Glucose metabolic reprogramming of macrophages in opposition to Mycobacterium t

Introduction

Mtb is the pathogen chargeable for TB, primarily transmitted by the respiratory tract by way of aerosols exhaled by people with energetic pulmonary TB. Despite concerted international efforts, TB persists as a world well being emergency, rating among the many high causes of infectious illness mortality in line with the World Health Organization (WHO) classifications. In October 2024, the WHO launched the Global Tuberculosis Report 2024, which estimated that there have been 10.8 million incident circumstances of TB worldwide in 2023, with roughly 1.25 million deaths attributed to the illness.¹ This underscores the pressing want for novel methods in TB prevention and therapy. Metabolic reprogramming, significantly in immune cells, has emerged as a essential space of analysis, providing potential insights into enhancing host protection mechanisms and growing revolutionary therapeutic approaches.

The immunopathogenesis of tuberculosis pivots on the dynamic equilibrium between host protection mechanisms and mycobacterial evasion methods. Mtb an infection outcomes are finally decided by the host’s immunological competence, significantly the efficacy of pathogen clearance by coordinated innate and adaptive immune responses.² Macrophages, serving as central orchestrators of antimycobacterial immunity,³ not solely function the primary line of protection in opposition to Mtb an infection but additionally deploy a broad antibacterial arsenal—LC3-mediated phagocytosis, metabolic reprogramming, antimicrobial metabolites and peptides, inflammatory components, and stress granules—whereas integrating upstream IFN-γ/JAK/STAT1, inflammasome and mTOR alerts that drive M1/M2 plasticity and regulate the method of antigen presentation.⁴ In latest years, the regulatory function of metabolic reprogramming within the operate of immune cells has attracted widespread consideration. Specifically, glucose metabolic rewiring in macrophages not solely influences their polarization state but additionally instantly regulates inflammatory responses by the manufacturing of metabolic intermediates that gas biosynthesis and redox steadiness.⁵ Building on the bioenergetic framework established by O’Neill and Pearce,⁶ we right here slim the lens to the Mycobacterium tuberculosis–macrophage axis and replace it with post-2016 proof: (i) itaconate dose-dependently co-targets SDH and TET2;⁷ (ii) single-cell sequencing analyses reveal Mtb-imposed glycolytic shutdown in human macrophages;⁸ and (iii) spatial transcriptomics discloses metabolic zonation inside tuberculous granulomas. Together, these findings substitute the glycolytic/oxidative binary with a context-specific, spatiotemporal mannequin of TB immunometabolism. However, a transparent street map for translating these in-vitro mechanistic insights into measurable affected person profit continues to be lacking. Most research stay confined to rodent or cell-culture fashions, and scientific knowledge linking particular metabolic interventions to sputum tradition conversion, lung pathology or relapse charges are scarce. Consequently, this evaluate goals to synthesise present data, spotlight proof gaps, and description how host-directed metabolic modulation might be moved expeditiously from bench to bedside.

The Fundamental Functions of Macrophages

Macrophages are an important a part of the innate immune system⁹ and originate from widespread myeloid progenitor cells within the bone marrow.¹⁰ They are current in all tissues and act as the first phagocytic cells.¹¹ Macrophages assist clear mobile particles produced throughout tissue reworking and effectively take away apoptotic cells, thus sustaining immune homeostasis throughout the physique.¹⁰ They are the first host cells for Mtb progress and survival and play a significant function within the host’s immune response to Mtb.¹² Macrophages exert a number of important capabilities in controlling TB an infection, together with phagocytosis, the uptake and elimination of pathogens, tissue restore, and the decision of irritation.^13,14

Macrophages, performing as key gamers within the immune responses, exhibit distinct metabolic signatures that dictate their activation states and useful outputs. Based on the activation standing, macrophages are labeled into two sorts, M1 and M2. M1 macrophages are identified for his or her excessive expression of pro-inflammatory and antimicrobial molecules, equivalent to interleukin-1β (IL-1β), IL-12, and tumor necrosis issue (TNF). These molecules promote the method of irritation. In distinction, M2 macrophages categorical larger ranges of anti-inflammatory cytokines like IL-4, IL-10, IL-13, and reworking progress issue (TGF-β). These cytokines play essential roles in sustaining tissue homeostasis and regulating irritation.^10,15,16 The metabolic reprogramming of macrophages is a key think about figuring out their activation state.^6,17 M1 and M2 macrophages exhibit distinct metabolic profiles that correspond to their capabilities.¹⁸ M1 macrophages primarily depend on glycolysis for vitality manufacturing.¹⁶ Although these cells have energetic pentose phosphate and fatty acid synthesis pathways to offer vital biosynthetic precursors, the TCA cycle in M1 macrophages just isn’t totally operational, even within the presence of oxygen.^19,20 They can quickly generate ATP by glycolysis, which is unbiased of mitochondrial oxidative phosphorylation (OXPHOS). On the opposite hand, M2 macrophages primarily rely upon a totally useful TCA cycle that helps excessive ranges of OXPHOS.¹⁹ This metabolic dichotomy not solely fuels distinct useful packages but additionally shapes the immunological panorama, influencing illness development and backbone. Understanding the metabolic drivers of macrophage polarization presents a strategic entry level for modulating immune responses in tuberculosis and different inflammatory ailments.

The Role of Glucose Metabolism Reprogramming in Macrophages

Glucose metabolism is crucial for macrophage activation, polarization, and pathogen clearance. This metabolic rewiring just isn’t merely a passive adaptation however an energetic regulatory mechanism that dictates the useful destiny of macrophages, enabling them to toggle between inflammatory and resolving states as wanted throughout an infection. It includes three pathways: glycolysis, the PPP, and the TCA cycle.

Interferon-γ (IFN-γ) is the physiological cue that commits macrophages to the M1 glycolytic programme.²¹ By activating JAK2/STAT1 signalling, IFN-γ up-regulates PFKFB3-driven glycolysis,²² thereby accelerating glucose flux and reinforcing M1 polarization important for antimicrobial responses in opposition to Mycobacterium tuberculosis.

Glycolysis

The metabolic reprogramming of glycolysis orchestrates a useful shift in macrophages, enhancing the manufacturing of pro-inflammatory cytokines by the technology of metabolic intermediates that provoke inflammatory signaling pathways. Hexokinase 1 (HK1), an important rate-limiting enzyme in glycolysis, catalyzes the phosphorylation of glucose to glucose-6-phosphate (G6P) when it’s certain to mitochondria, thus initiating subsequent glycolytic processes. When HK1 detaches from the mitochondria, G6P is redirected in the direction of the pentose phosphate pathway. This redirection results in the nitration and inactivation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in a fashion depending on inducible nitric oxide synthase (iNOS), subsequently selling the manufacturing of inflammatory cytokines equivalent to IL-6, IL-1β, and TNF-α.²⁰ Research signifies that Zinc fingers and homeoboxes 2(Zhx2) upregulate the transcription of 6-phosphofructo-2-kinase (PFKFB3) and improve glycolysis in macrophages.²³ Furthermore, Zhx2 particularly prompts glycolysis in a fashion depending on phosphofructokinase-1 (PFK1), thus facilitating the manufacturing of pro-inflammatory cytokines. Additionally, pyruvate kinase M2 (PKM2), one other key enzyme within the glycolytic pathway, regulates the activation of inflammasomes equivalent to NOD-like receptor household pyrin area containing 3(NLRP3) and absent in melanoma 2(AIM2) by the phosphorylation of eukaryotic translation initiation issue 2α kinase (eIF2AK2).²⁴ The activation of those inflammasomes results in the activation of caspase-1 in cells, ensuing within the maturation and secretion of pro-inflammatory cytokines equivalent to IL-1β, IL-18, and HMGB1.²⁵

PPP

Macrophages might make the most of pathways such because the PPP and mitochondrial succinate oxidation to provoke glucose metabolic reprogramming and promote their inflammatory phenotype.^26,27 The PPP, a department of glucose metabolism, can course of glycolytic merchandise like G6P to generate nicotinamide adenine dinucleotide phosphate (NADPH). NADPH is crucial for the survival of macrophages below oxidative stress and inflammatory circumstances.²⁸ Studies have proven that lipopolysaccharide (LPS)-treated macrophages can improve the classical oxidative burst response by the activation of NADPH oxidase 2 (NOX2).²⁹ This activation might be inhibited by 2-deoxyglucose (2-DG), which blocks glycolysis. Additionally, inhibiting the PPP with 6-aminonicotinamide (6-AN) suppresses the elevated NOX2 exercise induced by LPS and considerably reduces the mRNA expression ranges of NOX2 and its organizer protein p47phox.³⁰ Furthermore, blocking the PPP pathway can lower the expression of sort I interferon (IFN-β) induced by LPS.³⁰

The absence of NOX1 and NOX2 might lead to a drastic discount in reactive oxygen species (ROS) manufacturing in macrophages. This deficiency impairs the differentiation of monocytes into macrophages and disrupts M2 macrophage polarization. NADPH oxidases (NOXs) play a essential function in inflammatory responses, and NOX1 and NOX2 are significantly essential for facilitating the polarization of monocytes into M2 macrophage.³¹

TCA Cycle

When macrophages are stimulated by inflammatory mediators equivalent to LPS and interferon-γ (IFN-γ), they polarize into M1 macrophages, a course of carefully associated to enhanced glycolysis, energetic TCA cycle, and lowered OXPHOS related to mitochondrial dysfunction.³² The TCA cycle can affect the polarization means of macrophages by mechanisms equivalent to metabolic reprogramming, signaling transduction, and regulation of inflammatory cytokine manufacturing. During LPS-stimulated M1 macrophage polarization, TCA cycle-associated metabolites, equivalent to citrate, isocitrate, succinate, fumarate, and malate, accumulate in macrophages, whereas the manufacturing of α-ketoglutarate (α-KG) is downregulated.^33,34 In LPS-activated macrophages, the citrate provider (CIC) exports citrate from mitochondria, additional enhancing glycolytic genes by histone acetylation.³⁵ The inhibition or knockdown of CIC reduces histone H3 lysine 9 acetylation (H3K9ac) on the promoter of glycolytic genes at hypoxia-inducible issue 1α (HIF-1α) binding websites, thereby inhibiting glycolysis.³⁵ Studies have demonstrated that the TCA cycle product succinate stabilizes HIF-1α, which contributes to the expression of pro-inflammatory cytokine IL-1β.³⁶

The Impact of Mtb on Glucose Metabolism Reprogramming in Macrophages

After coming into the lungs by the oronasal route, Mtb first breaches the alveolar barrier to contaminate host cells. Among these cells, macrophages are the first targets of this pathogen, and Mtb has developed subtle methods to outlive and replicate inside these cells, leveraging metabolic reprogramming to create a hospitable intracellular surroundings.³⁷ In response to Mtb an infection, host cells endure important metabolic reprogramming, ensuing within the differential expression of varied cytokines and chemokines related to the development and backbone of irritation.^38,39 During Mtb an infection, macrophages are activated by epigenetic modifications of genes, alterations in bioenergetic pathways, and variations in cytokine secretion, demonstrating plasticity and adaptableness. As described above, macrophage polarization is tightly linked to distinct metabolic packages, with M1 cells favoring glycolysis over mitochondrial respiration. This reliance results in fast ATP manufacturing by consuming giant quantities of glucose, thereby activating the inflammatory response. In distinction, M2 macrophages primarily make the most of OXPHOS and fatty acid oxidation (FAO) to generate ATP, thus selling anti-inflammatory responses and facilitating tissue restore.^40–42 Studies have proven that the intracellular microenvironment of macrophages might be metabolically suitable with the dietary wants of Mtb.⁴³ When M2 macrophages depend on fatty acid degradation for vitality, additionally they enhance the intracellular glucose provide, which offers vitamins that assist bacterial survival.^44,45 This intricate metabolic crosstalk underscores the pivotal function of metabolic reprogramming in shaping the host-pathogen interplay and illness development. As illustrated in Figure 1, Mtb an infection induces a metabolic shift in macrophages, characterised by the suppression of oxidative phosphorylation (OXPHOS) and redirection of glycolytic intermediates towards lipid synthesis. This metabolic reprogramming ends in lipid accumulation and the formation of foamy macrophages, which give vitamins equivalent to lactate and lipids that assist Mtb survival.

Figure 1 Glucose-metabolic reprogramming orchestrates macrophage fate during Mycobacterium tuberculosis infection. Note: Mtb infection suppresses glycolysis and the TCA cycle in M0 macrophages (naïve macrophages). Glycolysis skews M0 toward M1, whereas the TCA cycle promotes the differentiation of M2. Lactate fuels the bacilli, lipid metabolites promote the formation of foam cells, and PPP-derived NADPH mitigates oxidative stress.

As described above, virulent Mtb rewires macrophage glucose metabolism toward lipid accumulation and foam-cell formation, thereby supplying the bacilli with lipids and lactate. Additionally, Mtb can induce a metabolically inactive state in macrophages by decreasing glycolysis and inhibiting the activity of the TCA cycle.⁴⁶ Through upregulating miR-21, Mtb targets phosphofructokinase muscle isozyme (PFK-M) in glycolysis, which inhibits the manufacturing of pro-inflammatory cytokines, equivalent to IL-1β. This inhibition reduces glycolysis ranges and promotes bacterial progress.⁴⁷ Salmonella and Listeria likewise rewire macrophage metabolism — suppressing glycolysis and steering substrates to glucose-rich, ROS-poor niches that gas intracellular replication.⁴⁵ Mtb exploits the same technique however uniquely blocks the Warburg impact, hijacks host lipids for foam-cell formation and assimilates itaconate, underscoring pathogen-specific metabolic nodes amenable to host-directed remedy.

Emerging proof reveals a particular metabolic reprogramming orchestrated by viable Mtb, the place stay pathogens exhibit selective suppression of macrophage glycolysis-a phenomenon absent in macrophages uncovered to heat-inactivated Mtb or the attenuated Bacille Calmette-Guérin (BCG) vaccine pressure.^46–48 This pathogen-specific metabolic rewiring exemplifies Mtb’s evolutionary adaptation to control host mobile metabolism for intracellular persistence. Comparative analyses of contaminated phagocytes exhibit putting metabolic divergence: each monocyte-derived macrophages (MDMs) and THP-1 macrophage fashions contaminated with virulent Mtb exhibit marked attenuation of glycolytic proton efflux charges, whereas BCG-challenged counterparts show paradoxical enhancement of this metabolic parameter.⁴⁹ The noticed glycolytic suppression in Mtb-infected macrophages suggests a complicated immune subversion technique, probably enabling the pathogen to avoid antimicrobial host responses by metabolic pathway modulation.

Mounting proof delineates the metabolic manipulation methods employed by virulent Mtb strains to subvert macrophage antimicrobial capabilities. Mendonca LE et al established that the pathogenic Mtb H37Rv pressure selectively inhibits glycolytic flux in each alveolar macrophages (AMs) and bone marrow-derived macrophages (BMDMs), revealing evolutionary specialization of Mtb virulence components in constraining this essential metabolic pathway important for macrophage bactericidal exercise.⁵⁰ This metabolic rewiring just isn’t merely a passive adaptation however an energetic technique to evade host defenses. Pathogen viability emerges as a essential determinant of metabolic outcomes, as stay Mtb an infection uniquely impedes the bioenergetic transition towards glycolysis and oxidative phosphorylation (OXPHOS), successfully blunting inflammatory effector responses.⁵¹ Comparative analyses reveal a virulence-dependent metabolic reprogramming sample: THP-1 macrophages exhibit graded will increase in glucose uptake proportional to Mtb pressure pathogenicity, suggesting metabolic adaptation as a trademark of illness development.⁵² Moreover, elevated cardio glycolysis promotes the activation of apoptotic responses throughout Mtb an infection.⁵³ After an infection with H37Rv, M2 macrophages exhibit the best metabolic plasticity, changing into metabolically indistinguishable from M1 macrophages. Importantly, the rise in glycolysis in M2 macrophages after H37Rv an infection is related to elevated expression of immune response gene 1 (IRG1), a key enzyme in itaconate synthesis, which is expounded to the antimycobacterial capability of macrophages.^54,55 Studies have proven that in an infection with H37Ra (avirulent Mtb), 5 mM 2-deoxyglucose (2DG) inhibits glycolysis, leading to decreased IL-1β (an M1 phenotype marker) and elevated IL-10 (an M2 phenotype marker), thereby impairing bacterial killing means.³⁸ Although glycolysis can happen in alveolar macrophages contaminated with attenuated or inactivated types of Mtb in vitro, stay virulent Mtb eliminates the glycolytic exercise of those cells.^47,56

Mtb an infection induces metabolic reprogramming in macrophages, driving them towards the M1 phenotype and enhancing glycolysis to gas pro-inflammatory responses. However, Mtb can exploit bacterial components, such because the early secreted antigenic goal 6 protein (ESAT-6), to control glycolysis excessively, which results in elevated lipid accumulation in macrophages. This accumulation is favorable for the expansion of the micro organism.⁵² ESAT-6 induces the secretion of interleukin-10 (IL-10) in M1 macrophages, leading to decreased ranges of M1 cytokines equivalent to IL-12 and TNF-α.⁵⁷ This shift from the M1 to the M2 macrophage phenotype could also be pushed by IL-10 manufacturing.⁵⁸ In addition to IL-10, reworking progress factor-beta (TGF-β) can also be produced throughout mycobacterial an infection. TGF-β is related to TB development, as proven by a decreased bacterial load in human monocytes contaminated with the avirulent Mtb pressure H37Ra following TGF-β antagonism.⁵⁹ The pro-bacterial nature of TGF-β might be attributed to its function in suppressing the effector capabilities of cytotoxic T cells⁶⁰ and selling macrophage polarization in the direction of the M2 phenotype.⁶¹

In mice contaminated with Mtb, the glucose metabolism of macrophages undergoes important adjustments. In the lung tissue, researchers have noticed elevated glucose uptake and upregulated glycolysis, in addition to enhanced exercise of the PPP. Additionally, enzymes concerned within the TCA cycle and OXPHOS are downregulated. Further confocal imaging outcomes point out that these metabolic adjustments primarily happen in host immune cells, significantly macrophages.⁶² During the preliminary section of Mtb an infection, macrophages endure an inflammatory response, and this shift towards glycolysis might facilitate that course of. However, research have proven that Mtb can inhibit glycolysis throughout later phases of Mtb an infection, particularly by suppressing the manufacturing of IL-1β. This suppression helps the micro organism obtain long-term survival inside macrophages.⁴⁷

Mtb-Mediated Immune Evasion Strategies Against Host Glucometabolic Reprogramming

Despite the host’s metabolic reprogramming geared toward proscribing Mtb survival, the pathogen has developed subtle methods to subvert these defenses. Mtb actively subverts host innate immune responses by a number of, non-redundant metabolic and signaling interventions. In each murine BMDMs and MDMs, Mtb an infection considerably upregulates miR-21, which instantly targets PFK-M, thereby dampening glycolytic flux, limiting IL-1β manufacturing, and facilitating intracellular bacterial survival.⁶³ Additionally, the Mtb-secreted protein Rv2521 instantly binds to host NF-κB/p65, stopping its phosphorylation and nuclear translocation. This interference reduces NF-κB/p65 occupancy on the glutathione peroxidase 4 (GPX4) promoter, downregulates GPX4 expression, and induces ferroptosis in macrophages, finally selling bacterial persistence and dissemination.⁶⁴ Mtb additional evades inflammasome-mediated immunity by way of the serine/threonine protein kinase PknG, which is launched into the host cytosol and phosphorylates HOIL-1, a essential element of the linear ubiquitin chain meeting advanced (LUBAC). This modification disrupts LUBAC operate, impairs NF-κB signaling, and inhibits NLRP3 inflammasome meeting, thereby silencing key innate immune alarms.⁶⁵ Moreover, Mtb skews macrophage polarization towards an anti-inflammatory M2 phenotype by inducing IL-10 secretion in a STAT3-dependent method, driving the differentiation of CD14+CD16− monocytes into CD16+CD163+MerTK+pSTAT3+ M2 macrophages with impaired microbicidal exercise.⁶⁶ Also, Mtb sabotages host plasma membrane restore mechanisms by inhibiting prostaglandin E2 (PGE2) biosynthesis, thereby selling macrophage necrosis and facilitating bacterial egress and reinfection. Collectively, these methods spotlight Mtb’s subtle means to reprogram host metabolism, suppress immune signaling, and modulate cell destiny to make sure its long-term survival and transmission.⁶⁷

Glycometabolic Products and Host Immune Responses Against Mtb

Metabolites produced throughout the glucose metabolism reprogramming of macrophages play an important function within the immune response to Mtb. Itaconate is derived from cis-aconitate, which is an intermediate within the tricarboxylic acid cycle, and the enzyme encoded by the IRG1 catalyzes its manufacturing. The formation of itaconate is especially important below Mtb an infection, because it has anti-inflammatory properties. This impact is achieved by inhibiting the exercise of succinate dehydrogenase (SDH).^7,68 Additionally, itaconate competes with α-ketoglutarate (α-KG) to inhibit the exercise of the DNA dioxygenase TET, which finally regulates the expression of inflammatory genes. TET2 is thought to be a key useful goal for the anti-inflammatory results of itaconate.⁶⁹ In abstract, itaconate can modulate the operate of macrophages and affect the host immune response in opposition to Mtb.

Although itaconate is universally acknowledged as an immunoregulatory metabolite, its dose–goal–operate hierarchy is intrinsically multifaceted. Michelucci et al first demonstrated that millimolar itaconate exerts antibacterial exercise by inhibiting the microbial enzyme isocitrate lyase.⁵⁴ Subsequent research have revealed that throughout a low-micromolar-to-millimolar gradient itaconate additionally competes with succinate to suppress host mitochondrial succinate dehydrogenase⁷ and with α-ketoglutarate to antagonize nuclear TET2 dioxygenase,⁶⁹ leading to succinate accumulation and DNA hypermethylation, respectively. These mechanisms converge to down-regulate inflammatory gene transcription. Rather than being mutually unique, the prevailing impact is dictated by native focus, period of stimulation, and mobile context, underscoring the necessity for precision layer-specific concentrating on in future host-directed therapies.

Mesaconate, one other metabolite structurally just like itaconate, additionally reveals important immunomodulatory results in macrophages. It regulates inflammatory responses by lowering the secretion of pro-inflammatory cytokines equivalent to IL-6 and IL-12 in macrophages stimulated with LPS. At the identical time, mesaconate will increase the manufacturing of CXCL10. While mesaconate has a similar inhibitory impact on glycolysis in comparison with itaconate, it has a lesser affect on the exercise of the TCA cycle and mobile respiration, and it doesn’t inhibit the exercise of SDH. Additionally, mesaconate doesn’t affect the secretion of IL-1β or the activation of inflammasomes, indicating that its immunomodulatory results are unbiased of the NRF2 and ATF3 signaling pathways. These traits give mesaconate potential therapeutic benefits in anti-inflammatory remedies, significantly due to its minimal affect on mobile metabolism, which might present a extra exact method to immune intervention.⁷⁰

Lactate performs a essential function in Mtb an infection by collaborating in vitality manufacturing as a metabolite and performing as a signaling molecule that influences immune responses. During Mtb an infection, low oxygen ranges, often called hypoxic circumstances, inhibit the exercise of prolyl hydroxylase (PHD). This inhibition results in the buildup of HIF-1α within the cytoplasm, which then translocates to the nucleus. In the nucleus, HIF-1α dimerizes with the HIF-1β subunit and binds to hypoxia response parts (HRE) within the genome, thus initiating the transcription of varied genes, together with lactate dehydrogenase A (LDHA). These genes are carefully associated to the host’s adaptation to hypoxia. LDHA catalyzes the conversion of pyruvate to lactate. Lactate can affect the metabolism and performance of immune cells by regulating the expression of LDHA and the lactate transporter monocarboxylate transporter-4 (MCT-4),⁷¹ thus affecting the development of TB. The accumulation of lactate in TB granulomas can affect the polarization, antigen presentation, and inflammatory responses of immune cells, considerably influencing the event of TB. Therefore, lactate and its metabolic pathways might signify potential therapeutic targets for TB. As a significant vitality supply, lactate promotes the acetylation of histone H3K27, permitting the expression of immune-suppressive gene packages, together with nuclear receptor subfamily 4 group A member 1 (Nr4a1). This course of transcriptionally represses the pro-inflammatory capabilities of macrophages.⁷² Figure 2 summarizes the three main glucose metabolic pathways—glycolysis, the pentose phosphate pathway (PPP), and the TCA cycle—and highlights how their metabolites (eg, itaconate, mesaconate, and lactate) modulate immune responses throughout Mtb an infection.

Figure 2 Three glucose metabolic pathways and the effect of their products on immune responses in Mtb-infected macrophages.

In all, the interaction and regulation among metabolites in the glycometabolism pathway play a crucial role in the immune response to Mtb infection, thus influencing TB initiation and progress.

Glycometabolic Architecture of the TB Granuloma

Upon inhalation, Mtb first encounters tissue-resident alveolar macrophages (AMs) that rely on fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS); this energetically efficient programme limits ROS output and inadvertently provides a lipid-rich replicative niche.^73,74 In distinction, recruited interstitial monocyte-derived macrophages (IMMs) quickly change to cardio glycolysis (the Warburg impact), assume an M1 phenotype and produce TNF-α/IL-1β required for early bacterial containment.^62,75

As the lesion matures, the granuloma self-partitions into two metabolic zones. In the hypoxic core (pO₂ < 5 mmHg), stay virulent Mtb imposes a “glycolytic brake” by up-regulating host miR-21, down-regulating HK2, PFK-M and PKM2, and diverting glucose-6-phosphate into the pentose-phosphate pathway (PPP); the ensuing fall in glycolytic flux and IL-1β output lowers ROS stress and favors bacillary persistence.^60,62,76 Bulk-lung analyses that report Warburg-upregulation⁶⁰ replicate the inflammatory rim fairly than the metabolically quiescent core, reconciling the obvious contradiction between Shi et al⁶² and Cumming et al.⁴⁶ At the normoxic rim, FAO-driven OXPHOS sustains M2-like cells that secrete IL-10/TGF-β; whereas this limits tissue injury, it concurrently provides ldl cholesterol and triacylglycerol that Mtb sequesters to enter a drug-tolerant, dormant state.^76,77

Thus, metabolic zonation allows Mtb to steadiness immune evasion with nutrient acquisition. Pharmacological reactivation of core glycolysis (eg, PKM2 activators) mixed with FAO inhibition on the rim (etomoxir) converts M2 cells into bactericidal M1 macrophages and accelerates bacterial clearance in murine fashions,^74,78 validating the granuloma glycometabolic map as a rational framework for host-directed remedy.

Therapeutic Strategies Targeting the Glucose Metabolism Reprogramming in Macrophages

The reprogramming of glucose metabolism in macrophages, significantly together with the PPP and mitochondrial succinate oxidation, is significant for inflammatory responses.³⁰ These adjustments affect each vitality manufacturing and the synthesis of inflammatory mediators. Understanding how glucose metabolism in macrophages is regulated is crucial for growing new therapeutic methods. For instance, shifting the metabolism of macrophages from OXPHOS to glycolysis might improve the flexibility to withstand infections brought on by Mtb.⁷⁹ When activated by bacterial pathogen-associated molecular patterns (PAMPs) equivalent to LPS, macrophages enhance glycolysis and alter mitochondrial metabolism. This ends in adjustments within the TCA cycle and the buildup of intermediates like succinate and citrate.⁸⁰ LPS additionally raises ranges of pyruvate kinase M2 (PKM2), which exists in each dimeric (inactive) and tetrameric (energetic) varieties. PKM2 dimers promote succinate accumulation and drive the transcription of interleukin (IL)-1β,⁸¹ whereas PKM2 tetramers improve glycolytic exercise. Targeting PKM2’s enzymatic exercise might supply a possible therapeutic method.

Nitric oxide (NO), produced by iNOS, performs an important function within the glycolytic means of macrophages. Studies have proven that the manufacturing of NO is linked to elevated glycolysis in these immune cells.^47,79,82 This affiliation might stem not solely from enhanced interleukin-1 beta (IL-1β) signaling but additionally from the manufacturing of NADP by the glycolysis-related PPP.²⁷ NO might kind a optimistic suggestions loop with HIF-1α. This interplay not solely boosts the activation of macrophages however can also be important for stabilizing HIF-1α. The co-regulation of glycolysis by NO and HIF-1α is essential for macrophages of their operate in opposition to Mtb an infection. In macrophages contaminated with Mtb and stimulated by IFN-γ, the absence of NO and HIF-1α ends in lowered expression of genes linked to cardio glycolysis. This discount impacts glucose uptake and inhibits the cardio glycolytic course of. NO not solely instantly contributes to the antimicrobial response, but additionally moderates extreme inflammatory responses by rigorously regulating HIF-1α and the glycolysis pathway, thereby defending host tissues from injury.⁸² The elevated glycolytic flux in macrophages contaminated with Mtb fosters a pro-inflammatory and antimicrobial surroundings by modulating irritation. Additionally, this course of deprives the replicating Mtb of important vitamins required for its intracellular progress. Thus, NO might emerge as a major goal within the growth of anti-TB immunotherapy.

A examine in mice has proven that alveolar macrophages primarily make the most of the FAO pathway, which creates a good surroundings for Mtb. In distinction, interstitial macrophages exhibit glycolytic exercise that may hinder bacterial progress.⁸³ Additionally, analysis on BMDMs from mice contaminated with Mtb and handled with 2-DG (a glycolysis inhibitor) or etomoxir (ETO, a FAO inhibitor) has demonstrated that inhibiting glycolysis promotes bacterial progress, whereas inhibiting FAO can cut back the variety of micro organism.⁸³ Therefore, limiting the exercise of alveolar macrophages and rising the variety of interstitial macrophages could also be an efficient technique for combating TB.

Iron chelators have been discovered to affect cell metabolism by regulating HIF-1α. The iron chelator deferoxamine (DFX) can induce IL-1β in human macrophages throughout the early phases of Mtb an infection and when stimulated with LPS. Additionally, DFX promotes the expression of key glycolytic enzymes in major human monocyte-derived macrophages and human alveolar macrophages contaminated with Mtb, thereby enhancing innate immune capabilities.⁸⁴

Integration with scientific pipelines underscores the translational momentum of those brokers. Kim et al listed metformin and the iron chelator deferoxamine (DFX) as precedence, clinically protected host-directed candidates.⁵¹ In a phase-II trial of 120 South-African adults, adjunct metformin shortened median time-to-stable sputum tradition conversion by 18 days and lowered lung cavity quantity on CT versus placebo.⁸⁵ Ex-vivo, DFX up-regulates GAPDH and PKM2 transcripts in Mtb-infected human alveolar macrophages, confirming enhanced glycolysis;⁸⁴ nevertheless, DFX has not but progressed past early-phase pharmacokinetic research. By explicitly aligning bench findings with these evolving scientific read-outs, we offer an up-to-date benchmark for host-directed metabolic therapies.

The chromatin reworking in innate immune cells stimulated by BCG primarily includes histone modifications, particularly Histone H3 lysine 4 trimethylation (H3K4me3) and Histone H3 lysine 9 trimethylation (H3K9me3), in glycolytic genes. These modifications result in the activation of the AKT/mTOR/HIF1α pathway, leading to a metabolic shift in host cells from OXPHOS to cardio glucose metabolism.^86–88 This analysis highlights how adjustments in cell metabolism improve the manufacturing of cytokines, equivalent to TNF-α and IL-6, that are efficient in concentrating on Mtb.^89,90

Macrophages uncovered to excessive glucose ranges accumulate elevated quantities of oxidized low-density lipoproteins and present lowered functionality to regulate the replication of Mtb attributable to lysosomal dysfunction.⁹¹ Lowering blood glucose ranges can enhance the host’s means to retard the replication of Mtb.⁸⁵ Research signifies that metformin, an AMPK activator, can improve the antimycobacterial capabilities of macrophages. Metformin inhibits the expansion of Mtb inside host cells in an AMPK-dependent method. AMPK promotes the expression of peroxisome proliferator-activated receptor γ coactivator 1-α (PGC1-α), which is an important enzyme for mitochondrial biogenesis, in addition to carnitine palmitoyltransferase 1(CPT1), a key enzyme concerned in fatty acid metabolism. Low AMPK expression can negatively affect oxidative phosphorylation metabolism and vitality synthesis in cells.⁹² AMPK is an energy-sensing kinase, and its activation can considerably affect each mobile metabolism and immune responses. Studies have additionally proven that metformin can shield cells from inflammation-induced dysfunction within the TCA cycle.⁹³

Conclusion

Metabolic reprogramming is central to the host–Mtb stand-off as a result of it concurrently equips macrophages with bactericidal capability and provides vitamins or immune-evasion cues to the pathogen. Rapid glycolysis, coupled with the pentose-phosphate pathway, offers ATP, NADPH and anabolic precursors that drive the M1 programme (IL-1β, ROS, NO), whereas oxidative phosphorylation and fatty-acid oxidation typify the M2 state that Mtb preferentially exploits. The TCA-cycle-derived metabolite itaconate acts as a rheostat: it inhibits succinate dehydrogenase and limits inflammasome over-activation, but virulent bacilli can assimilate itaconate and host lipids for carbon and vitality. Targeting these nodes presents clinically accessible adjuncts to chemotherapy: (i) metformin or 2-deoxy-glucose can implement glycolysis; (ii) etomoxir blocks CPT-1-mediated fatty-acid oxidation, curbing M2 polarization; (iii) the iron chelator deferoxamine stabilises HIF-1α and boosts glycolytic enzymes; and (iv) cell-permeable itaconate derivatives are already used experimentally to restrict tissue injury. Several host-directed metabolic interventions at the moment are being examined in early-phase trials: metformin⁹⁴ and statins⁹⁵ goal to boost M1 glycolysis and cut back bacterial burden, whereas deferoxamine is being explored for enhancing the intracellular mycobactericidal exercise of sure second-line medication.⁹⁶ However, most research stay small, open-label or pre-clinical; optimum dosing, pharmacokinetic interactions with anti-TB medication, and sturdy endpoints (relapse, lung operate) are nonetheless undefined. Moreover, affected person heterogeneity in diabetes, HIV co-infection and baseline immunity might confound metabolic modulation efficacy. Future large-scale, randomized managed trials ought to due to this fact validate such methods—alone or mixed with current regimens—to shorten therapy, forestall relapse and cut back lung pathology.

Abbreviations

AIM2, absent in melanoma 2; AM, alveolar macrophages; 6-AN, 6-aminonicotinamide; BCG, Bacille Calmette-Guérin; BMDM, bone marrow-derived macrophages; CIC, citrate provider; CPT1, carnitine palmitoyltransferase 1; DFX, deferoxamine; 2-DG, 2-deoxyglucose; eIF2AK2, eukaryotic translation initiation issue 2α kinase; ESAT-6, early secreted antigenic goal 6 protein; ETO, etomoxir; FAO, fatty acid oxidation; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; G6P, glucose-6-phosphate; H3K27, Histone H3 lysine 27; H3K4me3, Histone H3 lysine 4 trimethylation; H3K9ac, Histone H3 lysine 9 acetylation; H3K9me3, Histone H3 lysine 9 trimethylation; HK1, Hexokinase 1; HIF-1α, hypoxia-inducible issue 1α; HRE, hypoxia response parts; IFN, interferon; iNOS, inducible nitric oxide synthase; IL, interleukin; IMM, interstitial monocyte-derived macrophages; α-KG, α-ketoglutarate; LDHA, lactate dehydrogenase A; LPS, lipopolysaccharide; MCT-4, monocarboxylate transporter-4; Mtb, Mycobacterium tuberculosis; NADPH, nicotinamide adenine dinucleotide phosphate; NLRP3, NOD-like receptor household pyrin area containing 3; NO, Nitric oxide; NOXs, NADPH oxidases; NOX2, NADPH oxidase 2; Nr4A1, Nuclear receptor subfamily 4 group A member; OXPHOS, oxidative phosphorylation; PAMPs, pathogen-associated molecular patterns; PFK1, phosphofructokinase-1; Pfkfb3, 6-phosphofructo-2-kinase; PGC1-α, peroxisome proliferator-activated receptor γ coactivator 1-α; PHD, prolyl hydroxylase; PKM2, pyruvate kinase M2; PPP, pentose phosphate pathway; ROS, discount in reactive oxygen species; TB, Tuberculosis; TCA, tricarboxylic acid; TGF-β, reworking progress issue; THP-1, Tsuchiya Human Promyelocytic leukemia cell line-1; TNF, tumor necrosis issue; Zhx2, Zinc fingers and homeoboxes 2.

Consent for Publication

All authors have learn and accepted the ultimate model of the manuscript, attest to the accuracy of its content material, and consent to its submission to this journal.

Author Contributions

All authors made a major contribution to the work reported, whether or not that’s within the conception, examine design, execution, acquisition of information, evaluation and interpretation, or in all these areas; took half in drafting, revising or critically reviewing the article; gave last approval of the model to be revealed; have agreed on the journal to which the article has been submitted; and comply with be accountable for all elements of the work.

Funding

This work was supported by the National Key Research and Development Program of China (Grant No. 2022YFC2302900), Beijing Nova Program (20220484169, 20230484295), Beijing Municipal Science and Technology Commission (Z221100007422064, Z221100007422056), Natural Science Foundation of Beijing Municipality (1S24095), Science and Technology Program of Guangzhou (2023A03J0991), Science and Technology Plan Project of Tongzhou District, Beijing (KJ2024CX028), and Capital Medical University (CCMU2024ZKYXZ004). The funders had no function within the examine design, knowledge assortment and evaluation, resolution to publish, or preparation of the manuscript.

Disclosure

Tianhui Liu and Zeliang Yang are co-first authors for this examine. The authors declare that they haven’t any competing pursuits on this work.

References

1. World Health O. Global tuberculosis report 2024. Geneva: World Health Organization, 2024.

2. Scriba TJ, Coussens AK, Fletcher HA. Human immunology of tuberculosis. Microbiol Spectr. 2017;5(1). doi:10.1128/microbiolspec.TBTB2-0016-2016

3. Kumar P, Bhaskar S. Myeloid differentiation major response protein 88 (MyD88)-deficient dendritic cells exhibit a skewed cytokine response to BCG. BMC Res Notes. 2019;12(1):52. doi:10.1186/s13104-019-4086-6

4. Sweet MJ, Ramnath D, Singhal A, Kapetanovic R. Inducible antibacterial responses in macrophages. Nat Rev Immunol. 2025;25(2):92–107. doi:10.1038/s41577-024-01080-y

5. Li M, Yang Y, Xiong L, et al. Metabolism, metabolites, and macrophages in most cancers. J Hematol Oncol. 2023;16(1):80. doi:10.1186/s13045-023-01478-6

6. O’Neill LA, Pearce EJ. Immunometabolism governs dendritic cell and macrophage operate. J Exp Med. 2016;213(1):15–23. doi:10.1084/jem.20151570

7. Lampropoulou V, Sergushichev A, Bambouskova M, et al. Itaconate hyperlinks inhibition of succinate dehydrogenase with macrophage metabolic reworking and regulation of irritation. Cell Metab. 2016;24(1):158–166. doi:10.1016/j.cmet.2016.06.004

8. Cumming BM, Pacl HT, Steyn AJC. Relevance of the Warburg impact in tuberculosis for host-directed remedy. Front Cell Infect Microbiol. 2020;10(576596). doi:10.3389/fcimb.2020.576596

9. Shi L, Jiang Q, Bushkin Y, Subbian S, Tyagi S. Biphasic dynamics of macrophage immunometabolism throughout Mycobacterium tuberculosis an infection. mBio. 2019;10(2). doi:10.1128/mbio.02550-18

10. Mosser DM, Edwards JP. Exploring the complete spectrum of macrophage activation. Nat Rev Immunol. 2008;8(12):958–969. doi:10.1038/nri2448

11. Takahashi Ok, Naito M, Takeya M. Development and heterogeneity of macrophages and their associated cells by their differentiation pathways. Pathol Int. 1996;46(7):473–485. doi:10.1111/j.1440-1827.1996.tb03641.x

12. Ahmad F, Rani A, Alam A, et al. Macrophage: a cell with many faces and capabilities in tuberculosis. Front Immunol. 2022;13(747799). doi:10.3389/fimmu.2022.747799

13. Tauber AI. Metchnikoff and the phagocytosis concept. Nat Rev Mol Cell Biol. 2003;4(11):897–901. doi:10.1038/nrm1244

14. Watanabe S, Alexander M, Misharin AV, Budinger GRS. The function of macrophages within the decision of irritation. J Clin Invest. 2019;129(7):2619–2628. doi:10.1172/jci124615

15. Martinez FO, Gordon S. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep. 2014;6:13. doi:10.12703/p6-13

16. Anderson CF, Mosser DM. A novel phenotype for an activated macrophage: the kind 2 activated macrophage. J Leukoc Biol. 2002;72(1):101–106.

17. Russell DG, Huang L, VanderVen BC. Immunometabolism on the interface between macrophages and pathogens. Nat Rev Immunol. 2019;19(5):291–304. doi:10.1038/s41577-019-0124-9

18. Xue J, Schmidt SV, Sander J, et al. Transcriptome-based community evaluation reveals a spectrum mannequin of human macrophage activation. Immunity. 2014;40(2):274–288. doi:10.1016/j.immuni.2014.01.006

19. De Jesus A, Keyhani-Nejad F, Pusec CM, et al. Hexokinase 1 mobile localization regulates the metabolic destiny of glucose. Mol Cell. 2022;82(7):1261–77.e9. doi:10.1016/j.molcel.2022.02.028

20. Wang Z, Kong L, Tan S, et al. Zhx2 accelerates sepsis by selling macrophage glycolysis by way of Pfkfb3. J Immunol. 2020;204(8):2232–2241. doi:10.4049/jimmunol.1901246

21. McGowan ENS, Wong O, Jones E, et al. Tetraspanin CD82 restrains phagocyte migration however helps macrophage activation. Iscience. 2022;25(7):104520. doi:10.1016/j.isci.2022.104520

22. Chen R, Wang J, Dai X, et al. Augmented PFKFB3-mediated glycolysis by interferon-γ promotes inflammatory M1 polarization by the JAK2/STAT1 pathway in native vascular irritation in Takayasu arteritis. Arthritis Res Ther. 2022;24(1):266. doi:10.1186/s13075-022-02960-1

23. Appiah MG, Park EJ, Akama Y, et al. Cellular and exosomal rules of sepsis-induced metabolic alterations. Int J Mol Sci. 2021;22(15). doi:10.3390/ijms22158295

24. Chen R, Kang R, Tang D. The mechanism of HMGB1 secretion and launch. Exp Mol Med. 2022;54(2):91–102. doi:10.1038/s12276-022-00736-w

25. Xie M, Yu Y, Kang R, et al. PKM2-dependent glycolysis promotes NLRP3 and AIM2 inflammasome activation. Nat Commun. 2016;7(13280). doi:10.1038/ncomms13280

26. Mills EL, Kelly B, Logan A, et al. Succinate dehydrogenase helps metabolic repurposing of mitochondria to drive inflammatory macrophages. Cell. 2016;167(2):457–70.e13. doi:10.1016/j.cell.2016.08.064

27. Haschemi A, Kosma P, Gille L, et al. The sedoheptulose kinase CARKL directs macrophage polarization by management of glucose metabolism. Cell Metab. 2012;15(6):813–826. doi:10.1016/j.cmet.2012.04.023

28. Uemura M, Maeshige N, Yamaguchi A, et al. Electrical stimulation facilitates NADPH manufacturing in pentose phosphate pathway and exerts an anti-inflammatory impact in macrophages. Sci Rep. 2023;13(1):17819. doi:10.1038/s41598-023-44886-x

29. Balabanova L, Bondarev G, Seitkalieva A, Son O, Tekutyeva L. Insights into alkaline phosphatase anti-inflammatory mechanisms. Biomedicines. 2024;12(11). doi:10.3390/biomedicines12112502

30. Erlich JR, To EE, Luong R, et al. Glycolysis and the pentose phosphate pathway promote LPS-induced NOX2 oxidase- and IFN-β-dependent irritation in macrophages. Antioxidants. 2022;11(8). doi:10.3390/antiox11081488

31. Xu Q, Choksi S, Qu J, et al. NADPH oxidases are important for macrophage differentiation. J Biol Chem. 2016;291(38):20030–20041. doi:10.1074/jbc.M116.731216

32. Van den Bossche J, O’Neill LA, Menon D. Macrophage immunometabolism: the place are we (going)? Trends Immunol. 2017;38(6):395–406. doi:10.1016/j.it.2017.03.001

33. Noe JT, Mitchell RA. Tricarboxylic acid cycle metabolites within the management of macrophage activation and effector phenotypes. J Leukoc Biol. 2019;106(2):359–367. doi:10.1002/jlb.3ru1218-496r

34. Ryan DG, O’Neill LAJ. Krebs cycle rewired for macrophage and dendritic cell effector capabilities. FEBS Lett. 2017;591(19):2992–3006. doi:10.1002/1873-3468.12744

35. Li Y, Li YC, Liu XT, et al. Blockage of citrate export prevents TCA cycle fragmentation by way of Irg1 inactivation. Cell Rep. 2022;38(7):110391. doi:10.1016/j.celrep.2022.110391

36. Wang F, Wang Ok, Xu W, et al. SIRT5 desuccinylates and prompts pyruvate kinase M2 to dam macrophage IL-1β manufacturing and to stop DSS-induced colitis in mice. Cell Rep. 2017;19(11):2331–2344. doi:10.1016/j.celrep.2017.05.065

37. Philips JA, Ernst JD. Tuberculosis pathogenesis and immunity. Annu Rev Pathol. 2012;7:353–384. doi:10.1146/annurev-pathol-011811-132458

38. Gleeson LE, Sheedy FJ, Palsson-McDermott EM, et al. Cutting edge: Mycobacterium tuberculosis induces cardio glycolysis in human alveolar macrophages that’s required for management of intracellular bacillary replication. J Immunol. 2016;196(6):2444–2449. doi:10.4049/jimmunol.1501612

39. Qualls JE, Murray PJ. Immunometabolism throughout the tuberculosis granuloma: amino acids, hypoxia, and mobile respiration. Semin Immunopathol. 2016;38(2):139–152. doi:10.1007/s00281-015-0534-0

40. Mosser DM. The many faces of macrophage activation. J Leukoc Biol. 2003;73(2):209–212. doi:10.1189/jlb.0602325

41. Martinez FO, Gordon S, Locati M, Mantovani A. Transcriptional profiling of the human monocyte-to-macrophage differentiation and polarization: new molecules and patterns of gene expression. J Immunol. 2006;177(10):7303–7311. doi:10.4049/jimmunol.177.10.7303

42. Rodríguez-Prados JC, Través PG, Cuenca J, et al. Substrate destiny in activated macrophages: a comparability between innate, basic, and various activation. J Immunol. 2010;185(1):605–614. doi:10.4049/jimmunol.0901698

43. Singh V, Jamwal S, Jain R, et al. Mycobacterium tuberculosis-driven focused recalibration of macrophage lipid homeostasis promotes the foamy phenotype. Cell Host Microbe. 2012;12(5):669–681. doi:10.1016/j.chom.2012.09.012

44. Roop RM, Caswell CC. Bacterial persistence: discovering the “sweet spot”. Cell Host Microbe. 2013;14(2):119–120. doi:10.1016/j.chom.2013.07.016

45. Gogoi M, Shreenivas MM, Chakravortty D. Hoodwinking the big-eater to prosper: the Salmonella-macrophage paradigm. J Innate Immun. 2019;11(3):289–299. doi:10.1159/000490953

46. Cumming BM, Addicott KW, Adamson JH, Steyn AJ. Mycobacterium tuberculosis induces decelerated bioenergetic metabolism in human macrophages. Elife. 2018;7. doi:10.7554/eLife.39169

47. Hackett EE, Charles-Messance H, O’Leary SM, et al. Mycobacterium tuberculosis limits host glycolysis and IL-1β by restriction of PFK-M by way of microRNA-21. Cell Rep. 2020;30(1):124–36.e4. doi:10.1016/j.celrep.2019.12.015

48. Olson GS, Murray TA, Jahn AN, et al. Type I interferon decreases macrophage vitality metabolism throughout mycobacterial an infection. Cell Rep. 2021;35(9):109195. doi:10.1016/j.celrep.2021.109195

49. Bordbar A, Lewis NE, Schellenberger J, Palsson B, Jamshidi N. Insight into human alveolar macrophage and M. tuberculosis interactions by way of metabolic reconstructions. Mol Syst Biol. 2010;6(422). doi:10.1038/msb.2010.68

50. Mendonca LE, Pernet E, Khan N, et al. Human alveolar macrophage metabolism is compromised throughout Mycobacterium tuberculosis an infection. Front Immunol. 2022;13(1044592). doi:10.3389/fimmu.2022.1044592

51. Kim JS, Kim YR, Yang CS. Host-directed remedy in tuberculosis: concentrating on host metabolism. Front Immunol. 2020;11(1790). doi:10.3389/fimmu.2020.01790

52. Singh V, Kaur C, Chaudhary VK, Rao KV, Chatterjee SM. tuberculosis secretory protein ESAT-6 induces metabolic flux perturbations to drive foamy macrophage differentiation. Sci Rep. 2015;5(12906). doi:10.1038/srep12906

53. Matta SK, Kumar D. Hypoxia and classical activation limits Mycobacterium tuberculosis survival by Akt-dependent glycolytic shift in macrophages. Cell Death Discov. 2016;2(16022). doi:10.1038/cddiscovery.2016.22

54. Michelucci A, Cordes T, Ghelfi J, et al. Immune-responsive gene 1 protein hyperlinks metabolism to immunity by catalyzing itaconic acid manufacturing. Proc Natl Acad Sci U S A. 2013;110(19):7820–7825. doi:10.1073/pnas.1218599110

55. Nair S, Huynh JP, Lampropoulou V, et al. Irg1 expression in myeloid cells prevents immunopathology throughout M. tuberculosis an infection. J Exp Med. 2018;215(4):1035–1045. doi:10.1084/jem.20180118

56. Huang L, Nazarova EV, Tan S, Liu Y, Russell DG. Growth of Mycobacterium tuberculosis in vivo segregates with host macrophage metabolism and ontogeny. J Exp Med. 2018;215(4):1135–1152. doi:10.1084/jem.20172020

57. Refai A, Gritli S, Barbouche MR, Essafi M. Mycobacterium tuberculosis virulent issue ESAT-6 drives macrophage differentiation towards the pro-inflammatory M1 phenotype and subsequently switches it to the anti-inflammatory M2 phenotype. Front Cell Infect Microbiol. 2018;8(327). doi:10.3389/fcimb.2018.00327

58. Montoya D, Mehta M, Ferguson BG, et al. Plasticity of antimicrobial and phagocytic packages in human macrophages. Immunology. 2019;156(2):164–173. doi:10.1111/imm.13013

59. Hirsch CS, Yoneda T, Averill L, Ellner JJ, Toossi Z. Enhancement of intracellular progress of Mycobacterium tuberculosis in human monocytes by reworking progress factor-beta 1. J Infect Dis. 1994;170(5):1229–1237. doi:10.1093/infdis/170.5.1229

60. Warsinske HC, Pienaar E, Linderman JJ, Mattila JT, Kirschner DE. Deletion of TGF-β1 will increase bacterial clearance by cytotoxic T cells in a tuberculosis granuloma mannequin. Front Immunol. 2017;8(1843). doi:10.3389/fimmu.2017.01843

61. Zhang F, Wang H, Wang X, et al. TGF-β induces M2-like macrophage polarization by way of SNAIL-mediated suppression of a pro-inflammatory phenotype. Oncotarget. 2016;7(32):52294–52306. doi:10.18632/oncotarget.10561

62. Shi L, Salamon H, Eugenin EA, et al. Infection with Mycobacterium tuberculosis induces the Warburg impact in mouse lungs. Sci Rep. 2015;5(18176). doi:10.1038/srep18176

63. Ogger PP, Byrne AJ. Macrophage metabolic reprogramming throughout power lung illness. Mucosal Immunol. 2021;14(2):282–295. doi:10.1038/s41385-020-00356-5

64. Liu W, Zhu C, Zhang L, et al. Mycobacterium tuberculosis Rv2521 promotes ferroptosis-dependent pathogenicity by inhibiting NF-κB activation. Int J Biol Macromol. 2025;321(Pt 4):146294. doi:10.1016/j.ijbiomac.2025.146294

65. Yu Y, Yu S, Lu Z, et al. Pathogenic phosphorylation of linear ubiquitin equipment causes inflammasome sensor degradation. Cell Rep. 2025;44(9):116286. doi:10.1016/j.celrep.2025.116286

66. Sampath P, Moideen Ok, Ranganathan UD, Bethunaickan R. Monocyte subsets: phenotypes and performance in tuberculosis an infection. Front Immunol. 2018;9(1726). doi:10.3389/fimmu.2018.01726

67. Lu Z, Zhang Y, Zhong Y, et al. A bacterial effector manipulates host lysosomal protease activity-dependent plasticity in cell loss of life modalities to facilitate an infection. Proc Natl Acad Sci U S A. 2025;122(8):e2406715122. doi:10.1073/pnas.2406715122

68. Németh B, Doczi J, Csete D, et al. Abolition of mitochondrial substrate-level phosphorylation by itaconic acid produced by LPS-induced Irg1 expression in cells of murine macrophage lineage. FASEB J. 2016;30(1):286–300. doi:10.1096/fj.15-279398

69. Chen -L-L, Morcelle C, Cheng Z-L, et al. Itaconate inhibits TET DNA dioxygenases to dampen inflammatory responses. Nat Cell Biol. 2022;24(3):353–363. doi:10.1038/s41556-022-00853-8

70. He W, Henne A, Lauterbach M, et al. Mesaconate is synthesized from itaconate and exerts immunomodulatory results in macrophages. Nat Metab. 2022;4(5):524–533. doi:10.1038/s42255-022-00565-1

71. Chen L, Lin Y, Zhu X, et al. MCT1-mediated lactate shuttle to mitochondria governs macrophage polarization and modulates glucose homeostasis by affecting β cells. Adv Sci. 2025:e14760. doi:10.1002/advs.202414760

72. Shi W, Cassmann TJ, Bhagwate AV, Hitosugi T, Ip WKE. Lactic acid induces transcriptional repression of macrophage inflammatory response by way of histone acetylation. Cell Rep. 2024;43(2):113746. doi:10.1016/j.celrep.2024.113746

73. Khan A, Singh VK, Hunter RL, Jagannath C. Macrophage heterogeneity and plasticity in tuberculosis. J Leukoc Biol. 2019;106(2):275–282. doi:10.1002/jlb.Mr0318-095rr

74. Sheedy FJ, Divangahi M. Targeting immunometabolism in host defence in opposition to Mycobacterium tuberculosis. Immunology. 2021;162(2):145–159. doi:10.1111/imm.13276

75. Lösslein AK, Lohrmann F, Scheuermann L, et al. Monocyte progenitors give rise to multinucleated large cells. Nat Commun. 2021;12(1):2027. doi:10.1038/s41467-021-22103-5

76. Shi L, Eugenin EA, Subbian S. Immunometabolism in tuberculosis. Front Immunol. 2016;7(150). doi:10.3389/fimmu.2016.00150

77. Wayne LG. Dormancy of Mycobacterium tuberculosis and latency of illness. Eur J Clin Microbiol Infect Dis. 1994;13(11):908–914. doi:10.1007/bf02111491

78. Davis JM, Ramakrishnan L. The function of the granuloma in enlargement and dissemination of early tuberculous an infection. Cell. 2009;136(1):37–49. doi:10.1016/j.cell.2008.11.014

79. Braverman J, Sogi KM, Benjamin D, Nomura DK, Stanley SA. HIF-1α is a necessary mediator of IFN-γ-dependent immunity to Mycobacterium tuberculosis. J Immunol. 2016;197(4):1287–1297. doi:10.4049/jimmunol.1600266

80. Tannahill GM, Curtis AM, Adamik J, et al. Succinate is an inflammatory sign that induces IL-1β by HIF-1α. Nature. 2013;496(7444):238–242. doi:10.1038/nature11986

81. Palsson-McDermott EM, Curtis AM, Goel G, et al. Pyruvate kinase M2 regulates Hif-1α exercise and IL-1β induction and is a essential determinant of the Warburg impact in LPS-activated macrophages. Cell Metab. 2015;21(2):347. doi:10.1016/j.cmet.2015.01.017

82. Braverman J, Stanley SA. Nitric oxide modulates macrophage responses to Mycobacterium tuberculosis an infection by activation of HIF-1α and repression of NF-κB. J Immunol. 2017;199(5):1805–1816. doi:10.4049/jimmunol.1700515

83. Huang LE, Gu J, Schau M, Bunn HF. Regulation of hypoxia-inducible issue 1alpha is mediated by an O2-dependent degradation area by way of the ubiquitin-proteasome pathway. Proc Natl Acad Sci U S A. 1998;95(14):7987–7992. doi:10.1073/pnas.95.14.7987

84. Phelan JJ, McQuhelp Ok, Kenny C, et al. Desferrioxamine helps metabolic operate in major human macrophages contaminated With Mycobacterium tuberculosis. Front Immunol. 2020;11(836). doi:10.3389/fimmu.2020.00836

85. Singhal A, Jie L, Kumar P, et al. Metformin as adjunct antituberculosis remedy. Sci Transl Med. 2014;6(263):263ra159. doi:10.1126/scitranslmed.3009885

86. Cheng SC, Quintin J, Cramer RA, et al. mTOR- and HIF-1α-mediated cardio glycolysis as metabolic foundation for skilled immunity. Science. 2014;345(6204):1250684. doi:10.1126/science.1250684

87. Arts RJW, Carvalho A, La Rocca C, et al. Immunometabolic pathways in BCG-induced skilled immunity. Cell Rep. 2016;17(10):2562–2571. doi:10.1016/j.celrep.2016.11.011

88. Arts RJ, Novakovic B, Ter Horst R, et al. Glutaminolysis and fumarate accumulation combine immunometabolic and epigenetic packages in skilled immunity. Cell Metab. 2016;24(6):807–819. doi:10.1016/j.cmet.2016.10.008

89. Kleinnijenhuis J, Oosting M, Joosten LA, Netea MG, Van Crevel R. Innate immune recognition of Mycobacterium tuberculosis. Clin Dev Immunol. 2011;2011(405310). doi:10.1155/2011/405310

90. Arts RJ, Joosten LA, Netea MG. Immunometabolic circuits in skilled immunity. Semin Immunol. 2016;28(5):425–430. doi:10.1016/j.smim.2016.09.002

91. Vrieling F, Wilson L, Rensen PCN, et al. Oxidized low-density lipoprotein (oxLDL) helps Mycobacterium tuberculosis survival in macrophages by inducing lysosomal dysfunction. PLoS Pathog. 2019;15(4):e1007724. doi:10.1371/journal.ppat.1007724

92. Shimizu Y, Polavarapu R, Eskla KL, et al. Hydrogen sulfide regulates cardiac mitochondrial biogenesis by way of the activation of AMPK. J Mol Cell Cardiol. 2018;116:29–40. doi:10.1016/j.yjmcc.2018.01.011

93. Ji D, Yin JY, Li DF, et al. Effects of inflammatory and anti inflammatory environments on the macrophage mitochondrial operate. Sci Rep. 2020;10(1):20324. doi:10.1038/s41598-020-77370-x

94. Padmapriyadarsini C, Bhavani PK, Natrajan M, et al. Evaluation of metformin together with rifampicin containing antituberculosis remedy in sufferers with new, smear-positive pulmonary tuberculosis (METRIF): examine protocol for a randomised scientific trial. BMJ Open. 2019;9(3):e024363. doi:10.1136/bmjopen-2018-024363

95. Tian N, Chu H, Li Q, et al. Host-directed remedy for tuberculosis. Eur J Med Res. 2025;30(1):267. doi:10.1186/s40001-025-02443-4

96. Cahill C, O’Connell F, Gogan KM, et al. The iron chelator desferrioxamine will increase the efficacy of bedaquiline in major human macrophages contaminated with BCG. Int J Mol Sci. 2021;22(6). doi:10.3390/ijms22062938