Dynamic metabolic programming of monocyte-derived cells defines immunity in CNS disease

Claire L Wishart; Jian Tan; Nicholas J C King

doi:10.1093/brain/awag149

. 2026 Apr 29;149(10):3325–3346. doi: 10.1093/brain/awag149

Dynamic metabolic programming of monocyte-derived cells defines immunity in CNS disease

Claire L Wishart ^1,², Jian Tan ^3,^4,^5,⁶, Nicholas J C King ^7,^8,^9,^10,^✉

PMCID: PMC13634636 PMID: 42052880

Abstract

Monocyte-derived cells (MCs) are highly adaptable innate immune cells that play essential roles in CNS inflammation. Their functional specialization is closely linked to their metabolic state, which is shaped by local cues such as nutrient availability, oxygen levels and pro- and anti-inflammatory signals.

In this review, we examine the major metabolic pathways that regulate MC behaviour, including glycolysis, oxidative phosphorylation, lipid metabolism and amino acid metabolism. We assess how these pathways support specific effector functions such as cytokine production, phagocytosis, antigen presentation and efferocytosis. Moving beyond the traditional pro-/anti-inflammatory (M1/M2) framework, we discuss the context-dependent nature of MC metabolism and its role in driving diverse functional states. We then explore how these metabolic programmes are engaged across key CNS disease settings, including sterile injury, demyelinating disease and viral encephalitis.

By integrating insights from immunometabolism and neuroinflammation, this review provides a framework for understanding the metabolic regulation of MCs in CNS pathology and highlights potential avenues for therapeutic intervention.

Keywords: monocyte-derived cells, immunometabolism, neuroinflammation, encephalitis

Wishart et al. review how metabolic pathways regulate the behaviour of monocyte-derived immune cells in brain disease. They show that local cues shape metabolism and drive context-dependent immune functions across conditions, highlighting immunometabolism as a framework for understanding CNS pathology.

Introduction

Monocytes and their tissue-associated progeny, collectively termed monocyte-derived cells (MCs), play critical roles in maintaining immune surveillance and orchestrating inflammatory responses across multiple tissues, including the CNS. As highly plastic members of the mononuclear phagocyte system, MCs exhibit remarkable adaptability, responding dynamically to environmental cues through coordinated transcriptional and metabolic reprogramming. These adaptations underpin virtually every aspect of MC biology, from survival and differentiation to effector functions such as antigen presentation, cytokine production and phagocytosis.

Historically, CNS myeloid research has focused predominantly on microglia^1-5—long-lived, yolk sac-derived resident CNS parenchymal macrophages—while the metabolic programmes and functional specialization of MCs infiltrating during CNS disease have remained comparatively underexplored. Yet MCs often dominate recruited inflammatory populations in neuroinflammatory disorders, including traumatic injury, demyelinating disease and viral encephalitis.⁶ On infiltration they rapidly adapt to the dynamic metabolic landscape in CNS pathology concurrently with the often more sedate microglial response shaped and maintained by the homeostatic CNS environment. Immunometabolism research has historically focused on macrophages and may not accurately reflect MCs, which exhibit distinct metabolic programmes and functional responses.

Elucidating metabolic regulation of MCs is critical for understanding mechanisms of tissue damage and repair to inform novel therapeutic approaches that can modulate inflammation without impairing essential homeostatic or immune functions.

Traditional models of macrophage activation, which dichotomize cells into pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes,^7-9 fail to capture the spectrum of metabolic and functional states adopted by MCs in vivo in the CNS.⁵ Recent evidence demonstrates that MC function and fate is context-dependent,¹⁰ governed by a complex interplay between local nutrient availability, oxygen tension, cytokine signalling and pathogen recognition.^8,11,12 Metabolic pathways such as glycolysis, oxidative phosphorylation (OXPHOS), fatty acid metabolism and amino acid metabolism are thus not passive reflections of cell state, but actively instruct distinct functional programmes in MCs, influencing cytokine responses, antimicrobial effector species production, efferocytosis and resolution of inflammation.

Given the growing recognition of MCs in CNS pathology, we review their metabolic programming in neuroinflammation, focusing on infiltrating MCs rather than resident microglia. We explore the major glucose, lipid and amino acid metabolic pathways governing MC function and adaptations to environmental stresses such as hypoxia. Emphasis is placed on how these pathways are engaged during CNS disease, shaping pro-inflammatory or reparative MC roles in sterile injury, demyelinating disease and viral infection. By delineating the unique metabolic challenges faced by MCs in the CNS, we provide a framework for understanding their unique functional continuum between pathology and repair, highlighting emerging interventions that may selectively target pathogenic MC functions without compromising critical immune functions.

Overview of monocytes and developmental origins

Monocyte classification

Monocytes are myeloid lineage haematopoietic cells integral to the mononuclear phagocyte system,^13,14 serving critical roles in innate immunity, inflammation and tissue homeostasis. In adulthood they arise from the definitive haematopoietic stem cells, developing from monocyte-dendritic cell precursors (MDP) and granulocyte-monocyte progenitors (GMP) in the bone marrow^15,16 and are released into the bloodstream after production. Monocyte developmental fate is determined by transcription factors such as PU.1, interferon regulatory factor 8, Kruppel-like factor 4 and GATA binding factor 2,^17-20 while their development, survival and proliferation are controlled by the growth factor receptor CD115 (also known as colony-stimulating factor-1 receptor, CSF-1R, or macrophage colony-stimulating factor receptor, M-CSFR), with its ligands, macrophage colony-stimulating factor (M-CSF or CSF-1) and interleukin (IL)-34.^21,22 CSF-1 signalling is not absolutely required for monocyte production, but is required for monocytes differentiating into macrophages that replenish the tissue-resident pool.²³ During inflammation, CSF-1 increases, accelerating myelopoiesis to meet increased myeloid cell demand.²⁴ CSF-1-driven myelopoiesis has been shown to require mTORC1-dependent metabolic reprogramming, driving enhanced glucose uptake, glycolysis, one-carbon metabolism and sterol biosynthesis.²⁵ In addition, metabolic perturbations like hyperglycaemia and obesity also enhance myelopoiesis: in a mouse obesity model, adipose tissue-derived signals, including S100A8/A9-driven activation of TLR4–MyD88 and NLRP3 inflammasome-dependent IL-1β production, bias haematopoiesis towards the myeloid lineage.²⁶ These conditions exhibit increased glucose availability, which supports the increased glycolytic demand of myelopoiesis.

Phenotypically, circulating monocyte subsets have different sizes, transcriptional profiles and migratory abilities. In humans, ‘classical’ monocytes, designated CD14⁺CD16⁻, comprise 80%–90% of monocytes, while ‘intermediate’ (CD14⁺CD16⁺) and ‘non-classical’ monocytes (CD14^loCD16⁺) make up the remaining 10%–20%.²⁷ In mice, ‘classical’ monocytes, also known as ‘inflammatory’, are defined by Ly6C^hi, CX3CR1^int (CX3C motif chemokine receptor 1), CD92⁺, CD62L⁺ and CD43^lo cell surface markers.²⁸ ‘Non-classical’ or ‘patrolling’ monocytes are Ly6C^lo, CX3CR1^hi, CD92^lo, CD62L⁻ and CD43⁺.^28-30 The CX3CR1^hi classification was based on gene expression in reporter mice; however, comparatively low surface protein expression makes CX3CR1 unreliable for discriminating monocyte subsets using antibody staining.³¹ Transcriptional analysis shows Ly6C^hi monocytes are analogous to classical CD14⁺CD16⁻ monocytes, while Ly6C^lo monocytes correspond to non-classical CD14^loCD16⁺ monocytes.³²

Presently, monocytes are viewed as a distinct cell type with multiple functions. They can migrate to tissues and retain their Ly6C^hi phenotype,³⁰ become Ly6C^lo monocytes or differentiate into tissue-resident macrophages.^33,34 During inflammation, monocytes develop into monocyte-derived macrophages and dendritic cells (DCs), collectively named MCs, with functions different from embryonically-derived resident cells.¹³ It is unclear whether monocytes have distinct metabolic profiles prior to differentiation into effector MCs. However, they undergo significant immunometabolic reprogramming during differentiation, adopting distinct metabolic programmes linked to divergent functional outcomes. For example, monocytes differentiating into DCs typically switch from glycolysis to OXPHOS, increase glutaminolysis and reduce dependence on fatty acid oxidation in humans.³⁵ In contrast, human monocytes differentiating into tolerogenic DCs become reliant on fatty acid oxidation to support their regulatory functions.³⁵

This distinct metabolic reprogramming during monocyte differentiation opens avenues for intervention when effector MCs cause significant damage. For instance, targeting fatty acid oxidation impaired monocyte differentiation into macrophages following cardiac transplant in mice, prolonging survival.³⁶

Interplay between cellular metabolism and monocyte-derived cell function

Macrophage activation as a continuum of functional states

Macrophages are adaptable cells that can polarize rapidly, choosing one functional state over a notionally opposite state. This is mediated by a variety of microenvironmental triggers, including cytokines, pathogens, apoptotic cells and other signalling molecules, resulting in a distinct functional phenotype. Macrophages are often divided into two polarization states, pro-inflammatory M1 macrophages and anti-inflammatory M2 macrophages, based on gene expression, surface markers, cytokine production and metabolic characteristics.^7-9

M1 macrophages, regarded as ‘pro-inflammatory’, are activated by pro-inflammatory microbial components, such as lipopolysaccharide (LPS) toll-like receptor (TLR) ligands or cytokines generated by T helper type 1 cells, including tumour necrosis factor (TNF) and interferon (IFN)-γ.³⁷ They can eliminate infections and present antigens to T cells to initiate adaptive immune responses. To eradicate pathogens and induce inflammation, they produce large amounts of various inflammatory molecules, including IL-1β, TNF, nitric oxide (NO) and reactive oxygen species (ROS).⁷ Co-stimulatory (e.g. CD80, CD86) and antigen presenting molecule (e.g. MHC-II) and transcription factor expression, including nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB) and hypoxia-inducible factor 1-α (HIF1-α), typically identify M1 macrophages. They switch quickly to aerobic glycolysis for ATP production, increasing glucose uptake in response to TLR-activating pathogen-derived danger signals like LPS, and cytokines, such as IFN-γ.^9,38,39 Glycolysis best meets the increased energy demands of rapid cytokine production and microbial killing^40,41 and supports ROS and NO generation for antimicrobial activity.

M2 macrophages (also known as alternatively-activated, regulatory or ‘anti-inflammatory’ macrophages) are activated by cytokines such as IL-13 or IL-4, produced by innate and adaptive immune cells like Th2 lymphocytes, mast cells and basophils.^42-44 The anti-inflammatory properties of M2 macrophages reduce inflammation and promote tissue repair. These cells express phagocytic markers (e.g. CD206 and CD36) and produce anti-inflammatory and pro-repair molecules, such as transforming growth factor-β (TGF-β).⁴¹ M2 macrophages have elevated arginase activity and produce collagen and polyamines crucial in tissue remodelling and wound healing. M2 macrophages are more reliant on fatty acid oxidation and glutaminolysis to fuel increased OXPHOS.^41,45,46

The M1/M2 dichotomy emerged from observations in macrophages showing that prototypical Th1 mouse strains (e.g. C57BL/6) more readily convert arginine into NO, whereas Th2 strains (e.g. BALB/c) preferentially direct arginine metabolism towards ornithine.⁴² However, since this classification captures only the extreme pro- or anti-inflammatory states of macrophages, it is widely regarded as oversimplified.⁴⁰ Furthermore, this strain-dependent framework does not directly translate to macrophage states in humans. Additionally, the functional and metabolic features of M1/2 macrophages were largely characterized in vitro following stimulation with specific cytokines or microbial antigens. In contrast, MCs in vivo exhibit a spectrum of activation states, reflecting their highly plastic and dynamic nature in response to multifarious cues, and can switch between metabolic processes.¹⁰ Moreover, macrophage activation depends on the tissue environment and the stimuli.^8,11,12 Indeed, even in controlled in vitro conditions, macrophages responding to defined stimuli adopt a spectrum of activation states, comprising at least nine distinct programmes regulated by specific transcriptional factors.⁸ This intricate relationship between macrophage metabolism and function therefore extends well beyond the traditional M1/M2 paradigm, which does not adequately represent this variability or account for the reversibility of macrophage phenotypes, a feature particularly important in understanding their roles in disease. Thus, for example, while antigen presentation and the production of inflammatory mediators are both considered M1-like functions, they require different biosynthetic intermediates and consequently different metabolic profiles. As such, researchers are moving towards a more refined understanding of MC activation that acknowledges the complex metabolic reprogramming that underlies distinct functions (Table 1), rather than viewing MC activation as simply a binary M1- or M2-polarized state. For historic context and practical purposes, it remains useful to classify macrophages into their major functional states. In this review, we refer to these states as pro-inflammatory or anti-inflammatory.

Table 1.

Metabolic regulation of various myeloid functions

Biological function	Associated immune response	Metabolic processes
Type I interferon response^47-53	Antiviral immunity	↑ Glycolysis ↑↓ HIF1-α signalling ↓ OXPHOS, ETC ↑ Hexosamine biosynthesis pathway-associated O-linked β-N-acetylglucosamine signalling ↓ Cholesterol biosynthesis ↓ Serine metabolism Itaconate boosts IFN response
Inflammatory response (pro-inflammatory cytokine production, inflammasome activation, NO production)^11,40,54-60	Inflammatory response, pathogen clearance, tissue damage	↑ Glycolysis ↑ HIF1-α signalling ↑ Fatty acid synthesis ↑ OXPHOS Succinate oxidation ↑ Citrate accumulation for FAS Engagement of aspartate-arginosuccinate shunt to regulate NO production Succinate accumulation
ROS production^30,59,61,62	Microbicidal activity, regulation of inflammatory response	↑ Oxidative PPP ↑ FAO ↑ FA metabolism OXPHOS (reverse electron flow)
Antigen presentation^63-65	Pathogen clearance, T-cell-mediated immunity	↑ Glycolysis ↑ Fatty acid synthesis ↓ OXPHOS, ETC
Phagocytosis^11,63,64,66	Pathogen clearance, tissue repair	↑ FA and cholesterol synthesis ↑ Glycolysis ↑ OXPHOS
Efferocytosis^67-76	Clearance of apoptotic debris, tissue repair	↑ OXPHOS ↑ Glycolysis ↑ PPP flux depending on oxygen availability ↑ Arginine and ornithine catabolism ↑ Kynurenine pathway ↑ Fatty acid oxidation ↑ Sterol pathway activity
Production of anti-inflammatory or pro-resolving mediators^77-79	Tissue repair, immune suppression, resolution of inflammation	↑ Glutamine metabolism ↑ Lipid synthesis (pro-resolving mediators) ↑ OXPHOS ↑ Mitochondrial uncoupling ↑ Itaconate ↓ Glycolysis
Myeloid cell migration^80,81	Infiltration into inflamed tissues	↑ Glycolysis ↑ HIF1-α signalling

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↑ = increase in; ↓ = decrease in; ETC = electron transport chain; FA = fatty acid; FAO = fatty acid oxidation; FAS = fatty acid synthase; HIF1-α = hypoxia-inducible factor 1-alpha; NO = nitric oxide; OXPHOS = oxidative phosphorylation; PPP = pentose phosphate pathway; ROS = reactive oxygen species.

Overview of metabolic pathways influencing monocyte function

Oxidative phosphorylation: the tricarboxylic acid cycle and electron transport chain

OXPHOS is a crucial metabolic process that occurs within the mitochondria. Known for its energy-producing efficiency, OXPHOS supports general homeostatic functions and is linked to the extended lifespan of cells like tissue-resident macrophages. OXPHOS comprises a complex series of reactions in the electron transport chain (ETC) dependent on tricarboxylic acid (TCA) cycle activity (Figs 1 and 2). The latter generates high-energy electron carriers, nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH₂), which donate their electrons to the ETC. The ETC is where the process of OXPHOS culminates, as the transfer of these electrons drives the electrochemical gradient that fuels the production of ATP from ADP. The TCA cycle begins with the condensation of acetyl-CoA with oxaloacetate to form citrate, with glycolysis-derived pyruvate typically serving as the dominant precursor for acetyl-CoA. However, this pathway is metabolically flexible, as acetyl-CoA can also be derived from fatty acids (via β-oxidation), ketone bodies (via ketolysis) and acetate (via acetyl-CoA synthetase) (Fig. 2). Additionally, catabolism of ketogenic amino acids, particularly leucine and lysine, can also supply acetyl-CoA. However, irrespective of the acetyl-CoA source, sustained TCA cycle flux requires net anaplerosis. Anaplerosis replenishes TCA cycle intermediates, commonly through pyruvate carboxylation (to generate oxaloacetate) and amino acid-driven anaplerosis (particularly glutaminolysis to generate α-ketoglutarate).

For image description, please refer to the figure legend and surrounding text. — **Overview of key metabolic pathways**. Glycolysis, the pentose phosphate pathway, the tricarboxylic acid (TCA) cycle, fatty acid oxidation and fatty acid signalling represent central metabolic pathways that shape monocyte-derived cell activation states and functionality in CNS disease. These pathways govern ATP generation, redox balance and provision of biosynthetic precursors essential for immune responses, tissue repair or chronic inflammation. Their activity is further influenced by metabolic regulators and signalling networks, such as hypoxia-inducible factor 1α (HIF-1α), which adapts macrophage metabolism to changes in oxygen tension, nutrient availability and inflammatory cues. Collectively, these integrated metabolic programmes orchestrate immune and metabolic adaptation within the CNS disease microenvironment. Figure adapted from Artyomov and Van den Bossche,⁸² reprinted with permission from Elsevier. ACAC = acetyl-CoA carboxylase; ACADM = acyl-CoA dehydrogenase, medium-chain; ARG1 = arginase 1; ASCT2 = alanine, serine, cysteine transporter 2 (SLC1A5); ASS1 = argininosuccinate synthase 1; ATP5A = ATP synthase subunit alpha; CAT2 = cationic amino acid transporter 2; CPT1A = carnitine palmitoyltransferase 1A; CS = citrate synthase; CytC = cytochrome c; ETC = electron transport chain; 6PGD = 6-phosphogluconate dehydrogenase; 6PGL = 6-phosphogluconolactonase; G6PD = glucose-6-phosphate dehydrogenase; GAPDH = glyceraldehyde-3-phosphate dehydrogenase; GLS = glutaminase; GLUD = glutamate dehydrogenase; GLUT1 = glucose transporter 1 (SLC2A1); GOT2 = glutamic-oxaloacetic transaminase 2 (mitochondrial aspartate aminotransferase); HADHA = hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha; HIF1A = hypoxia-inducible factor 1 alpha; HK1 = hexokinase 1; IDO1 = indoleamine 2,3-dioxygenase 1; IDH = isocitrate dehydrogenase; iNOS = inducible nitric oxide synthase (NOS2); KEAP1 = Kelch-like ECH-associated protein 1; LAT1 = L-type amino acid transporter 1 (SLC7A5); mTOR = mechanistic target of rapamycin; NRF1 = nuclear respiratory factor 1; NRF2 = nuclear factor erythroid 2–related factor 2; ODH = oxoglutarate dehydrogenase; OXPHOS = oxidative phosphorylation; PFK1 = phosphofructokinase 1; PFK2 = phosphofructokinase 2 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase); PKM2 = pyruvate kinase M2; PPARγ = peroxisome proliferator-activated receptor gamma; PRDX2 = peroxiredoxin 2; R5P = ribose-5-phosphate; R5PI = ribose-5-phosphate isomerase; Ru5P = ribulose-5-phosphate; S6P = ribosomal protein S6 phosphorylation; SDH = succinate dehydrogenase; XBP1 = X-box binding protein 1. Created in BioRender. King, N. (2026) https://BioRender.com/ds0ng5j.

The TCA cycle undergoes significant modifications based on bioenergetic needs. For example, anti-inflammatory macrophages exhibit a functional, complete TCA cycle. In mice, this is crucial for fulfilling the biosynthetic requirements for UDP-GlcNAc production supported by glutaminolysis, which drives N-glycosylation of lectin and mannose receptors, and hallmark proteins like RELMα, essential for their anti-inflammatory function.⁵⁴ In contrast, the relationship between glycolysis and the TCA cycle in pro-inflammatory macrophages shows distinct temporal phases. Macrophage activation in mice initially triggers an upregulation of both glycolysis and the TCA cycle, with enhanced TCA cycle flux supporting chromatin remodelling needed for inflammatory responses.⁸³ As inflammation progresses, NO accumulation inhibits mitochondrial aconitase, leading to accumulation of citrate⁸⁴ and cis-aconitate. In both mice and humans, cis-aconitate is subsequently diverted to itaconate, via upregulated aconitate decarboxylase 1 (Fig. 1).^85,86 Itaconate has anti-bacterial properties and may play a role in immunomodulation, suppression of inflammation and immune tolerance.⁸⁷ Itaconate also inhibits succinate dehydrogenase (SDH), promoting succinate accumulation in LPS-activated murine macrophages, leading to reduced mitochondrial respiration, increased ROS production, pro-inflammatory cytokine release and inflammasome activation.⁸⁷ In parallel, itaconate alkylates KEAP1, stabilizing NRF2 and inducing a transcriptional programme that enhances antioxidant capacity and constrains inflammatory signalling.⁸⁸ In a related mouse study, this constrained inflammatory response was shown to be NRF2-independent, driven instead by electrophilic stress-induced ATF3.⁸⁹ NRF2 activation has also been associated with mitochondrial fusion, increased redox metabolism and suppression of type I interferon responses in anti-inflammatory murine macrophages.⁹⁰ These metabolic rerouting events generate discrete ‘breaks’ in the TCA cycle upstream at aconitase and downstream at SDH, resulting in the export of citrate, itaconate and succinate from the mitochondria to execute their regulatory roles on various metabolic pathways in the cytoplasm (Fig. 1).

Citrate is a critical metabolic regulator that helps sustain inflammatory macrophage responses. It is produced in the TCA cycle from glycolysis-derived pyruvate or fatty acid oxidation. In activated human macrophages with sustained TCA cycle activity, citrate accumulates in the cytosol and drives the production of pro-inflammatory ROS, NO and prostaglandin E2.⁹¹ This accumulation relies on efficient mitochondrial export to the cytosol, primarily by the citrate carrier SLC25A1. Alteration to citrate transport, and its partitioning, can thus profoundly alter cellular metabolic programming and functional outcomes.⁹¹ SLC25A1 is transcriptionally regulated, strongly activated by the pro-inflammatory cytokines, TNF and IFN-γ, and by LPS in human cells.^55,91 Although cytosolic citrate can inhibit glycolysis⁹² and stimulate lipid synthesis and gluconeogenesis (e.g. as shown in rats),⁹³ this has been observed in other cell types and is not the dominant pathway in macrophages and monocytes.

Succinate is an intermediate of the TCA cycle produced from succinyl-CoA by the enzyme SDH. As shown initially in mouse studies, succinate increases HIF1-α stability under normoxic conditions by blocking prolyl hydroxylase, which otherwise constantly ubiquitinylates HIF1-α for proteasomal degradation in the presence of oxygen.⁵⁶ Furthermore, during inflammation, succinate is released by human inflammatory macrophages and can accumulate in the extracellular milieu.⁹⁴ This was also observed in ischaemic tissue⁹⁵ and CNS inflammation⁹⁶ in mice. Itaconate promotes succinate accumulation by inhibiting SDH and disrupting TCA cycle flux, amplified by increased glutamine-driven anaplerosis via α-ketoglutarate and the gamma-aminobutyric acid (GABA) shunt. In murine macrophages, succinate directly upregulates mitochondrial ROS production to sustain pro-inflammatory function in vitro by supporting metabolic repurposing of mitochondria through SDH-dependent electron flux.⁹⁷ This mechanism was further shown to be driven by the oxidation of succinate in both mouse and human macrophages, which maintains a reduced Coenzyme Q pool and elevates mitochondrial potential, thereby enabling ROS generation at complex I of the ETC through reverse electron transport.⁹⁸ In multiple sclerosis, chronically activated microglia exhibit an analogous metabolic phenotype, with increased complex I activity, elevated mitochondrial membrane potential and enhanced ROS generation in both experimental autoimmune encephalomyelitis (EAE) models and human lesions.⁹⁹ This highlights similar macrophage-like metabolic reprogramming in chronically activated microglia during chronic CNS inflammation.

While OXPHOS is needed for phagocytosis, cytokine production relies on the upregulation of both OXPHOS and glycolysis following TLR2 stimulation.¹¹ In this study, ETC inhibition with rotenone significantly reduced the phagocytic capacity of TLR2-stimulated human monocytes, whereas untreated or LPS (TLR4)-stimulated monocytes were unaffected. Glycolysis inhibition did not affect phagocytic capacity, suggesting that OXPHOS, but not glycolysis, is an important determinant of human monocyte phagocytic capacity.

Glycolysis and the pentose phosphate pathway

Enhanced glycolysis is a hallmark of most rapidly activating immune cells. It enables ATP production and, importantly, provides biosynthetic intermediates to support effector functions triggered by stimulation of antigen receptors, pattern-recognition receptors (PRRs) and cytokine receptors.¹⁰⁰ In inflammatory macrophages, glycolysis serves as a central metabolic regulator that enables phagocytosis, antigen presentation, ROS production, antiviral responses and the release of pro-inflammatory cytokines⁴¹ (Table 1) by supplying glycolytic intermediates for nucleotide and amino acid synthesis.

Glycolysis begins with the uptake of extracellular glucose into the cytosol for metabolism (Figs 1 and 3). The first step involves the irreversible conversion of glucose into glucose-6-phosphate by hexokinase, committing glucose to the glycolysis pathway. Another key step is the conversion of the glycolytic intermediate glyceraldehyde-3-phosphate into D-glycerate 1,3-bisphosphate by the enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH), which also produces NADH from NAD⁺. NADH plays a critical role by acting as an electron donor and reducing agent and is important for the regeneration of NAD⁺ and ATP production via ETC and OXPHOS in the mitochondria. Through subsequent steps, glucose-6-phosphate is ultimately transformed into pyruvate, generating two ATP molecules per glucose unit. Glycolysis is relatively inefficient in ATP production; however, it is pivotal for cellular metabolic adaptation, providing intermediates for the pentose phosphate pathway (PPP) to generate NADPH and ribose-5-phosphate for macromolecule synthesis, including ribose, amino acids and fatty acids (Fig. 3).

In macrophages, the switch to glycolysis involves the initiation of various transcription factors and signalling molecules. In response to TLR4 stimulation, histone deacetylase 7 regulates the glycolytic enzyme pyruvate kinase M2 (PKM2) to link glycolysis and inflammatory responses in murine macrophages.¹⁰¹ PKM2 catalyses the final step of glycolysis by converting phosphoenolpyruvate to pyruvate. Beyond its metabolic role, PKM2 functions as a key immunometabolic regulator. In both human monocytes and macrophages, increased glucose utilization drives mitochondrial ROS production, promoting PKM2 dimerization to act as a protein kinase that phosphorylates STAT3 to induce IL-6 and IL-1β production.¹⁰² PKM2 itself can also complex with HIF1-α and bind to the IL-1β promoter to reinforce inflammatory pathways downstream of glycolytic reprogramming in murine macrophages.³⁹ In addition, HIF1-α plays a pivotal role in the transition to glycolysis under both oxygen-poor (hypoxic) and oxygen-rich (normoxic) conditions, as demonstrated in mice.¹⁰³ Notably, HIF1-α is a cardinal metabolic and functional orchestrator in both mice and human macrophages, regulating the gene expression of glycolytic enzymes,¹⁰⁴ transporters and inflammatory mediators.^41,103,105 Other glycolytic enzymes can also exert direct immunomodulatory functions independent of their metabolic function. In resting macrophages, GAPDH binds AU-rich elements within untranslated mRNA for TNF to repress translation. Upon LPS stimulation of murine macrophages, GAPDH undergoes lysine malonylation, resulting in its dissociation from bound mRNA, which permits TNF translation to drive pro-inflammatory responses.¹⁰⁶

The PPP, which also takes place in the cytosol, has two distinct phases (Fig. 3). The first, or oxidative phase, uses the energy derived from the transformation of glycolytic intermediate glucose-6-phosphate, in three enzymatic steps initiated by glucose-6-phosphate dehydrogenase (G6PD), into ribulose-5-phosphate to reduce two molecules of NADP⁺ to NADPH (Fig. 3). Numerous enzymes use NADPH, including NADPH oxidase (NOX) and inducible nitric oxide synthase (iNOS), to produce ROS and NO, respectively. Elevated NADPH levels also protect against oxidative stress and provide the reducing capacity necessary to produce the antioxidant glutathione. Accordingly, individuals with severe deficiency in G6PD are susceptible to life-threatening infections, primarily due to their inability to control infection-induced oxidative stress, causing acute haemolytic anaemia.¹⁰⁷ The second, non-oxidative phase of the PPP uses ribulose-5-phosphate as the substrate for producing ribose-5-phosphate, an essential precursor for nucleotide and amino acid synthesis required for cell growth and proliferation. Alternatively, ribulose-5-phosphate can be converted into xylulose-5-phosphate and rearranged to form glycolytic intermediates fructose-6-phosphate and glyceraldehyde-3-phosphate, which can feed back into glycolysis, thereby establishing a bi-directional link between the PPP and glycolysis¹⁰⁸ (Fig. 3). This circuitry provides functional flexibility, allowing for repeated passage to oxidative PPP (pentose cycling) to generate additional NADPH when required. Conversely, if pentose production exceeds anabolic demand, such as ribose demand for nucleotide synthesis, excess carbon can be returned to glycolysis (pentose overflow).

HIF1-α is a regulator of metabolism and migration

Hypoxia is a common feature of inflammation.¹⁰⁹ MCs metabolically adapt to reduced oxygen concentrations via the transcription factor HIF1-α, to reduce mitochondrial oxygen consumption by altering cellular metabolism.^104,110 This involves an increase in glycolytic activity,¹¹¹ the production of fatty acids or lipogenesis^112,113 and the breakdown of glutamine through glutaminolysis.^114,115 Beyond metabolism, HIF1-α also regulates MC function by regulating gene expression of glycolytic enzymes and transporters, and the production of inflammatory mediators and inflammatory signalling in mouse and human cells.^41,103,105

A further critical mechanism by which HIF1-α influences monocyte function is by its effect on myeloid cell migration. In mice, hypoxia accelerates macrophage migration, an effect that is diminished with the deletion of HIF1-α in myeloid cells.⁸⁰ This effect is mediated by the relationship between HIF1-α and glycolysis: HIF1-α-induced pyruvate dehydrogenase kinase isozyme 1 induces glycolytic reprogramming by inactivating pyruvate dehydrogenase, redirecting pyruvate conversion into lactate rather than acetyl-CoA,⁸⁰ a process that actively changes glucose metabolism from glucose oxidation to glycolysis.⁸⁰ This in turn supports cytoskeletal actin remodelling that occurs during cellular migration.

Lipid metabolism

Fatty acid synthesis

The anabolic process of fatty acid synthesis results in production of fatty acids vital for macrophage biology. They serve as essential components of membrane phospholipids, signalling molecules that regulate transcription factors, e.g. Peroxisome Proliferator-Activated Receptor Gamma (PPARγ), and the production of inflammatory mediators, such as prostaglandins, prostacyclins, thromboxanes, leucotrienes, lipoxins, resolvins, protectins and maresins, which exhibit immunoregulatory effects on immune cells, including macrophages.¹¹⁶

Fatty acids can be synthesized de novo through core metabolic processes such as the TCA cycle, glycolysis and glutaminolysis.¹¹⁷ Alternatively, they can be hydrolysed from intracellular lipid stores or obtained directly from the extracellular space. The rate-limiting enzyme acetyl-coenzyme A carboxylase (ACAC) plays a central role in lipid metabolism by converting acetyl-CoA to malonyl-CoA for de novo fatty acid synthesis (Fig. 4).

Cellular membranes and organelles, comprised of essential fatty acids like phospholipids, fluctuate in shape and extent in response to changes in cell morphology, activation and function. Increased fatty acid synthesis supports membrane structural integrity and enhances membrane fluidity.¹¹⁸ This enables cytoskeletal remodelling and local membrane reorganization and facilitates macrophage functions like phagocytosis,¹¹⁸ migration across endothelial barriers and cell adhesion.¹¹⁹ Furthermore, as shown in murine myeloid cells, de novo fatty acid synthesis supports the expansion of endoplasmic reticulum and Golgi apparatus, aiding in the synthesis, transport and secretion of proteins during inflammatory responses.⁶³

Beyond altering membrane composition, de novo fatty acid synthesis also plays a key role in inflammatory responses. Genetic inhibition of fatty acid synthesis reduces NO production and pro-inflammatory signalling in human macrophages upon TLR stimulation.¹²⁰ Moreover, murine studies show that ACAC is necessary for the LPS-induced switch to glycolysis for the production of inflammatory cytokines but is dispensable for IL-4-induced reprogramming of anti-inflammatory macrophages.⁵⁷ Thus, fatty acid synthesis is required for sustained production of pro-inflammatory cytokines in TLR-activated macrophages. In this complex interplay, however, different TLR ligands also have distinct effects on fatty acid synthesis and the lipidome of murine macrophages.¹²¹ MyD88-dependent TLR stimulation (e.g. TLR1/2, TLR7 or TLR9) increases the synthesis of saturated fatty acids and monounsaturated fatty acids, while TLR3 stimulation diminishes both.¹²¹ The varied production of different fatty acids also seems to be dependent on the specific PRR, with PRRs that induce a strong type I response potentially opposing the effects of TLR3 stimulation.¹²¹ Similarly, accumulation of the cholesterol precursor, 7-dehydrocholesterol, was shown to act as a signalling lipid that enhanced the type I IFN response through interferon regulatory factor 3 phosphorylation in murine macrophages and human cell lines.⁴⁷ This led to enhanced antiviral immunity against vesicular stomatitis virus and Zika virus.⁴⁷ Therefore, PRR- or cytokine-specific lipid remodelling is likely fundamental for regulating and coordinating pathogen-specific inflammatory responses in macrophages.

In addition, lipid droplets, specialized lipid organelles produced in response to inflammatory challenge, such as LPS, can act as dynamic immunometabolic organelles to mediate diverse innate immune responses. Lipid droplets from infected cells are selectively enriched in various immunity-related proteins, including IFN-inducible GTPases, viperin and cathelicidin to directly restrict intracellular pathogens.¹²² In murine macrophages, CCL2-induced lipid droplets compartmentalize arachidonic acid metabolism, serving as sites for leucotriene production, thereby amplifying inflammatory signals.¹²³ Macrophages can also phagocytose extracellular lipid droplets, which unexpectedly dampened inflammation, at least in TREM2-expressing murine hepatic macrophages.¹²⁴ Consistent with this, accumulation of lipid droplets in murine microglia supported remyelination, while TREM2 deficiency led to endoplasmic reticulum (ER) stress and demyelination.¹²⁵ Thus, TREM2-mediated orchestration of lipid droplet responses appears to promote protective myeloid phenotypes. One potential mechanism is that TREM2 acts as a lipid sensor to trigger LXR-mediated cholesterol efflux, reducing cholesterol accumulation that promotes ER stress.¹²⁶ Consistent with its neuroprotective effects, TREM2 has also been shown to sustain microglial responses to Aβ accumulation in a mouse model of Alzheimer's disease.¹²⁷

Fatty acid oxidation

Fatty acid oxidation, also known as β-oxidation, is a catabolic process that breaks down fatty acids to generate energy. This process occurs primarily in the mitochondria but can also occur in peroxisomes for very long-chain fatty acids (Fig. 4). The carnitine shuttle system, via carnitine palmitoyltransferase 1α (CPT1α), is the primary means for long-chain fatty acids to enter the mitochondria. The resultant fatty acids, in the form of acetyl-CoA, can enter the TCA cycle to drive substantial ATP production via OXPHOS, as well as supporting signalling and macromolecule synthesis.¹¹⁷ Fatty acid oxidation enables cells to use fats as a substitute energy source, particularly in glucose-limited environments. Consistent with macrophages tailoring catabolic metabolism to nutrient availability, murine Kupffer macrophages in the lipid-rich liver are more reliant on fatty acids over glucose as a primary energy source.¹²

Fatty acid oxidation is often associated with an anti-inflammatory macrophage response, partly due to the shift away from glycolysis-coupled inflammatory effector reprogramming.⁴⁰ Metabolic intermediates of OXPHOS, such as itaconate (discussed earlier) and α-ketoglutarate, also participate in its anti-inflammatory effects, directing transcriptional control of anti-inflammatory programmes in mice.¹²⁸ In particular, amino acid catabolism can intersect with mitochondrial respiration to sustain inflammatory signalling.

Amino acid metabolism

Amino acids in macrophages have considerable functional and regulatory roles. Immune cell activation increases the demand for amino acids, leading to the upregulation of amino acid transporters such as L-type amino acid transporter 1 (LAT1, CD98) (Fig. 1). Many amino acids are critical for energy generation, and their catabolism contributes to metabolic pathways, notably the TCA cycle. Moreover, amino acids are integral to the synthesis of inflammatory mediators. In myeloid cells, the uptake of amino acids, such as tryptophan, arginine, glutamine, serine and glycine, and the availability of their metabolites, are key drivers of cellular differentiation, functional polarization and interaction with other immune cells.

Arginine is a crucial amino acid in various metabolic processes, including the urea cycle, and serves as a precursor to compounds such as NO and citrulline (Fig. 1). Arginine metabolism, via enzymes such as arginase and iNOS, regulates macrophage activation: Nos2 expression by pro-inflammatory macrophages converts arginine into cytotoxic NO and citrulline, enhancing their antibacterial properties¹²⁹ (Figs 1 and 7). Importantly, extracellular uptake of arginine is essential for sustained NO production in murine macrophages, mediated by the cationic amino acid transporter CAT2 (Fig. 1).¹³⁰ Nevertheless, excessive generation of NO can lead to hyperinflammation and excessive tissue destruction, as observed in influenza and West Nile virus (WNV) encephalitis.^131,132 In contrast, anti-inflammatory macrophages express arginase 1, which directs the synthesis of ornithine and urea (Fig. 1). This process promotes cellular proliferation and tissue regeneration, but it may also impede crucial T cell activities.^133,134

Tryptophan, an essential amino acid, is a precursor for NAD⁺ synthesis, playing a crucial role in glycolysis, the TCA cycle and OXPHOS, inter alia. It is mainly degraded through the kynurenine pathway, facilitated by the enzyme indoleamine-2,3-dioxygenase (IDO), which converts tryptophan into kynurenine and other molecules¹³⁵ (Fig. 1). IDO expression generally increases during inflammation¹³⁶ and can protect uninfected cells from viral infection due to tryptophan starvation.¹³⁷ Increased IDO expression can induce an anti-inflammatory macrophage phenotype, while decreased IDO expression promotes a pro-inflammatory state.¹³⁸ This effect may be mediated by the inverse relationship between IDO and the inflammatory mediator NO, with NO downregulating IDO expression^139,140 (Fig. 1), and both being induced by IFN-γ, suggesting their relationship is influenced by local structural cellular responses and the temporal flux of responding immigrant immune cells.^141,142

Glutamine also serves multiple roles, contributing to nucleotide synthesis, NADPH and energy production, among other biosynthetic pathways involved in cellular proliferation and functions (Fig. 1). Glutamine usage is flexible, accommodating both pro- and anti-inflammatory macrophage phenotypes, depending on the metabolic demands of the cell. Pro-inflammatory macrophages primarily use glutamine for succinate synthesis. In mice, this is facilitated by disruption of the TCA cycle, stabilizing HIF1-α through the GABA shunt.⁵⁶ Furthermore, recent mouse studies indicate that glutamine can fuel lactate production and fatty acid oxidation in a glucose-independent manner, even in the absence of a disrupted TCA cycle.¹⁴³ This metabolic flexibility seemingly encourages epigenetic reprogramming towards a pro-inflammatory macrophage phenotype. On the other hand, anti-inflammatory murine macrophages exploit glutamine metabolism at various stages to adapt to their specific needs. First, α-ketoglutarate derived from glutaminolysis (glutamine derived from glutamate) serves as fuel for OXPHOS and fatty acid oxidation.¹²⁸ Second, glutamine metabolism contributes to the promotion of ‘M2-specific’ gene expression through epigenetic reprogramming.¹²⁸ Lastly, glutamine inhibits the expression of HIF1-α, thus diverging from the pattern observed in pro-inflammatory macrophages.

Serine is a key amino acid in one-carbon metabolism and supports metabolic processes required for nucleotide, NADPH and glutathione synthesis in murine macrophages.¹⁴⁴ Within the CNS, serine is critical for the synthesis of the nerve sheath and is also a neuroprotectant. Serine availability within the CNS relies on de novo synthesis, due to the lack of transporters for crossing the blood–brain barrier. Previous work indicates that murine macrophages depend largely on extracellular serine rather than de novo synthesis, with sufficiency required to prevent mitochondrial dysfunction and aberrant pro-inflammatory cytokine production.¹⁴⁵ This may be pertinent in the context of CNS MCs, if the same dependency exists, as the lack of serine influx into the CNS may perpetuate neuroinflammation. Serine metabolism is also a key driver of macrophage polarization. In mice, macrophages deficient in serine metabolism adopted a pro-inflammatory IFN-dominated phenotype, while suppressing an anti-inflammatory IL-4-dominated phenotype.¹⁴⁶ Another potential pathway is the involvement of serine in homocysteine remethylation, a process that converts homocysteine, a toxic metabolite at high concentrations, into methionine. High levels of homocysteine are associated with human macrophage polarization towards a pro-inflammatory phenotype via m6A methylation of the scavenger receptor CD209 and CD163L1.¹⁴⁷ Homocysteine may also directly promote TNF and IL-1β production, at least in RAW264.3 cells.¹⁴⁸ Serine has also been shown to be required for optimal LPS-induced IL-1β production in murine macrophages, by acting as a substrate for glycine synthesis to drive the glutathione synthesis pathway.¹⁴⁴ In mice, reduced serine availability can also potentiate macrophage antiviral responses by enhancing IFN-β expression.⁴⁸ Thus, serine and its related metabolic intermediates appear to be key for both macrophage polarization and their functional activity.

Glycine interconnects with serine and can be generated via a reversible reaction involving serine hydroxymethyltransferase. Circulating levels of glycine are inversely correlated with metabolic diseases like obesity, Type 2 diabetes mellitus and metabolic dysfunction-associated steatotic liver diseases,¹⁴⁹ and are also reflected in the immunometabolic regulation of anti-inflammatory MCs. Glycine itself is also a substrate for glutathione synthesis, and accumulation of glycine can participate in antioxidant responses. In murine macrophages, glycine activates Gly receptor alpha-4, resulting in activation of the AKT1/mTOR pathway to inhibit NLRP3 activation and IL-1β production.¹⁵⁰ This pathway was shown to alleviate LPS-induced sepsis syndrome in mice. In human monocytes, glycine exerts a similar anti-inflammatory effect via Gly receptor activation, as evidenced by strychnine sensitivity, suppressing TNF and IL-1β production while promoting IL-10 expression.¹⁵¹

Metabolic profiles of monocytes in CNS disease

Inflammation of the CNS is a pathological feature of various neurological disorders, often associated with neurodegeneration and declining neurological function. Monocytes are major contributors to this process and can exacerbate tissue damage in diseases such as sterile tissue injury, autoimmune inflammation and viral infection. Although these conditions differ in cause, mitigating uncontrolled inflammation—largely driven by inflammatory monocytes—is a shared treatment objective.

Monocytes exhibit a degree of functional overlap across different disease states; however, they also develop unique and disease-specific phenotypes, transcriptional signatures, metabolic patterns and functions. This is evident from recent technological advances in single-cell profiling, which have revealed a wide array of disease-associated monocyte states and functions.

Sterile injury

Overview of sterile injury

Sterile CNS injury frequently results from ischaemic stroke, traumatic brain injury (TBI) or spinal cord injury (SCI), all of which share common immunological sequelae. Ischaemic stroke is caused by vascular occlusion causing tissue hypoxia,^152,153 while SCI and TBI involve mechanical injury followed by secondary ischaemic injury.^154-156 Together, these insults trigger neuroinflammation which contributes to secondary damage and long-term neurological deficits. Monocyte infiltration into the CNS is central to this process and can be protective or pathological depending on context and timing.^157-161

The post-injury environment, characterized by hypoxia and altered nutrient availability, influences monocyte fate and function. Excessive lipid uptake from myelin debris promotes foam cell formation and sustains inflammation, while increased glycolysis enhances cytokine production and antigen presentation. These metabolic changes directly shape monocyte function after CNS injury, as discussed later.

Metabolic profiles of monocytes in sterile injury

Monocytes help resolve neuroinflammation and support tissue repair by phagocytosing apoptotic cells and debris.¹⁶² In mice following SCI, myelin debris accumulates and impairs regeneration.¹⁶³ Although monocytes can support remyelination, excessive intracellular lipid accumulation (though not strictly dependent on myelin uptake) can disrupt intracellular lipid homeostasis and drive formation of pro-inflammatory, foamy macrophages^164-166 (Fig. 5). These macrophages have reduced functionality and sustain chronic inflammation, which exacerbates myelin debris accumulation and hinders regeneration.¹⁶⁷

Macrophages initially take on a pro-inflammatory and migratory phenotype in the acute stage of SCI in mice.¹⁶⁸ As the injury persists, these cells transition to a lipid metabolic phenotype, which is influenced by nuclear receptors that sense lipids, such as liver X receptor/retinoid X receptor and peroxisome proliferator-activated receptor-α, which regulate the synthesis and breakdown of fatty acids.¹⁶⁸ By 7 days post-injury, macrophages adopt a foam cell-like phenotype. In this study, deletion of CD36, a receptor that binds to oxidized lipids, reduced lipid droplet build-up in macrophages.¹⁶⁸ This suggests that foam cell formation impairs myelin debris clearance, likely because the route responsible for recycling cholesterol becomes overloaded, which consequently exacerbates inflammation and impairs further regeneration after SCI.¹⁶²

Chronic SCI in mice is also characterized by lipid accumulation in resident microglia. In a thoracic contusion model, microglia adopt a persistent, metabolically altered inflammatory state linked to glycolysis and fatty acid-binding protein 5-dependent lipid handling, culminating in a foam cell-like phenotype.¹⁶⁹ A subsequent mouse study of spinal cord hemi-contusion injury demonstrated this phenotype was supported by lipid droplet and cholesterol ester accumulation driven by a glycolytic-dominant metabolic profile and coordinated rewiring of fatty acid and cholesterol metabolism.¹⁷⁰

Myelin breakdown after ischaemic stroke also releases polyunsaturated fatty acids, free cholesterol, cholesterol esters and phospholipids,^171,172 which undergo parallel metabolic and oxidative processes. Stroke-induced infarcts drive enzymatic and non-enzymatic lipid peroxidation, increasing lipoprotein particle oxidation,¹⁷³ which are recognized by scavenger receptors, such as CD36.¹⁷⁴ In addition, after stroke in mice, rats and humans, myeloid cells upregulate cholesterol metabolism required for myelin clearance.¹⁷⁵ Microglia and recruited monocytes showed increased phagocytic capacity, including increased CD36 expression.¹⁷⁵ These findings further support the important role of myeloid cells in removing lipid debris after a stroke.

Despite these studies, our understanding of MC metabolic profiles following CNS injury is limited, with much insight on post-injury processes drawn from in vitro systems or peripheral injury models. For example, efferocytosis, a critical process following injury, relies on aerobic glycolysis, as indicated by increased glucose uptake and lactate release in phagocytic LR73 cells.⁶⁷ This process supports cytoskeletal rearrangement during phagocytosis⁶⁷ and the upregulation of receptors recognizing apoptotic cells for phagocytosis in murine macrophages.¹⁷⁶ Arginine and ornithine derived from apoptotic cells also support cytoskeletal rearrangement, being metabolized in the polyamine putrescine pathway in macrophages via arginase 1 and ornithine decarboxylase during efferocytosis.⁶⁸

Fatty acids derived from apoptotic cells promote anti-inflammatory signalling through activation of the IL-10 transcription factor, pre-B cell leukemia transcription factor-1 in murine macrophages.⁶⁹ They are associated with an increase in lipid metabolites associated with their oxidation, along with increased mitochondrial electron transport and OXPHOS gene expression. Furthermore, glutamine catabolism through a non-canonical transaminase pathway in mice fuels OXPHOS and ATP production to potentiate efferocytosis, while enabling the synthesis of the antioxidant glutathione to prevent oxidative stress from phagocytosis of apoptotic cells.¹⁷⁷ Finally, efferocytosis stimulates the kynurenine pathway,⁷⁰ enhances fatty acid oxidation⁶⁹ and activates the sterol pathway.⁷¹ However, metabolic responses vary by target cell; in a mouse lung tumour model, neoplastic cell uptake induced OXPHOS, glycolysis, gluconeogenesis and ribosomal gene expression.¹⁷⁸ Efferocytosis of certain cells following CNS injury, such as apoptotic neurons or oligodendrocytes, thus likely induces distinct metabolic programmes. These findings demonstrate that efferocytosis relies on various metabolic processes, including aerobic glycolysis, arginine and ornithine metabolism, fatty acid oxidation and glutamine catabolism, which collectively support the engulfment of apoptotic cells and subsequent cellular functions.

Beyond phagocytosis, MCs may exacerbate damage through ROS production, which can injure neurons and contribute to secondary damage. ROS generation involves diversion of glycolytic intermediates into the oxidative PPP, producing NADPH to fuel NOXs.⁴¹ In contrast, anti-inflammatory macrophages use the non-oxidative PPP to maintain redox balance and support antioxidants such as glutathione.¹⁷⁹ Post SCI and TBI in rats, macrophages and microglia increase NOX2 at injury sites,^180,181 which is associated with increased ROS production by macrophages and microglia. Accordingly, NOX inhibition improves SCI and TBI outcomes in mice,^182-184 and NOX2 deficiency increases anti-inflammatory murine macrophage/microglial activation under in vitro culture conditions mimicking the inflammatory environment in TBI.¹⁸⁵ These findings highlight the influence of redox-associated metabolic processes on the inflammatory response following CNS injury, which may be a viable therapeutic target to reduce oxidative stress and promote recovery following injury.

Finally, in the early stage of experimental ischaemia, CD11b⁺ cells in the damaged CNS of mice with a permanent middle cerebral artery occlusion express genes linked to both glycolysis and OXPHOS. Glycolytic genes, such as lactate dehydrogenase A and PKM2, remain elevated after injury in mice.¹⁸⁶ In rats, inhibition of hexokinase 2, a rate-limiting glycolytic enzyme, reduces microglial activation and provides neuroprotection in vivo,¹⁸⁷ corroborating the association between glycolytic reprogramming and pro-inflammatory myeloid responses after ischaemic injury.

Demyelinating disease

Overview of demyelinating disease

Multiple sclerosis is a chronic inflammatory CNS disorder marked by immune-mediated demyelination and progressive neurodegeneration, leading to cumulative physical and cognitive impairment.^188,189 Although the precise aetiology is unclear, it is widely regarded as autoimmune, involving both innate and adaptive immunity.^190-192

MCs contribute to pathogenesis through several energetically demanding roles, including cytokine secretion, antigen presentation, phagocytosis of cellular debris and support for remyelination,⁶ which are strongly linked to their metabolic state. In multiple sclerosis and its animal models, monocyte function is shaped not only by inflammatory signals but also by intrinsic metabolic programming, as discussed later. Targeting monocyte metabolism may therefore help limit inflammation and support tissue repair in demyelinating disease.

Metabolic profiles of monocytes in demyelinating disease

Glycolysis is closely linked to inflammation in multiple sclerosis. Patients with relapsing-remitting multiple sclerosis show elevated serum glycolytic metabolites compared with healthy controls, reflecting a disease-associated metabolic state.¹⁹³ In EAE, the glycolysis inhibitor, 2-deoxy-D-glucose (2-DG), attenuated both myelin-specific immune cell proliferation and pro-inflammatory cytokine production and induced anti-inflammatory IL-10.¹⁹³ 2-DG competes with glucose for uptake and phosphorylation by hexokinase, resulting in accumulation of poorly-metabolized 2-deoxy-D-glucose-6-phosphate which inhibits hexokinase, reducing glycolytic flux. Treatment with 2-DG also significantly reduced the pro-inflammatory phenotype of monocytes/macrophages and associated glycolytic activity, as indicated by decreased glucose and lactate levels and lower expression of glycolytic enzymes.¹⁹³ Notably, adoptive transfer of 2-DG-treated monocytes into EAE mice resulted in milder symptoms,¹⁹³ supporting glycolysis inhibition as a promising strategy to mitigate acute inflammation in multiple sclerosis progression by promoting an anti-inflammatory monocyte phenotype.

Glycolysis not only promotes a pro-inflammatory phenotype but is also essential for monocyte transmigration across the blood–brain barrier in EAE. Monocytes in perivascular cuffs show elevated expression of lactate dehydrogenase A⁸¹ and monocarboxylate transporter-4 (MCT4), supporting pyruvate-to-lactate conversion and lactate efflux from glycolytically active cells¹⁹⁴ (Fig. 6). Intriguingly, this expression is confined to the perivascular spaces, not the CNS parenchyma, with similar patterns observed in multiple sclerosis patient brains,¹⁹⁵ emphasizing the importance of glycolysis in migrating across endothelial barriers. Glycolytic dependency is further evidenced by the reduced transmigration following lactate dehydrogenase A and MCT4 knockdown in mice.⁸¹

Inflammatory lesions in multiple sclerosis are often hypoxic and acidic, with increased expression of hypoxic markers and glucose transporters compared to healthy patients, consistent with increased glycolysis in infiltrating cells.¹⁹⁵ HIF1-α, a regulator of glycolysis under hypoxic conditions, is also stabilized in these inflammatory macrophages (Fig. 6). As the switch towards aerobic glycolysis in activated macrophages is at least in part orchestrated by HIF1-α, this suggests a complex glycolytic reprogramming that supports monocyte infiltration into the brain in multiple sclerosis pathology.

Glycolysis-associated signalling molecules such as lactate¹⁹⁶ and HIF1-α¹⁹⁷ also regulate metabolic signalling in murine monocytes and macrophages. In EAE, lactate and HIF1-α signalling exerts an immunosuppressive effect on infiltrating myeloid cells.¹⁹⁸ DCs in the CNS showed increased levels of HIF1-α and signalling, and deletion of Hif1a in DCs exacerbated EAE symptoms and increased pro-inflammatory T cells in the CNS. Lactate, as a metabolite, was identified as a stabilizing factor for HIF1-α, and lactate treatment reduced the expression of pro-inflammatory cytokines by T cells in a HIF1-α-dependent manner. This suggests that lactate triggers a regulatory loop in DCs via HIF1-α, which can limit inflammation. Exploring the potential for clinical application, an engineered probiotic Escherichia coli strain producing D-lactate increased HIF1-α and improved EAE symptoms when administered orally, supporting therapeutic targeting of this pathway in CNS autoimmunity.¹⁹⁸

In demyelinating diseases like multiple sclerosis, damaged myelin is cleared by phagocytes and replaced by new myelin from existing or newly-differentiated oligodendrocytes. Cholesterol, a major myelin component,¹⁹⁹ cannot be degraded and must be recycled locally or exported. In mouse demyelination models, manipulating cholesterol and lipid metabolism revealed tight links between myelin breakdown, intracellular cholesterol/lipid trafficking, efflux and recycling, as well as the inflammatory profile of phagocytes (Fig. 6).^166,200,201 In active lesions from multiple sclerosis post-mortem tissue, myelin-containing phagocytes exhibit increased cholesterol, consistent with foamy macrophage formation. In mice, myelin uptake temporarily promotes a disease-resolving phenotype in microglia and macrophages, but sustained myelin accumulation drives a lesion-promoting, pro-inflammatory phenotype.¹⁶⁶ This phenotypic shift involves fatty acid-associated enzymes such as stearoyl-CoA desaturase-1 that contribute to reduced cholesterol efflux in phagocytes.¹⁶⁶ Similarly, sterol synthesis is upregulated in phagocytes within actively demyelinating lesions—a common mechanism across various mouse models of multiple sclerosis.²⁰² Interestingly, functional CNS phagocyte sterol synthesis following myelin uptake mediates cholesterol efflux and limits inflammation.²⁰² Genetic loss of sterol synthesis leads to lipid-laden foamy phagocytes due to downregulated efflux transporters.²⁰²

In contrast to active lesions, chronic lesions contain abundant foam cells with retained myelin, indicating impaired lipid recycling.²⁰³ Monocytes derived from the blood of patients with relapsing-remitting multiple sclerosis show reduced expression of lipid-sensing nuclear receptors, such as peroxisome proliferator-activated receptors, which was associated with foam cell formation and altered cholesterol metabolism.²⁰⁴ Together, these findings highlight the tight regulation of intracellular lipid metabolism in shaping phagocyte inflammatory phenotypes during demyelination and remyelination.

Although myeloid cells are often associated with a pro-inflammatory phenotype resulting in demyelination, they also promote remyelination through distinct amino acid-linked metabolic programmes. Interleukin-4-induced 1 (IL4I1), which converts aromatic amino acids such as phenylalanine into α-keto acids, is produced by myeloid cells during remyelination,²⁰⁵ limits demyelination and promotes inflammation resolution in a chemical demyelination mouse model of multiple sclerosis.^205,206 IL-4 signalling was shown to induce IL4I1 expression in myeloid cells, promoting an anti-inflammatory phenotype and skewing CD4⁺ T cells towards an immunomodulatory T helper type 2 cell phenotype,²⁰⁶ which facilitated remyelination and reduced disease severity. The immunomodulatory effect of IL4I1 was ascribed to α-keto acids, which are the enzymatic by-products of IL4I1.²⁰⁵ These α-keto acids influence the lipid metabolism of myeloid cells,²⁰⁵ a phenotype associated with resolving inflammation and assisting in remyelination (Fig. 6).^207,208 However, whether the amino acid-driven phenotype arises from MCs or microglia remains unclear.²⁰⁶

Together, these studies show that intracellular lipid handling shapes myeloid inflammatory phenotypes during demyelination and remyelination. Diet further modulates these programmes. In EAE, a high carbohydrate diet increased glycolysis in T cells and DCs, which promoted Th1 and Th17 responses, promoted inflammatory macrophage infiltration into the CNS and exacerbated neuroinflammation.²⁰⁹ In contrast, a high fat diet protected from disease, reducing neuroinflammation and limiting macrophage and microglial activation. Protection was associated with increased lipid storage in immune cells and elevated IL-10 production across monocytes, DCs and B cells. High fat feeding also transcriptionally and epigenetically preconditioned naïve T cells towards regulatory T cell differentiation. These findings indicate that dietary substrate availability reprogrammes myeloid cell metabolism, adding a systemic layer of regulation to local lipid recycling and suggesting dietary manipulation as a strategy to modulate pathogenic versus regulatory responses in CNS autoimmunity.

Viral encephalitis

Overview of viral encephalitis

Viral encephalitis, the inflammation of brain parenchyma caused by viral infection, is associated with high mortality and severe neurological sequelae. Viral replication within neural cells triggers cytokine and chemokine release, recruiting peripheral immune cells, including monocytes. In flavivirus encephalitis, monocytes can comprise over 50% of the CNS-infiltrating leucocytes,^132,210 as shown in both murine models^132,210 and human autopsy cases of severe WNV encephalitis.^211-213 Although monocyte recruitment is essential for antiviral defence, mouse studies have demonstrated that excessive or prolonged activation promotes NO production and pro-inflammatory cytokine production, contributing to neuronal injury and seizures.^{132,210,214,215}

Metabolic pathways in monocytes supporting antiviral innate immunity

As key players in the antiviral immune response, monocytes must adapt their metabolism to fulfil various roles. These roles range from directly phagocytosing viral particles, to antigen presentation and the production of pro-inflammatory mediators.

Recent studies in WNV encephalitis,^{132,210,214,216,217} a pro-inflammatory macrophage-driven disease marked by infiltration of NO-producing myeloid cells, have provided detailed insight into MC metabolic regulation in mice. Temporal profiling showed that bone marrow monocytes initially exhibit a catabolic, energy-conserving profile with high TCA cycle and ETC activity.²¹⁸ As disease progressed, these cells migrated into the brain and transitioned through a HIF1-α⁺ intermediate state there, before bifurcating into two metabolically and functionally distinct subsets in the inflamed brain: a highly glycolytic, iNOS⁺ inflammatory population and a comparatively glycolytically quiescent, MHC-II⁺ antigen-presenting cell (APC) population. Glycolysis inhibition with 2-DG treatment during WNV encephalitis reduced neuroinflammation, lowered expression of inflammatory cytokines and chemokines and improved clinical outcomes without impacting viral load.²¹⁸ This protection was associated with a preferential reduction in the infiltration and differentiation of iNOS⁺ MCs, while MHC-II⁺ APC-like cells were preserved and even proportionally enriched. Importantly, systemic antigen presentation and T cell priming remained intact under glycolysis inhibition, indicating that the pathogenic iNOS⁺ programme is selectively dependent on glycolysis, whereas antigen-presenting fates can persist with reduced glycolytic demand.²¹⁸ These findings highlight glycolysis as a key driver of NO-producing monocyte pathology in viral encephalitis, while also highlighting the potential to reprogramme MC differentiation towards less inflammatory, antigen-presenting states. However, whether such skewing is beneficial or detrimental is likely to depend on disease context, since APC-driven responses may support viral clearance in encephalitis but exacerbate autoimmunity in settings such as EAE. Notably, as this was the first study to investigate monocyte metabolism in viral encephalitis in vivo, more specific studies in additional viral encephalitis models will be required to determine whether the divergent metabolic programmes identified in WNV infection are broadly applicable, or whether distinct viruses shape monocyte metabolism in unique ways depending on the nature of the inflammatory response and the balance between antiviral immunity and immunopathology.

In addition to being influenced by the CNS microenvironment during viral encephalitis, MC function may also be primed in the bone marrow prior to their infiltration into the brain. In WNV encephalitis, bone marrow monocytes from mice treated with the glycolysis inhibitor 2-DG showed a reduced capacity to differentiate into NO-producing MCs upon restimulation ex vivo and a skewing towards an antigen-presenting phenotype.²¹⁸ This suggests metabolic preprogramming in the bone marrow shapes subsequent MC fate. Supporting this, foundational studies in mice have shown that different microbial pathogen-associated molecular patterns skew monocytes towards different monocyte differentiation programmes: LPS and TLR4 stimulation favour GMP-derived neutrophil-like monocytes with antibacterial functions, whereas TLR9 stimulation with CpG promotes MDP-derived monocytes with antiviral capacity.¹⁶ Notably, this skewing may also be reflected metabolically, as in human monocytes, different pathogens similarly induce distinct metabolic programmes linked to phagocytosis and cytokine production.¹¹ Ontogeny also likely contributes; in mice, MHC II⁺ monocytes exposed to granulocyte-macrophage colony-stimulating factor become antigen-presenting MCs, whereas MHC II⁻ monocytes exposed to microbial stimuli differentiate into iNOS⁺ MCs.²¹⁹ Thus, systemic metabolic responses to microbial antigens or cytokines may prime bone marrow monocytes, skewing their differentiation towards distinct functions suited to specific inflammatory contexts. This highlights the complexity of macrophage activation, where metabolic and kinetic factors shape monocyte differentiation into functionally distinct subsets during viral encephalitis.

Despite the limited research on monocyte metabolic responses to CNS viral infection in vivo, valuable insights can be drawn from peripheral infection and in vitro studies (Fig. 7). Nutrient availability plays a significant role in monocyte functionality during in vivo viral infection. For instance, in mice with influenza A, a fibre-rich diet increased Ly6C⁻ monocyte production in the bone marrow, promoted anti-inflammatory macrophages in the lungs, reduced neutrophil influx and tissue damage, and improved survival.²²⁰ Dietary manipulation may therefore shape bone marrow myelopoiesis and prime the inflammatory capacity of monocytes prior to their infiltration into inflamed tissues. However, these effects may be virus- or dose-dependent, as a high-fibre diet had minimal impact on monocyte-mediated immunopathology in flavivirus infection.²²¹

Moreover, recent studies show that glucose availability shapes monocyte inflammatory responses during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In the context of SARS-CoV-2, monocytes contribute to immunopathology in patients via the production of pro-inflammatory cytokines.²²² This leads to the detrimental ‘cytokine storm’. Particularly in the context of diabetic individuals, high blood glucose levels are a prominent risk factor for severe coronavirus disease,²²³ pointing to the local glucose levels as a determining factor in monocyte function and virus replication. Indeed, SARS-CoV-2-infected monocytes produce elevated pro-inflammatory cytokines in a glucose-dependent manner, associated with a shift to aerobic glycolysis sustained by mitochondrial ROS-mediated stabilization of HIF1-α, enhancing glycolytic gene expression and IL-1β production.²²⁴ Given that influenza and SARS-CoV-2 can be neuroinvasive and that pro-inflammatory monocyte responses are shared across CNS infections such as WNV encephalitis, targeting glucose metabolism, for example with glycolysis inhibitors such as 2-DG, may help limit excessive inflammation and immune-mediated damage during viral encephalitis.

The production of inflammatory mediators, such as NO, is an additional important component of the antiviral response. Classical in vitro activation of murine macrophages elicits the expression of iNOS, generating large amounts of NO and disrupting mitochondrial respiration.¹³⁴ Upregulation of glycolysis and a disrupted TCA cycle underpin this switch to a pro-inflammatory phenotype. iNOS catalyses the conversion of arginine, a non-essential amino acid, into NO and citrulline, providing macrophages with ‘cytotoxic’ potential.¹²⁹ In this process, NO reacts with oxygen or ROS spontaneously, leading to the formation of numerous antimicrobial species.²²⁵ The citrulline produced by iNOS is recycled back into arginine through the activity of argininosuccinate synthase 1, thereby maintaining NO production.²²⁶ Sustained NO production, however, can lead to hyperinflammation and tissue damage in various diseases, for example in severe influenza virus infection, severe coronavirus disease and WNV encephalitis.^131,132,227

In addition to the production of inflammatory cytokines, signalling initiated by viral nucleic acids, followed by the activation of type I IFNs, influences the innate immune response against viral infections and, by triggering metabolic adaptations in MCs, provides crucial support for antiviral defences. Cytosolic viral recognition occurs through secondary IFN signalling, leading to a preferential increase in glycolytic activity in macrophages.⁴⁹ This metabolic shift involves the induction of the glycolytic activator, 6-phosphofructose-2-kinase/fructose-2,6-bisphosphatase. Glycolysis driven by this enzyme serves as a selective enhancer of the antiviral capacity of macrophages by facilitating efferocytosis of virus-infected cells.⁴⁹

Lipid metabolism also plays a critical role in regulating the type I IFN response. During viral infection, IFN signalling modifies cholesterol synthesis in murine macrophages through the degradation of key biosynthetic pathway enzymes.^228,229 Reprogramming of sterol metabolism by IFN signalling has been shown to facilitate cellular resistance to viral invaders and can intrinsically promote IFN-mediated inflammation in mice.^47,228-230 Mechanistically, downregulation of de novo cholesterol synthesis during murine macrophage activation restrains engagement of the inflammasome, thereby ensuring that effective type I IFN signalling proceeds.²³¹ Hence, inhibiting cholesterol synthesis pathways appears to be a key factor in enhancing the type I IFN response and ensuring the elimination of viruses. Interestingly, viruses such as flaviviruses modulate fatty acid and cholesterol biosynthesis during replication,²³² although it is unclear whether this contributes to yet another flaviviral immune evasion strategy via the type I IFN pathway.²³³

Type II IFN, IFN-γ, also plays a critical role in the antiviral response. IFN-γ is crucial in antiviral immunity, primarily by activating immune cells, enhancing antigen presentation and directing T helper cells towards a T helper type 1 response, which is vital for fighting viral infections. Recently, it was shown that mitochondrial respiration, and in particular complex I of the ETC, was essential for IFN-γ responses in APCs.²³⁴ Complex I was required for the IFN-γ-mediated induction of important co-signalling molecules and expression of MHC-II on murine APCs and is necessary for antigen presentation and T cell activation.²³⁴

Finally, it is essential to acknowledge that metabolic responses to viral recognition in monocytes are tailored rather than generic. Although the Warburg effect links glycolysis to pro-inflammatory macrophages and OXPHOS to anti-inflammatory states,^235,236 this shift is not universal. In human monocytes, a shift from OXPHOS to glycolysis occurs in response to LPS (i.e. TLR4 stimulation) and not alternative TLR activation (e.g. TLR2 via Pam3CysSK4) or other bacterial lysates.¹¹ Interestingly, under Pam3CysSK4 stimulation, IL-1β production and phagocytosis depend on OXPHOS, whereas these functions are OXPHOS-independent after LPS challenge.¹¹ Furthermore, glycolysis inhibition does not impair phagocytosis, supporting OXPHOS as the primary metabolic driver of this process.¹¹ Interestingly, in mice, distal stimuli such as LPS and proximal threats such as whole uropathogenic E. coli induce distinct metabolic programmes via the enzyme histone deacetylase 7.²³⁷ Thus, pathogen-specific metabolic adaptation drives distinct functional outputs, including phagocytosis and cytokine production, enabling tailored inflammatory responses. Accordingly, systemic metabolism is adjusted to support the specific demands of viral or bacterial infection. During bacterial inflammation, glucose restriction promotes ketogenesis, improving resistance to ROS-induced brain damage and reducing mortality. In contrast, during viral inflammation in mice, glucose utilization limits type I IFN-driven ER stress and prevents neuronal injury.²³⁸ Thus, glucose metabolism supports survival in viral infection but may be detrimental in bacterial disease, highlighting pathogen-specific metabolic requirements for optimal protection.

Conclusions

Immunometabolism has become an important focus in immunology, highlighting how metabolic processes shape immune cell function and plasticity. Metabolism does not simply support MC activity but actively regulates cell fate and specialization. In CNS diseases, the behaviour of MCs is shaped by a combination of metabolic signals, inflammatory cues and their developmental origin, making metabolism a central factor in their functional response.

The metabolic flexibility of MCs means that traditional frameworks, such as the M1/M2 polarization model, do not capture their full functional range. Rather than adopting fixed states, MCs display diverse metabolic profiles that depend on the disease context, timing and their developmental history. This variation reflects their need to perform different functions, including pathogen clearance, cytokine production, tissue repair and resolution of inflammation.

Understanding the specialized and tailored metabolic pathways that guide MC states, as discussed in this review, may open doors to targeted therapies that dictate their function in specific disease settings. For example, lipid metabolism plays a major role in diseases such as multiple sclerosis, SCI and TBI. In these conditions, MCs are responsible for clearing lipid-rich debris from damaged cells, such as oligodendrocytes. Supporting this clearance process, while preventing excessive lipid accumulation and foam cell formation, could reduce inflammation and support repair. However, the timing of intervention is important. While lipid scavenging may be helpful in acute injury, prolonged lipid uptake can lead to foam cell formation, oxidative stress and impaired tissue regeneration. In addition, targeting glycolysis may also be useful in diseases where MCs contribute to excessive inflammation. In models of EAE or viral encephalitis, inflammatory MCs often rely on glycolysis to support cytokine production and migration. Reducing glycolytic activity in these cells may limit damaging inflammation and promote a more balanced immune response. This approach may be particularly relevant in viral encephalitis, where different MC subsets play opposing roles. For example, antigen-presenting MCs and inflammatory MCs may differ in their reliance on glycolysis, offering a potential way to support adaptive immune antiviral defence while limiting tissue damage.

Existing immunometabolism-based targeting of MCs for neuroinflammation, while limited, has shown potential. Administration of itaconate, or its derivative dimethyl itaconate, improved disease outcomes in models of Parkinson’s disease, multiple sclerosis and SCI by limiting inflammation.^239-241 A related metabolite, 4-octyl itaconate, could also attenuate microglial-mediated inflammation in EAE by activating NRF2 and downregulating Immune-responsive Gene 1.²⁴¹ Upstream, selective inhibition of glycolysis via 2-DG has been shown to be effective against experimental autoimmune neuritis in rats.²⁴² Similarly, 2-DG reduced neuroinflammation without impairing viral control by preferentially targeting glycolysis-dependent iNOS⁺ inflammatory MCs in viral encephalitis.²¹⁸ Classically, dimethyl fumarate has been shown to be highly effective for the treatment of relapsing multiple sclerosis, likely via multiple mechanisms. Dimethyl fumarate promotes succination of GAPDH, downregulating aerobic glycolysis in myeloid cells to promote anti-inflammatory effects.²⁴³ It can also stabilize NRF2, to suppress mitochondrial ROS production. Interestingly, the protective effects of dimethyl fumarate on EAE were found to require hydroxycarboxylic acid receptor (HCA2), a receptor that binds the active metabolite of dimethyl fumarate, monomethyl fumarate.²⁴⁴ Of note, HCA2 is also a receptor for the microbial metabolite butyrate and its related ketogenic metabolite β-hydroxybutyric acid, both of which have anti-inflammatory effects on MCs and other immune cells.²⁴⁵

Although not discussed extensively in this review, it remains important to consider the influence of systemic factors on MCs. Indeed, monocytes may be metabolically or functionally ‘primed’ in the bone marrow by signals generated by infection, injury or systemic inflammation. This priming can affect their later responses once they enter tissues. This understanding may prove beneficial in future work and provides an additional layer in the framework in understanding MC responses in CNS disease and may provide further opportunity for therapeutic targeting, as intervening at this earlier stage could help tailor MC behaviour before they contribute to CNS pathology.

In conclusion, a more detailed understanding of the metabolic pathways that guide MC behaviour can inform the development of targeted therapies for CNS diseases. Moving beyond simple classifications, and towards a model that accounts for metabolic context, timing, cellular origin and insult type, will allow for more precise interventions. These strategies may help reduce harmful inflammation, improve tissue repair and ultimately lead to better clinical outcomes in CNS disease.

Acknowledgement

The thumbnail image for the online table of contents was created in BioRender. King, N. (2026) https://BioRender.com/mvcuc6h.

Contributor Information

Claire L Wishart, Infection, Immunity, Inflammation Research Theme, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia; Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia.

Jian Tan, Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia; Faculty of Medicine and Health, Sydney Institute for Infectious Diseases, The University of Sydney, Sydney, NSW 2006, Australia; Sydney Medical School Nepean, The University of Sydney, Sydney, NSW 2747, Australia; Nepean Hospital, Department of Obstetrics and Gynaecology, Nepean Blue Mountains Local Health District, Sydney, NSW 2747, Australia.

Nicholas J C King, Infection, Immunity, Inflammation Research Theme, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia; Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia; Faculty of Medicine and Health, Sydney Institute for Infectious Diseases, The University of Sydney, Sydney, NSW 2006, Australia; Faculty of Science, The University of Sydney Nano Institute, The University of Sydney, Sydney, NSW 2006, Australia.

Funding

C.L.W. was supported by a Merridew Foundation PhD Scholarship. J.T. was supported by an MS Australia Incubator grant. N.J.C.K. was supported by National Health and Medical Research Council Project Grants 1088242, 1030897, and the Merridew Foundation.

Competing interests

The authors report no competing interests.

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PERMALINK

Dynamic metabolic programming of monocyte-derived cells defines immunity in CNS disease

Claire L Wishart

Jian Tan

Nicholas J C King

Abstract

Introduction

Overview of monocytes and developmental origins

Monocyte classification

Interplay between cellular metabolism and monocyte-derived cell function

Macrophage activation as a continuum of functional states

Table 1.

Overview of metabolic pathways influencing monocyte function

Oxidative phosphorylation: the tricarboxylic acid cycle and electron transport chain

Figure 1.

Figure 2.

Glycolysis and the pentose phosphate pathway

Figure 3.

HIF1-α is a regulator of metabolism and migration

Lipid metabolism

Fatty acid synthesis

Figure 4.

Fatty acid oxidation

Amino acid metabolism

Figure 7.

Metabolic profiles of monocytes in CNS disease

Sterile injury

Overview of sterile injury

Metabolic profiles of monocytes in sterile injury

Figure 5.

Demyelinating disease

Overview of demyelinating disease

Metabolic profiles of monocytes in demyelinating disease

Figure 6.

Viral encephalitis

Overview of viral encephalitis

Metabolic pathways in monocytes supporting antiviral innate immunity

Conclusions

Acknowledgement

Contributor Information

Funding

Competing interests

References

ACTIONS

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