Article

ISSN 0006-2979, Biochemistry (Moscow), 2024, Vol. 89, No. 5, pp. 817-838 © Pleiades Publishing, Ltd., 2024.

817

REVIEW

Metabolic Adaptations and Functional Activity

of Macrophages in Homeostasis and Inflammation

Taisiya R. Yurakova

, Ekaterina A. Gorshkova

, Maxim A. Nosenko

and Marina S. Drutskaya

1,3,a

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia

Trinity Biomedical Sciences Institute, Trinity College Dublin, D02F306 Dublin, Ireland

Division of Immunobiology and Biomedicine, Center of Genetics and Life Sciences,

Sirius University of Science and Technology, 354340 Federal Territory Sirius, Russia

e-mail: marinadru@gmail.com

Received November 27, 2023

Revised February 6, 2024

Accepted February 8, 2024

Abstract— In recent years, the role of cellular metabolism in immunity has come into the focus of many studies.

These processes form a basis for the maintenance of tissue integrity and homeostasis, as well as represent an

integral part of the immune response, in particular, inflammation. Metabolic adaptations not only ensure energy

supply for immune response, but also affect the functions of immune cells by controlling transcriptional and

post-transcriptional programs. Studying the immune cell metabolism facilitates the search for new treatment

approaches, especially for metabolic disorders. Macrophages, innate immune cells, are characterized by a high

functional plasticity and play a key role in homeostasis and inflammation. Depending on the phenotype and

origin, they can either perform various regulatory functions or promote inflammation state, thus exacerbating

the pathological condition. Furthermore, their adaptations to the tissue-specific microenvironment influence the

intensity and type of immune response. The review examines the effect of metabolic reprogramming in macro-

phages on the functional activity of these cells and their polarization. The role of immunometabolic adaptations

of myeloid cells in tissue homeostasis and in various pathological processes in the context of inflammatory and

metabolic diseases is specifically discussed. Finally, modulation of the macrophage metabolism-related mecha-

nisms reviewed as a potential therapeutic approach.

DOI: 10.1134/S0006297924050043

Keywords: proinflammatory cytokines, macrophage polarization, immunometabolism

Abbreviations: 2-DG,2-deoxyglucose; 2-HG,2-hydroxyglutarate; ARG1,arginase 1; ACLY,ATP citrate lyase; AMPK,AMP-ac-

tivated protein kinase; CPT,carnitine palmitoyltransferase; DMF,dimethyl fumarate; ETC,electron transport chain; FA,fat-

ty acid; HIF-1α, hypoxia-inducible factor 1-alpha; IDH, isocitrate dehydrogenase; iNOS, inducible nitric oxide synthase;

LDHA,lactate dehydrogenase; LPS,lipopolysaccharide; mTOR,mammalian target of rapamycin; OXPHOS,oxidative phos-

phorylation; PGE

, prostaglandin E2; PKM2, pyruvate kinase M2; PPP, pentose phosphate pathway; ROS, reactive oxygen

species; SDH,succinate dehydrogenase.

* To whom correspondence should be addressed.

INTRODUCTION

The majority of immunological studies in cell and

animal models have been focused on the functions

of immune cells, in particular, antigen recognition,

as well as elimination and production of active com-

pounds and cytokines. Because of this, immune re-

sponse has become increasingly viewed as a systemic

body response leading to metabolic rewiring and func-

tional changes in tissues and organs. The association

between metabolism and immune system was first dis-

covered in the last century by physiologist Otto War-

burg, who noticed that upregulation of glycolysis was

characteristic not only of tumor cells, but also of the

activated leukocytes [1, 2]. Now, it is commonly recog-

nized that metabolic adaptations are an integral part

YURAKOVA et al.818

BIOCHEMISTRY (Moscow) Vol. 89 No. 5 2024

of the immune response [3-8]. The discovery of regula-

tory pathways involved in the metabolic control of im-

mune processes during infection, cancer, and tissue re-

generation at the cellular, tissue, and organ levels have

led to the emergence of a new interdisciplinary field of

research, immunometabolism [3, 8]. Immunometabolic

disorders are responsible for many diseases typical

for the modern human population, including obesity,

diabetes, sepsis, autoimmune and autoinflammatory

diseases [3]. Hence, understanding the mechanisms

by which physiological microenvironment of immune

cells in tissues and organs regulates their functions is

very important. Among immune cells, macrophages

are of a special interest because they can be found in

almost all animal tissues and represent an integral

component in the maintenance of tissue homeostasis

[9]. The review describes the relationship between the

functional and metabolic features of macrophages in

homeostasis and immunometabolic disorders, as well

as discusses possible therapeutic approaches based on

the modulation of macrophage metabolism.

FUNCTIONAL AND PHENOTYPIC

DIVERSITY OF MACROPHAGES

Macrophages had been initially considered as a

part of the mononuclear phagocytic system responsi-

ble for the removal of pathogens and apoptotic cells,

but the current understanding of the functions and

Fig. 1. Macrophage differentiation and polarization. a)Tissue-resident macrophages differentiate from three types of hemato-

poietic stem cell precursors found in the yolk sac, embryonic liver, and bone marrow. b)Origin of tissue-resident macrophages

in different organs. Tissue-resident macrophages are formed in closed niches during embryogenesis; in adults, peripheral

blood monocytes do not migrate into these niches. In open niches, monocytes are recruited at different rates (slow or fast)

and replace tissue-resident macrophage pool formed during embryogenesis. c)Phenotype of tissue-resident macrophages is a

result of their differentiation and polarization. Macrophages polarize into pro-inflammatory(M1) or anti- inflammatory(M2)

phenotypes under the influence of external stimuli. Created with the BioRender.com based on previously published

data[20, 24-26].

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BIOCHEMISTRY (Moscow) Vol. 89 No. 5 2024

the origin of macrophages have been significantly ex-

panded. Macrophages were shown to play an import-

ant role in homeostasis, tissue formation during em-

bryogenesis, and wound healing, as well as in various

tissue-specific functions [10]. Thus, tissue-specific mac-

rophages determine normal development and func-

tioning of the brain, bones, ovaries, and adipose tissue.

Macrophages are involved in the control of systemic

metabolism and temperature adaptation [11, 12]. Fi-

nally, macrophages play an important role in the de-

velopment of metabolic diseases, such as atherosclero-

sis [13], osteoporosis, obesity, and type  2 diabetes [14,

15]. Pathogenic contribution of macrophages to fibro-

sis [16] and tumor development has been recognized

as well [17].

Tissue-resident macrophages can vary dramati-

cally in both phenotype and functions. A population of

macrophages in an organ or tissue is characterized by

the functional heterogeneity that depends on the cell

location, tissue condition, cell origin, and many other

factors. Tissue-resident macrophages can differentiate

from the precursors of hematopoietic stem cells found

in the yolk sac, embryonic liver, and bone marrow [18,

19]. The proportion of macrophages originating from

different migration waves varies depending on the or-

gan [20] (Fig.1, a and b).

The phenotype of a macrophage largely depends

on the surrounding signals [21]. The two main mac-

rophage phenotypes are pro-inflammatory (M1) and

anti-inflammatory (M2). M1 macrophages induce and

maintain inflammation via release of pro-inflammato-

ry cytokines, activation of endothelial cells, and attrac-

tion of other immune cells to the site of inflammation.

M2 macrophages counteract inflammation by phago-

cytosis of apoptotic cells, triggering of collagen depo-

sition, coordination of tissue repair processes, and re-

lease of anti-inflammatory cytokines [22]. It should be

noted that the M1 and M2 phenotypes could be clear-

ly distinguished mainly in in  vitro experiments using

certain combinations of stimuli. Under physiological

conditions, the phenotype of macrophages is greatly

influenced by various signaling molecules and tissue

microenvironment, so pure M1 or M2 phenotypes are

rarely observed in vivo [23]. Depending on the con-

text, macrophages acquire an intermediate or unique

phenotype and are typically represented by a mixed

heterogeneous population of M1 and M2 cells [23].

Therefore, macrophage polarization in  vivo should be

viewed as a complex tissue-specific process developing

in time (Fig.1) [24-26].

There are two stages of “decision-making” at the

molecular level in polarization [27]. The first one is al-

teration in the functional state of M1/M2 macrophages

that involves activation of signaling pathways associat-

ed with either innate immunity, such as signaling via

pattern recognition receptors (PRR), or stimuli from

T cells [28, 29]. Signals leading to macrophage polar-

ization in  vivo are often difficult to identify [21]. Bac-

terial endotoxin, lipopolysaccharide (LPS), or a com-

bination of LPS and interferon gamma (IFNγ, main

Th1-associated cytokine) are generally used to polarize

M1 macrophages in  vitro. M2 macrophages are polar-

ized using Th2-associated cytokine interleukin-4 (IL-4)

or a combination of IL-4 and IL-13 [22]. IRF, STAT,

and NF-κB transcription factors play a key role in the

control of M1/M2 polarization, M1 regulators (NF-κB-

p50-p65, STAT1, IRF5, SOCS3, and HIF-1α) being antag-

onists of M2 regulators (NF-κB-p50-p50, STAT6, IRF4,

SOCS1, and HIF-2). The second stage of “decision-mak-

ing” involves interaction of transcription factors [30]

and is closely related to the activity of the two main

regulators of cellular metabolism– AMP-activated pro-

tein kinase (AMPK) and mammalian target of rapamy-

cin (mTOR). The most important outcome of the second

stage is altered expression of metabolism-associated

genes, which affects a variety of metabolic processes,

such as glycolysis, Krebs cycle, oxidative phosphoryla-

tion (OXPHOS), pentose phosphate pathway (PPP), for-

mation of NADPH and reactive oxygen species (ROS),

biosynthesis of nucleotides and amino acids, as well as

nitrogen metabolism.

METABOLIC ADAPTATIONS

OF MACROPHAGES DURING POLARIZATION

To meet the demands for ATP and NADPH, M1

macrophages use aerobic glycolysis and PPP, leading to

the breaks in the Krebs cycle at two points and reduc-

tion in the cellular respiration, in particular, OXPHOS,

as well changes in the metabolism of fatty acids (FAs)

(upregulation of beta oxidation and suppression of

synthesis of FAs). M2 macrophages do not depend on

glycolysis and mainly use OXPHOS as a source of en-

ergy, so that there are no breaks in the Krebs cycle.

During M2 polarization, glucose is utilized mainly by

the PPP and used for the synthesis of uridine diphos-

phate N-acetylglucosamine (UDP-GlcNAc) [31]. The

changes in the metabolism of FAs in M2 macrophages

are opposite to those observed in M1 cells, i.e., the

synthesis of FAs is decreased and their beta oxida-

tion is upregulated [22, 30]. Based on the changes in

the characteristic properties of M1 or M2 phenotypes

(Table  1) acquired as a result of pharmaceutical or ge-

netic suppression of metabolic enzymes, it is possible

to assess the contribution of particular metabolic path-

ways to the macrophage polarization. Below, we dis-

cuss in detail the metabolic changes that occur during

macrophage polarization.

Glucose metabolism. Glucose is important in both

M1 and M2 polarization [32,  33], but its distribution be-

tween metabolic pathways is different for these two

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Table 1. Properties of M1 and M2 macrophages

Polarization property M1 (LPS + IFNγ) M2 (IL-4 + IL-13)

Stimuli

LPS + IFNγ;

bacterial products; LPS and other ligands

of Toll-like receptors (TLRs);

cytokines of Th1 lymphocytes (IFN-γ, TNF)

IL-4 + IL-13;

basophiles;

mast cells; Th2 lymphocytes

Cell-derived

mediators

TNF, IL-1β, IL-6, IL-12, IL-23;

ROS, PGE

IL-10, TGFβ, IGF-1, VEGF-A,

EGF, PDGF

Cell surface markers CD80, CD86, CIITA, MHCII

mannose receptor (CD206),

CD36, IL1Rα, CD163 CD36,

RELMα (FIZZ1in humans), MMP

Signaling pathways

NF-κB (p50-p65), STAT1, IRF5, HIF-1α, SOCS3, AP1;

inflammasome activation

NF-κB (p50-p50), STAT6, IRF4,

HIF2, SOCS1, GATA3, PPARγ,

(in mice also YM1)

Functions

elimination of bacteria; tumor resistance;

Th1 response; pathogen elimination and antigen

presentation to T lymphocytes

anti-inflammatory response;

tissue remodeling;

wound healing; angiogenesis

types of macrophage activation. M1 macrophages sig-

nificantly increase glucose entry via upregulation of

the GLUT1 transporter [34], while glucose utilization

by M2 macrophages remains unchanged [35]. Glycol-

ysis has been considered as the main metabolic path-

way conjugated with ATP production in immunome-

tabolism. However, recent data indicate an important

role of PPP and glycosylation in the metabolism of acti-

vated immune cells. The studies of glucose metabolism

typically use glucose analogue 2-deoxyglucose (2-DG).

However, the effect of this compound in immune cells

is nonspecific, as it blocks all glucose catabolism path-

ways, not only glycolysis [36]. As a result, 2-DG dis-

rupts polarization of both M1 and M2 macrophages,

which has led to erroneous conclusion on a significant

contribution of glycolysis to both types of macrophage

polarization.

A more detailed study has demonstrated a criti-

cal importance of glycolysis for M1 macrophages [31].

Activation of M1 macrophages is associated with the

increase in the expression of several variants of the

key glycolysis enzyme– phosphofructokinase (PFK1-M

and PFK2) [35,  37]. The reaction catalyzed by this en-

zyme is irreversible and represents a commitment step

for glycolysis. Upregulation of the PFK-M expression

is associated with the suppression of production of mi-

croRNA-21 upon macrophage stimulation by IFNγ [37].

PFK2 suppression leads to a decrease in the expression

of inducible NO synthase (iNOS) and mitogen-inducible

form of cyclooxygenase (COX2) by M1 macrophages[35].

Only M1 (but not M2) macrophages demonstrate in-

creased expression of the phosphofructokinase regu-

lator (PFKFB3); inhibition of this protein prevents up-

regulation of glycolysis and activation of M1 macro-

phages [38]. Inhibition of glyceraldehyde 3-phosphate

dehydrogenase (GAPDH), one of the key glycolytic en-

zymes, suppresses IL-1β production similar to 2-DG

[32, 39]. Finally, suppression of lactate dehydrogenase

(LDHA) and pyruvate dehydrogenase  1 (PDK1) genes

also caused a decrease in the IL-1β production by the

macrophages [40]. The critical importance of glycolysis

for M1 macrophages remains poorly understood. Pre-

sumably, it might be due to the OXPHOS suppression

during M1 polarization, which requires a compen-

satory upregulation of glycolysis to ensure ATP pro-

duction. OXPHOS remains active in M2 macrophages,

making glycolysis nonessential for maintaining ener-

gy balance [36].

The most important transcription factor regu-

lating glycolysis is hypoxia-inducible factor 1-alpha

(HIF-1α) [41]. HIF-1α controls expression of genes

coding for glycolytic enzymes, glucose transporter

GLUT1, inflammatory mediators, LDHA, and PDK.

LDHA catalyzes pyruvate conversion to lactate; PDK

inactivates pyruvate dehydrogenase (PDH) and reduc-

es pyruvate entry into the Krebs cycle. Pyruvate con-

version to lactate is important for M1 macrophages

as it provides restoration of the NAD

pool in order

to maintain glycolytic reactions. HIF-1α expression is

regulated by signals from the innate immune recep-

tors and proinflammatory cytokines via NF-κB [42-44]

and growth factors. For example, granulocyte-macro-

phage colony-stimulating factor (GM-CSF) activates

HIF-1α through the PI3K/AKT/mTOR pathway [45-49].

Although HIF-1α is inactivated in the presence of

oxygen, it can be stabilized by succinate produced

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BIOCHEMISTRY (Moscow) Vol. 89 No. 5 2024

in the mitochondria due to breaks in the Krebs cycle

[22, 32].

Expression of different isoforms of pyruvate kinase

M2 (PKM2) accounts for different regulation of glycol-

ysis in M1 and M2 macrophages [35, 50, 51]. PKM2 has

two conformations: the tetramer is enzymatically ac-

tive and participates in glycolysis, while the dimer,

which lacks the enzymatic activity, localizes to the

nucleus and functions as a transcription factor that

regulates expression of HIF-1α-dependent genes, in-

cluding Il1b. Stabilization of the PKM2 tetramer with

the small TEPP-46 molecule reduces activation of M1

macrophages and makes them phenotypically similar

to M2 cells [50].

Pentose phosphate pathway takes place in the

cytoplasm. The oxidative phase of PPP plays an im-

portant role in the metabolism of M1 macrophages

[32, 52]. During this phase, glucose-6-phosphate is con-

verted to ribulose-5-phosphate, which is accompanied

by the NADPH formation from H and NADP

. NADPH

is involved in the synthesis of glutathione, an antiox-

idant that protects cells from oxidative stress. On the

other hand, NADPH is a substrate for many ROS-pro-

ducing enzymes, for example, NADPH oxidases (NOXs)

are essential for the pathogen destruction by M1 mac-

rophages [22, 53]. NADPH is also required for the syn-

thesis of FAs and prostaglandins.

PPP is less important in M2 macrophages and is

involved in cell metabolism to a much lesser extent.

On the one hand, UDP-GlcNAc synthesized from ri-

bose-5-phosphate produced during the PPP oxidation

stage, is used in N-glycosylation of the mannose re-

ceptor abundantly present on the surface of M2 mac-

rophages [54]. UDP-GlcNAc can be synthesized from

glucose-1-phosphate independently of PPP during M2

polarization [31]. The importance of N-glycosylation for

the M2 phenotype development has been confirmed in

the experiments using the inhibitor of N-glycosylation

tunicamycin [31]. On the other hand, it was recently

demonstrated that activation of PPP suppresses effero-

cytosis (phagocytosis of tolerogenic apoptotic cell) that

is characteristic for M2 macrophages [55].

Oxidative phosphorylation. OXPHOS is the main

source of ATP in the cells under normoxic conditions,

including inactive macrophages (M0). Polarization in-

creases energy requirements of the cells regardless of

polarization type, but the activity of OXPHOS in M1

and M2 macrophages differs. M1 macrophages are

characterized by OXPHOS suppression, while M2 po-

larization, on the contrary, increases the activity of the

electron transport chain (ETC) [56]. Nitric oxide (NO)

suppresses OXPHOS in M1 macrophages by blocking

the ETC and prevents their repolarization into M2

macrophages [57]. Besides, recognition of live bacteria

by the macrophages results in the reduction of active

complexes  I and III of the ETC due to the ROS produc-

tion [58]. Activation of STAT6 during M2 polarization

leads to the upregulated expression of genes involved

in the FA oxidation and OXPHOS [59]. OXPHOS sup-

pression, in turn, interferes with the expression of M2

markers, such as arginase 1 (ARG1) and mannose re-

ceptor.

The functioning of the ETC is inevitably accompa-

nied by the generation of ROS. Thus, ROS generation

in the mitochondria is a result of electron leakage

through the complexes I, II, and III in the case of dis-

ruption of the ETC or mitochondrial membrane po-

tential. ROS production in the mitochondria depends

on the metabolic state of these organelles [60,  61].

Itshould be noted that the decrease in the respiration

during M1 polarization is associated with the increase

in the production of mitochondrial ROS, which stim-

ulates secretion of proinflammatory cytokines [62].

Thus, activation of macrophages with LPS leads to the

ROS production, apparently, via reverse electron flow

from the succinate dehydrogenase (SDH) complex in

the ETC. Moreover, activation of the toll-like receptors

(TLRs) 1, 2, and 4 stimulates mitochondrial ROS gen-

eration due to the TRAF6 translocation into the mito-

chondria [63]. Macrophages produce ROS in response

to a pathogen or activation by proinflammatory cyto-

kines; ROS generation is associated with the activation

of NOXs and is independent of cyanides that block the

complex IV of the respiratory chain. ROS production

by cells of the innate immune system, including mac-

rophages, is necessary to fight pathogens, however, a

prolonged inflammatory process increases ROS pro-

duction, resulting in oxidative stress, which leads to

the dysfunction of the vascular endothelium and other

disorders [64].

The Krebs cycle, also known as the tricarboxyl-

ic acid cycle, is a central metabolic pathway that pro-

vides cells with ATP. During macrophage activation,

many processes, such as proliferation, synthesis of

cytokines and other proinflammatory mediators, mi-

gration, and phagocytosis, require ATP. Moreover, M2

macrophages need ATP to maintain high levels of gly-

cosylation of lectin and mannose receptors. Intermedi-

ate metabolites of the Krebs cycle are also important

for the macrophage activation and polarization. Their

accumulation in the cell can result from the breaks in

the Krebs cycle due to the inhibition of isocitrate de-

hydrogenase (IDH) or SDH. The impact of Krebs cycle

intermediates (citrate, itaconate, succinate, fumarate,

and alpha-ketoglutarate) on the macrophage polariza-

tion is described in detail in [65, 66].

Citrate is synthesized in the Krebs cycle via con-

densation of oxaloacetate and acetyl-CoA formed from

pyruvate or as a product of FA catabolism. M1 macro-

phages accumulate citrate in the cytosol due to the IDH

suppression at the transcriptional level and overex-

pression of the mitochondrial citrate carrier (CIC) [67].

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Despite its ability to suppress glycolysis by affecting

phosphofructokinases directly and pyruvate kinase in-

directly, as well as to stimulate gluconeogenesis [68],

citrate seems to be essential in the regulation of FA

synthesis in M1 macrophages. Citrate is a substrate of

ATP-citrate lyase (ACLY), an important source of ace-

tyl-CoA utilized in the FA synthesis cycle. Inhibition of

ACLY leads to a decrease in the production of prosta-

glandin E2 (PGE

), NO, and ROS, that play an important

role in the inflammation and oxidative stress [69].

Itaconate is one of the most abundant metabolites

in M1 polarization [31]. It is produced from cis-aconi-

tate by aconitate decarboxylase 1 (ACOD1), whose ex-

pression is upregulated in M1 macrophages. On one

hand, itaconate is a competitive SDH inhibitor that

interrupts the Krebs cycle and suppresses OXPHOS in

proinflammatory macrophages [70,  71]. On the other

hand, itaconate binds covalently to cysteine residues

in proteins [72], thus suppressing their biological func-

tions. For example, itaconate alkylates cysteines in

fructose-1,6-bisphosphate aldolase (ALDOA), GAPDH,

and LDHA, i.e., the key glycolytic enzymes, thus block-

ing their activity and leading to the reduction of glu-

cose consumption and lactate production by the cells

[72]. By alkylating KEAP1, itaconate activates NRF2

transcription factor which stimulates expression of

genes involved in cell protection from the oxidative

stress [73]. Finally, itaconate inhibits the production of

NO and proinflammatory cytokines (TNF, IL-6, IL-1β,

IL-12, and IL-18) by M1 macrophages [70, 74] partially

due to the suppression of IκBζ, a regulator of transcrip-

tional activity of NF-κB. Itaconate promotes Activating

transcription factor 3 (ATF3) production in cultured

macrophages, which, in turn, leads to IκBζ suppression

at the post-transcriptional level [75]. In the case of

IL-1β, itaconate not only suppresses expression of the

Il1b gene, but also interferes with the cytokine pro-

duction at the post-translational level by reducing

caspase-1 activity [76]. Moreover, some itaconate deriv-

atives alkylate NLRP3 directly, preventing the assem-

bly of the inflammasome [77]. Itaconate presumably

participates in the feedback loop involved in acquisi-

tion of the M1 phenotype by slowing down and limit-

ing the activation of M1-associated genetic programs,

which may play an important role in the control of

immune response. M2 macrophages do not produce

itaconate, but can uptake it from the medium [78].

Itwas recently shown that exogenous itaconate inhib-

its differentiation of M2 macrophages by suppressing

the IL-4 signaling pathway mediated by JAK1/STAT6

[79]. There are also data that macrophage-derived

itaconate affects tumor cells [80] and T cells [81]. Al-

though itaconate is a specific metabolite of M1 po-

larization, it exerts a wide range of effects on sur-

rounding cells, contributing to the formation of the

M1-favorable microenvironment.

Succinate is generated in the Krebs cycle from

succinyl-CoA by succinyl-CoA-ligase and is converted

to fumarate by SDH. SDH is a part of the Krebs cycle

and a component of the complex II of the ETC. Itacon-

ate accumulating during M1 polarization reduces SDH

activity, leading to the accumulation of succinate in

the mitochondria [70]. Succinate can be transport-

ed by the dicarboxylate transporter (DIC, SLC25A10)

from the mitochondria to the cell cytoplasm, where it

has multiple functions. First, succinate inhibits prolyl

hydroxylase (PHD) and thereby blocks HIF-1α degra-

dation in the presence of oxygen. This results in the

HIF-1α accumulation and activation of aerobic gly-

colysis, also known as the Warburg effect, as well as

production of proinflammatory cytokines (e.g., IL-1β)

[32]. Second, it causes post-translational changes in

proteins via succinylation of lysine residues. For ex-

ample, succinylation of pyruvate kinase in M1 mac-

rophages leads to the HIF-1α-mediated increase in

the IL-1β production [82]. Finally, succinate serves as

a cell–cell mediator of inflammation; it is secreted by

inflammatory macrophages and interacts with G pro-

tein-coupled SUCNR1/GPR91 receptors, thus promot-

ing IL-1β production [83, 84]. It should be noted that

expression of succinate receptors on the macrophage

surface increases in response to inflammatory signals

(LPS, TNF, and IFNγ) [67].

Fumarate is a product of SDH activity. However,

fumarate levels are significantly elevated in M1 mac-

rophages despite the inhibition of SDH, which is due

to the increased expression of argininosuccinate syn-

thase (ASS1), an enzyme of the urea cycle, in proin-

flammatory macrophages. ASS1 catalyzes the synthesis

of argininosuccinate, which is then decomposed into

arginine and fumarate. Fumarate, a by-product of the

urea cycle, has a significant effect on the total fuma-

rate level which increases with inflammation. More-

over, according to some data, fumarate and arginino-

succinate are among the most produced metabolites in

activated macrophages compared to inactive cells [85].

Fumarate inhibits IL-10 production, thereby increas-

ing TNF biosynthesis. The effect of fumarate on IL-10

production may be associated with suppression of the

ERK signaling pathway and PI3K signaling [85].

Alpha-ketoglutarate (α-KG) is formed by IDH via

isocitrate conversion in the Krebs cycle. It is involved

in many immune processes [86], e.g., epigenetic repro-

gramming. First of all, α-KG is the main cofactor in

several families of histone demethylases, such as JMJD

(Jumonji C-domain-containing histone demethylases)

and TET (ten-eleven translation) enzymes [87, 88].

α-KG promotes transcription of IL-4-dependent genes

due to its action on JMJD3. On the other hand, exoso-

mal α-KG is also involved in M2 polarization by acti-

vating TET-mediated DNA demethylation, which leads

to the suppression of the STAT3/NF-κB pathways [89].

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Finally, α-KG stimulates FA oxidation, which is a com-

mon feature of M2 macrophages. Interestingly, a high

α-KG/succinate ratio contributes to M2 polarization,

while the low one, on the contrary, determines the

proinflammatory M1 phenotype. Since α-KG is a co-

factor of JMJD3, while succinate inhibits this enzyme,

their combined action allows to regulate H3K27 de-

methylation [90].

2-Hydroxyglutarate (2-HG), which exists in both

L- and D-isoforms, is also involved in the epigenetic

regulation. 2-HG can be synthesized by the nonspecific

activity of several enzymes, such as malate dehydro-

genase (MDH), LDHA, and mutant IDH1/2mut isoform

found in tumor cells [91, 92]. 2-HG, succinate, and fu-

marate inhibit α-KG at the epigenetic level [93,  94],

therefore, the ratio between these compounds, espe-

cially between 2-HG and α-KG, is important in several

immune processes. 2-HG accumulates in tissues under

hypoxic conditions or at low pH [95], as well as in M1

macrophages in response to LPS activation [96]. In  vitro

experiments have shown that L-2-HG inactivates HIF

prolyl hydroxylase, stabilizes HIF-1α, and thus pro-

motes IL-1β production and activation of glycolysis

[96]. In contrast, D-2-HG, also formed in M1 cells, con-

tributes to the suppression of inflammatory processes

at the late stage of LPS-induced response in  vitro and

is a regulator of local and systemic inflammatory re-

actions in  vivo [97].

Amino acid metabolism is important not only

in cell homeostasis and protein synthesis, but also in

many immune processes, including macrophage po-

larization [98]. The deficit of amino acids in the me-

dium impairs migration, proliferation, maturation,

and effector functions of immune cells. The effects of

arginine, glutamine, glycine, and serine on the macro-

phage functions have been studied in more detail.

Activated macrophages require arginine as a sub-

strate for two competing enzymes – ARG1 and iNOS.

Typically, ARG1 expression in M2 macrophages is in-

creased. ARG1 converts arginine into urea and orni-

thine; ornithine initiates the synthesis of polyamines

involved in tissue repair. Overall, ARG1 contributes to

the anti-inflammatory phenotype of macrophages and

thereby suppression of T cell proliferation and cyto-

kine production [94]. Ornithine is also essential for

the immune functions of macrophages in the context

of Mycobacterium tuberculosis infection [99, 100]. The

expression of iNOS in macrophages is upregulated by

proinflammatory stimuli (LPS, TNF, IFNγ). iNOS con-

verts arginine to nitric oxide and citrulline; NO spon-

taneously reacts with oxygen and ROS, resulting in

the generation nitrogen and oxygen species with the

antimicrobial and regulatory activities. ASS1 converts

citrulline into argininosuccinate, which is further de-

graded to arginine and thus maintains NO production.

In addition to the ROS generation, NO is involved in

the remodeling of mitochondrial ETC during M1 polar-

ization. Thus, the treatment of macrophages with LPS/

IFNγ leads to the induction of NO synthesis along with

the decrease in the activity of complexesI and II; the

short-term action of NO on the macrophages results in

the reversible inhibition of complex IV, due to the NO

competition with oxygen for the enzyme catalytic site

[101, 102]. Although disturbances in the functioning of

complex I contribute to the increase in the ROS pro-

duction in the mitochondria and expression of proin-

flammatory factors such as IL-1β and TNF [103], recent

studies have shown that this process is not directly re-

lated to the NO action [104, 105]. Apparently, at later

stages of activation, NO has the regulatory functions

due to the ability to inhibit mitochondrial complexes

and to reduce their number [106]. Moreover, the effect

NO on the ETC leads to changes in the mitochondrial

morphology and is one of the factors preventing re-

polarization of M1 macrophages to the respiration-de-

pendent M2 phenotype [57].

Another important compound for the macro-

phages is glutamine which is required for the syn-

thesis of amino acids and nucleotides, production

of NADPH and energy, and many other biosynthet-

ic processes [107, 108]. Depending on the metabolic

pathway, glutamine stimulates either M1 or M2 mac-

rophage polarization. On one hand, glutamine can en-

ter the Krebs cycle through α-KG, thereby stimulating

the synthesis of succinate in M1 macrophages [32],

which is also significant for the HIF-1α stabilization

and glycolysis maintenance [109]. At the same time,

upregulation of succinate biosynthesis is accompanied

by an increase in the expression of the SLC3A2 glu-

tamine transporter gene and activation of glutamine

uptake [110, 111]. Interestingly, some of succinate in

LPS-activated macrophages is produced by the gam-

ma-aminobutyric acid (GABA) shunt. In this pathway,

which bypasses the Krebs cycle, glutamine is used for

the sequential synthesis of glutamate, GABA, succinic

semialdehyde, and eventually succinate. Inhibition of

GABA transaminase, the key enzyme of this pathway,

significantly reduces the amount of succinate produced

from glutamine and, as a result, prevents HIF-1α sta-

bilization and IL-1β secretion in response to LPS [32].

On the other hand, the deficiency of glutamine in

the medium or inhibition of glutaminase by its se-

lective blocker bis-2-(5-phenylacetamido-1,3,4-thiadi-

azole-2-diyl) ethyl sulfide (BPTES) during macrophage

activation by LPS prevents the development of endo-

toxin tolerance [90], similar being demonstrated in a

mouse model of toxic shock [112]. Endotoxin tolerance

is an important mechanism of homeostasis mainte-

nance, as acquisition of the tolerance toward repeated

LPS stimulation by the macrophages helps to protect

the body against possible excessive immune system ac-

tivation [113]. Therefore, glutamine is involved in both

YURAKOVA et al.824

BIOCHEMISTRY (Moscow) Vol. 89 No. 5 2024

inflammatory response of M1 macrophages to LPS and

their subsequent negative regulation through the tol-

erance formation.

Glutamine metabolism can also contribute to the

M2 polarization, mainly by stimulating accumulation

of α-KG [90]. Like glucose, glutamine is necessary for

the synthesis of UDP-GlcNAc that is used by M2 mac-

rophages for glycosylation of mannose receptor and

RELMα [31]. M2 macrophages not only import gluta-

mine from the environment, but also synthesize it

from glutamate and ammonia using glutamine syn-

thetase (GS). GS is fundamental for the M2 phenotype.

It is almost absent in M1 macrophages and is highly

expressed in M2 macrophages, especially in response

to IL-10 [114]. Therefore, both the lack of glutamine in

the medium and the inhibition of glutaminolysis by

BPTES lead to disturbances in the alternative polariza-

tion of macrophages [31, 90].

Serine and glycine play an important role in the

regulation of redox balance, as both of them are in-

volved in the synthesis of glutathione. The mainte-

nance of the redox balance is important for the M1

polarization of macrophages, since ROS produced by

these cells cause oxidative stress [63, 115, 116]. This

triggers the activity of the NRF2 transcription factor

and results in the reduction of the LPS-induced NF-κB

activity, in particular, due to the regulation of gluta-

thione metabolism [117,  118]. Serine conversion to

glycine may be necessary for glutathione production

[119]. At the same time, endogenous synthesis of ser-

ine in LPS-activated macrophages is known to lead

to the production of S-adenosylmethionine, which is

involved in the epigenetic regulation of IL-1β expres-

sion[119].

Fatty acid synthesis and oxidation. FAs are es-

sential for the synthesis of cell membranes and vari-

ous bioactive compounds, e.g., eicosanoids. Moreover,

FAs are another important “energy currency” of the

body; their oxidation results in the synthesis of ATP.

Macrophage polarization is highly dependent on

FA metabolism. Thus, FA anabolism is typical for M1

macrophages: activation of TLRs, e.g., by IFNγ, caus-

es accumulation of triacylglycerides (in a form of fat

droplets), diacylglycerides, and cholesterol esters [120,

121], which correlates with the phenotype of foam

cells, i.e., macrophages associated with atherosclero-

sis, granulomas, and other inflammatory pathologies

[122]. Accumulation of fats is preceded by the activa-

tion of lipogenesis due to the activity of the transcrip-

tion factor SREBP-1 [123] and ACLY, which produces

acetyl-CoA from citrate for subsequent utilization by

fatty acid synthase (FAS) [124]. Macrophages from

mice deficient for these transcription factors, enzymes,

and some carrier proteins involved in FA anabolism,

such as uncoupling protein  2 (UCP2) [125] and ace-

tyl-CoA carboxylase (ACC) [126]), demonstrated a de-

creased ability for proinflammatory response, mainly

due to the inflammasome disruption. It was recently

shown that fat droplets in M1 macrophages serve as a

source of PGE

production. PGE

is responsible for the

activation of phagocytosis and production of IL-1β and

IL-6 in macrophages. The blockade of DGAT1 (carrier

involved in FA deposition) causes suppression of the

in  vitro and in  vivo inflammatory responses of macro-

phages [120].

As mentioned above, the Krebs cycle remains

undisturbed in alternatively activated macrophages,

which maintains higher OXPHOS levels; the main

source of acetyl-CoA in M2 macrophages is FA. Beta ox-

idation occurs in the mitochondria, and the entry of

FAs into these organelles is provided by carnitine pal-

mitoyltransferases 1 (CPT1, located in the outer mito-

chondrial membrane) and 2 (CPT2, located in the inner

mitochondria membrane). Recent experiments with

pharmacological and genetic blockade of CPT1/2 have

shown that the inhibition of beta oxidation does not

block the acquisition of the M2 phenotype by mouse

[127] and human [128] macrophages, contrary to the

previous views [129]. Both synthesis and beta oxida-

tion of FAs are important for the inflammasome func-

tioning. Thus, NLRP3 activation can be inhibited by the

activity of NOX4, which, in turn, regulates CPT1A [130].

The balance between the FA synthesis and oxidation

is the most important regulator of inflammasome ac-

tivation, and, therefore, of the inflammatory response

of M1 macrophages [131]. Although, the role of FA me-

tabolism in the M2 phenotype is currently undergoing

revision, modulation of FA metabolism is still consid-

ered as a promising therapy for reprogramming tu-

mor-associated M2-like macrophages [132, 133].

REGULATION OF METABOLIC

REPROGRAMMING OF MACROPHAGES

DURING POLARIZATION

Reprogramming of metabolic pathways during

macrophage activation largely depends on the key met-

abolic master regulators mTOR and AMPK [134-136].

mTOR forms two types of complexes: mTORC1 and

mTORC2 [137]. mTORC1 integrates information coming

from the extracellular (growth factors, cellular stress)

and intracellular stimuli (concentration of amino acids

in the lysosomes, sugar levels, and lipid content) and

transmits it further, activating HIF-1α, PPARγ, SREBP-1,

and MYC, which promotes cell division, activates bio-

synthesis of nucleic acids, proteins, and lipids, and

suppresses catabolic processes and autophagy [136,

137]. The balance of the mTORC1/mTORC2-mediated

signaling is critically important for the macrophage

differentiation and polarization and is controlled

by signaling cascades mediated by innate immunity

METABOLIC CHANGES IN MACROPHAGE POLARIZATION 825

BIOCHEMISTRY (Moscow) Vol. 89 No. 5 2024

Table 2. Correlation between metabolic changes and macrophage polarization

Metabolic pathway and factors M1 (LPS + IFNγ) M2 (IL-4 + IL-13)

Glycolysis

highly activated;

involved in maintaining the pro-inflamma-

tory properties of macrophages

activated;

important for macrophage

response to IL-4

GLUT1 ↑ –

PFK ↑ –

6-Phosphofructo-2-kinase/

fructose-2,6-bisphosphatase 3 (PFKFB3)

↑–

PKM2 dimer tetramer

PPP

activated; essential for ROS generation

by NOX, NO production, nucleotide

and protein synthesis

participates in the synthesis

of UDP-GlcNAC

Oxidizing phase of PPP:

phosphogluconate dehydrogenase (PGD)

↑–

Non-oxidizing phase of PPP:

sedoheptulose kinase carbohydrate

kinase-like protein (CARKL)

↓↓

Krebs cycle and OXPHOS

weakened by NO and itaconate;

reverse electron transport, ROS production,

HIF-1α stabilization; IL-1β expression

OXPHOS activation;

intact Krebs cycle

Mitochondrial morphology

predominance

of fragmented mitochondria

predominance

of mitochondrial networks

Citrate = first cycle break

IDH ↓ –

CIC ↑ –

ACLY ↑ –

Itaconate

ACOD1

↑–

Succinate = second cycle break

SDH

↓–

Amino acid metabolism

Arginine

iNOS ↑ ↓

ARG1 ↓ ↑

Tryptophan

Indoleamine 2,3-dioxygenase (IDO) ↓ ↑

Glutamine

GS ↓ ↑

PHD ↑ ↓

Lipid metabolism fatty acids synthesis ↑ fatty acids oxidation ↑

SREBP ↑ –

Liver X receptor (LXR) – ↑

Note. “↑”, green, increased compared to inactivated macrophages (M0); “–”, grey, no changes compared to M0; “↓”, red, decreased

compared to M0.

YURAKOVA et al.826

BIOCHEMISTRY (Moscow) Vol. 89 No. 5 2024

receptors, cytokines, and growth factors [138]. mTORC1

is essential for M1 polarization, while mTORC2 appears

to be important for both types of macrophage activa-

tion [137]. The involvement of mTORC1 is largely asso-

ciated with its ability to regulate anabolism via coor-

dination of production of many factors mediating the

functions of activated macrophages. Thus, SREBP-1 ac-

tivation by mTORC1 is critically important for cytokine

production, synthesis of lipids and lipid mediators,

and phagocytosis. SREBP-1 also controls NADH produc-

tion in the PPP necessary for the ROS generation [136].

The PI3K/AKT/mTOR signaling pathway is important

for the stimulation of glycolysis and cell proliferation

[136, 139]. Finally, mTOR is associated with glutamine

metabolism. The mTORC2/IRF4 signaling pathway is in-

volved in metabolic reprogramming occurring during

alternative macrophage activation [140]. mTORC1 also

promotes M2 polarization, in particular, by stimulat-

ing the synthesis of UDP-GlcNAc and N-glycosylation

of lectins [31]. Moreover, the mTORC1-dependent syn-

thesis of lipid mediators (which is associated with the

expression of COX2 in M1 macrophages and of COX1

in M2 macrophages) is involved in the production of

both proinflammatory and anti-inflammatory media-

tors [141].

AMPK, along with mTOR, participates in the inte-

gration of various signals and regulates cell metabo-

lism through the enzyme-mediated post-translational

modification of target proteins [142]. These master

regulators complement each other. While mTOR senses

the level of nutrients and triggers anabolic processes,

AMPK detects the deficit in energy and activates cat-

abolic processes aimed at ATP synthesis [143]. Thus,

in the case of energy deficit (e.g., during starvation),

AMPK responds to the intracellular AMP content and

phosphorylation state of RAPTOR and TSC2 proteins

and suppresses signaling pathways associated with

mTORC1 [144]. Therefore, AMPK activation in macro-

phages typically results in the suppression of inflam-

matory response and M1 polarization [145-149]. The

absence of AMPK leads to the hyperpolarization of

macrophages towards the M1 phenotype in response

to the LPS stimulation and to the upregulation of ex-

pression of the key enzymes involved in the metabo-

lism of glucose, arginine, prostaglandins, and choles-

terol and synthesis of itaconate. This results in the

increased production of PGE

, NO, IL-6, and IL-12 and

reduction in the biosynthesis of IL-10 [150]. In addi-

tion, AMPK is necessary for the acquisition of the M2

phenotype by the macrophages, for example, during

muscle regeneration [146].

Summarizing all the above, metabolic changes

play an essential role in the polarization of macro-

phages and their immunological functions (Table 2).

These processes are not only interconnected, but also

dependent on each other. On one hand, regulation

of immunometabolic enzymes is mediated by nutri-

ents and metabolites (amino acids, citrate, succinate,

itaconate, FAs, etc.). This method of control appeared

at the early stages of evolution and has been function-

ing successfully so far. On the other hand, the regula-

tion of cell functions, including immune response, in

accordance with the body’s needs and environmen-

tal conditions is impossible without more complex

mechanisms that had evolved later. Such mechanisms

mediated, for example, by mTOR and AMPK, include

integration of intracellular signals with subsequent

post-translational modification of proteins and epigen-

etic modification of genes [142]. Immunometabolic ad-

aptation of macrophages to incoming signals underlies

the maintenance of homeostasis not only in individual

tissues, but in an entire organism as well. As a result,

disruption of such regulation can lead to the develop-

ment of various diseases and maladaptive states.

MODULATION OF MACROPHAGE METABOLISM

AS A THERAPEUTIC STRATEGY

Disruption of macrophage immunometabolic

functions as a pathology factor. Recently, the under-

standing of the role of macrophages in various patho-

logical processes has significantly expanded [23, 151]

(Fig.2). On one hand, M2 macrophages are involved in

the metabolic control, while M1 macrophages, on the

contrary, are associated with metabolic pathologies,

such as diabetes, obesity, metabolic syndrome, and in-

sulin resistance. On the other hand, M1 macrophages

mediate the antitumor effects, while M2 macrophages

create an immunosuppressive environment and pro-

mote tumor development. M2 macrophages are respon-

sible for maintaining tissue homeostasis and wound

healing; however, excessive or prolonged activation of

both M1 and M2 macrophages results in tissue damage

and impaired function in such diseases as arthritis, ath-

erosclerosis, glomerulonephritis, and atopic dermatitis.

Macrophages, which provide body protection against

bacteria, viruses, and macroparasites, are at the same

time able to cause a cytokine storm and an unbalanced

response to harmless environmental factors, thus par-

ticipating in the pathogenesis of allergies and asthma.

Since macrophages play a key role in many diseases,

they have become an important subject in the explora-

tion of new therapeutic strategies.

As described above, activated and polarized mac-

rophages undergo metabolic adaptations. Therefore,

modification of macrophage metabolism entails chang-

es in the direction and strength of their polariza-

tion. At the same time, due to the unique features of

metabolism in the activated macrophages, such effects

will be specific and should not affect other body cells,

which can open up the prospects for using this ap-

METABOLIC CHANGES IN MACROPHAGE POLARIZATION 827

BIOCHEMISTRY (Moscow) Vol. 89 No. 5 2024

Fig. 2. Macrophage polarization in normal and pathological conditions. Pink,polarization associated with pathology development;

green,physiological functions of macrophages. Created with BioRender software based on previously published data [23, 151].

proach in the therapy of inflammatory diseases with

substantial role of macrophage. Below, we discuss how

modulation of certain metabolic pathways in macro-

phages could be used as a therapeutic approach.

mTOR and AMPK modulation. As mentioned

above, mTOR is involved in the polarization of both

M1 and M2 macrophages [134]. Treatment of cul-

tured macrophages with rapamycin, an inhibitor of

mTORC1, contributed to the acquisition of the anti-in-

flammatory phenotype, while activation of mTORC1,

on the contrary, promoted formation of the inflam-

matory phenotype [138]. In the model of the CLP (ce-

cal ligation and puncture)-induced sepsis, rapamycin

protected the mice from death by acting on M1 mac-

rophages [152]. Apparently, the effect of rapamy-

cin is due to its ability to cause autophagy, leading

to a decrease in the IL-1β and IL-18 production by

M1 macrophages. This regulation takes place at the

post-transcriptional level and is associated with a de-

crease in the mitochondrial ROS and pro-IL-1β [153].

Modulation of mTOR can also be used in the therapy

of ulcerative colitis. Thus, dioscin (steroid saponin)

simultaneously inhibits signals through the mTORC1/

HIF-1α pathway and activates mTORC2/PPAR-γ signal-

ing, which results in the suppression of aerobic gly-

colysis, increase in the FA oxidation, and shift in mac-

rophage polarization from M1 to M2, resulting in the

mouse protection against the DSS (dextran sodium

sulfate)-induced ulcerative colitis [154]. On the other

hand, in many studies, the use of rapamycin has led

to the shift toward the M1 phenotype. A combination

of rapamycin and hydroxychloroquine caused the

elimination of anti-inflammatory M2 macrophages

in the glioblastoma model and increased the effec-

tiveness of checkpoint inhibitors [155]. Moreover, the

blockade of mTOR contributed to the M1 polarization

of macrophages and ensured plaque stabilization in

the arteries during progressive atherosclerosis [156].

The same effect was achieved by another mTOR block-

er, arsenic trioxide [157].

Modulation of AMPK provides another approach

to the regulation of macrophage metabolism. Met-

formin is used in the clinic for targeting AMPK. It in-

hibits the ETC complex I, which controls ATP and ROS

YURAKOVA et al.828

BIOCHEMISTRY (Moscow) Vol. 89 No. 5 2024

production. Blocking ATP production leads to the in-

crease in the AMP content and ADP/ATP ratio, thereby

activating AMPK [158]. Metformin is known to inhib-

it the LPS-induced IL-1β production and to promote

IL-10 production [115]. Some studies have shown that

metformin regulates the functions of macrophages

in atherosclerosis by suppressing monocyte differen-

tiation and reducing inflammation, oxidative stress,

and apoptosis [159]. It is important to note that met-

formin can regulate macrophage functions through

the AMPK- independent pathways (NF-κB, ABCG5/8,

SIRT1, FOXO1/FABP4, and HMGB1). In the future, a

combination of metformin with drugs affecting the

macrophage functions (e.g., SGLT2 inhibitors, statins,

IL-1β inhibitors) can enhance and expand its thera-

peutic potential [159].

Glycolysis blockade. Most conclusions on the role

of glycolysis in the polarization of macrophages have

been made based on the studies using 2-DG, an inhibi-

tor of glycolysis that also induces various other effects

[54]. New blockers based on 2-DG may have a higher

specificity [160]. Currently, such compounds are inves-

tigated for the anti-cancer activity, while their effect

on the macrophage metabolism remains unclear. Re-

cent studies have shown that cancer and immune cells

can accumulate a dimeric form of the PKM2 capable of

regulating the expression of HIF-1α-dependent genes

[50, 161]. The small-molecule inhibitor TEPP-46, which

inhibits this process and restores the PKM2 enzymatic

activity, has shown promising results in experimen-

tal models of cancer and infectious diseases [50,  162].

TEPP-46 suppresses activation of M1 macrophages and

promotes mitochondrial biogenesis [163]. Another ap-

proach is the direct HIF-1α inhibition. PX-478 (selective

HIF-1α blocker) suppressed tumor cell growth [164]

and was found to be efficient in the mouse model of

atherosclerosis [165]. However, the detailed mecha-

nism of this inhibitor on macrophage polarization still

has to be elucidated.

Application of Krebs cycle metabolites in ther-

apy. Inflammatory processes and malignant transfor-

mation are accompanied with the reprogramming of

the Krebs cycle, associated genes, and metabolites [70,

166, 167]. Dimethylmalonate and 4-octilitaconate (4-OI)

are small molecules that target SDH and were found

to reduce inflammation in several experimental mod-

els [73,  168]. As mentioned above, itaconate and its

derivatives activate NRF2, leading to the stimulation of

the antioxidant response and upregulation of expres-

sion of cytokine-limiting ATF3 [73, 75]. In particular,

4-OI targets the NRF2/KEAP1 pathway and prevents

cytokine storm during acute infection in mice [73].

Moreover, itaconate has recently been shown to inhibit

NLRP3 inflammasome [77]. Such significant immuno-

modulatory potential of itaconate and its derivatives

can be used in therapy. It was shown recently that

itaconate affects M2 polarization of macrophages by in-

hibiting the JAK1/STAT6 signaling pathway. A decrease

in the severity of steroid-resistant asthma in mice ad-

ministered with 4-OI indicates the therapeutic poten-

tial of this metabolite in Th2-dependent diseases [79].

As a compound affecting the NRF2 pathway and

glycolysis, dimethyl fumarate (DMF, a derivative of fu-

marate) is currently used as an immunomodulatory

drug in the treatment of multiple sclerosis and psoria-

sis [169-171]. DMF also inhibits NF-κB, ERK, and other

signaling pathways. It activates NRF2, resulting in cell

protection against oxidative stress, and promotes the

anti-inflammatory phenotype in macrophages [172].

DMF also affects glycolysis by reducing the GAPDH

activity, suggesting that DMF can also be used to mod-

ulate immunometabolism during infectious diseas-

es[170].

Modulation of amino acid and FA metabolism.

The difference between arginine consumption by M1

and M2 macrophages is a basis for a potential selec-

tive therapy. Thus, the inhibition of iNOS with ami-

noguanidine prevented NO production by the macro-

phages and reduced the symptoms of disease in the

mouse model of multiple sclerosis [173]. Other iNOS

inhibitors have shown efficacy in the mouse models

of ischemic kidney disease and lung inflammation

[174,  175]. At the same time, inhibition of ARG1 by

CB-1158 shifted macrophage polarization towards the

M1 phenotype in the mouse model of carcinogenesis.

This resulted in the inhibition of the immunosuppres-

sive microenvironment and increased the efficacy of

antitumor therapy [176,  177]. Currently, the effica-

cy of ARG1 inhibition in cancer therapy is tested in a

number of clinical trials (NCT02903914, NCT03910530,

NCT03314935, NCT03837509, NCT03361228). Inhibi-

tion of enzymes involved in glutamine metabolism by

BPTES or CB-839 has shown promising results in the

models of multiple sclerosis [178] and rheumatoid ar-

thritis [179]. Finally, amino acid deficiency can also be

used for targeting the macrophages. For example, ser-

ine restriction attenuates excessive macrophage acti-

vation during endotoxemia [180], so it could be useful

in the treatment of sepsis. Halofuginone, which mim-

ics amino acid deficiency by activating GCN2 (general

control nonderepressible 2 kinase), reduces intestinal

inflammation [181] and induces autophagy [182].

The role of FA metabolism in the formation of

pathogenetic macrophage phenotype is only partly un-

derstood. In recent years, special attention has been

focused on the drugs that suppress expression or block

the activity of carnitine palmitoyltransferases (e.g.,

etomoxir) [183]. The effect of these compounds on the

development of colitis-associated cancer [184,  185],

bronchial asthma [186] and obstructive pulmonary

disease [187] is currently under study. Some of these

studies have emphasized the correlation between the

METABOLIC CHANGES IN MACROPHAGE POLARIZATION 829

BIOCHEMISTRY (Moscow) Vol. 89 No. 5 2024

FA synthesis/oxidation and activity of NLRP3 inflam-

masome, since the inflammasome is significantly in-

volved in the chronic inflammation and carcinogene-

sis [184].

CONCLUSION

Taken together, the results of studies in recent de-

cades clearly suggest a close relationship between the

metabolism and functional characteristics of immune

cells, including macrophages, upon their activation.

The metabolic needs of activated cells are inextricably

linked to their functional features, so that there is a

significant difference between the cellular metabolism

of pro- and anti-inflammatory immune cells. At the

same time, many aspects of macrophage metabolism

remain poorly understood. The use of drugs aimed at

metabolism reprogramming is hindered by the limit-

ed selectivity of available inhibitors. Currently known

inhibitors tend to affect central processes, e.g., glucose

catabolism (in the case of 2-DG) or mTOR signaling.

The development of more specific drugs targeting cer-

tain metabolic pathways will allow to explore their

effect on the macrophage polarization in more detail.

Italso opens new prospects for immunometabolic ther-

apy through modulation of macrophage involvement

in disease pathogenesis.

Acknowledgments. The authors express their

gratitude to D.  Anisov for discussions and valuable re-

marks.

Contributions. M.S.D. supervised the study and

developed the concept of the review; T.R.Y., E.A.G.,

and M.A.N. carried out the search of literature sources

and discussed the data; T.R.Y. and M.A.N. prepared the

manuscript; M.S.D. and E.A.G. edited the manuscript;

T.R.Y. prepared the images.

Funding. This work was supported by the Russian

Science Foundation (project no.19-75-30032).

Ethics declaration. This work does not describe

any studies involving humans or animals as objects

performed by any of the authors. The authors of this

work declare that they have no conflicts of interest

infinancial or any other sphere.

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