 20% in patients receiving oxygen
ribonucleotide) leading to the increased production of the anti- support (without invasive mechanical ventilation) (244).
inflammatory factor adenosine. Methotrexate can induce the However, as a corticosteroid with an immunosuppressive action,
activation of AMPK and further inhibit the production of dexamethasone has been described to have several side effects and
IL1b, IL6 and TNFa in macrophages in response to LPS (and the dose used appears to be critical (245).
can also inhibit the activation of pro-inflammatory B and T cells Besides the drugs already approved in clinic, the development
and promote the generation of Treg) suggesting a potential of drugs inhibiting the metabolites implied in the mounting of an

immune response can be targeted as well (Table 2). For example, seen as a unique block, they all intersect each other and a break in a
the development of 2-DG (HK2 inhibitor, currently tested in 219 unique metabolite might largely affect the cell behavior rendering
clinical trials currently), TEPP-46 (PKM2 activator) or the things more complex. Despite these limitations, the possibility to
dimethylmalonate (DMM, SDH inhibitor, tested in phase 2 target metabolism in macrophages to control infectious disease has
clinical trials currently) might be an important advance in the shown a great potential and might play an important role in the
development of immunometabolic inhibitors (226). These finding for a cure of different infections, including COVID-19.
finding provide a crucial understanding on how using drugs Indeed, the modulation of macrophages phenotype is a promising
targeting macrophage immunometabolism (notably to prevent target since, contrary to many other immune cell types, it can be
the cytokine storm) might be used as therapeutic targets during targeted in a specific manner through the use of liposomes or other
infections and more specifically during SARS-CoV2 Infection. cellular “backpack”, thus limiting specificity and side effects (246,
247). Based on these facts, it is likely that an increase in macrophage
immunometabolism understanding will provide new insights to
cure infections.
CONCLUDING REMARKS
The past decade has seen a great development in our understanding
on how the metabolism can regulate immune responses. AUTHOR CONTRIBUTIONS
Macrophages have been demonstrated to be a key player in how
immunometabolism regulates the mount of a proper immune TG and WC drafted and edited the manuscript. All authors
response during different types of infections. Although the contributed to the article and approved the submitted version.
modulation of metabolism has been largely described in vitro in
response to LPS and IL4, its role in different complex
microenvironment and more importantly in vivo remains largely FUNDING
poorly understood. Moreover, much of the data has been published
in mice and the potential to target metabolism in humans must be This research was supported by the Intramural Research
further studied. While the different major metabolic pathways are Program of NIDCR.
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p a t h w a y t h e d i ff e r e n t g l y c o l y t i c m e t a b o l i t e s a r e cycle, AAM will use the glutaminolysis or the FAO. The

TABLE 1 | Metabolic changes induced during pathogen infections.

Pathogen Helminth Protozoa Bacteria Virus Trained

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TABLE 2 | Potential therapeutic molecules for the treatment of infections.

Molecule Target Consequence

Already used in clinic

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REFERENCES 13. Weiss G, Schaible UE. Macrophage Defense Mechanisms Against

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