bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2025–03–16
forty-four papers selected by
Dylan Ryan, University of Cambridge
  1. A functional single-cell metabolic survey identifies Elovl1 as a target to enhance CD8+ T cell fitness in solid tumours.
  2. Itaconate restrains acute proinflammatory activation of microglia MG after traumatic brain injury in mice.
  3. Dexamethasone has profound influence on the energy metabolism of porcine blood leukocytes and prevents the LPS-induced glycolytic switch.
  4. Indole-3-propionic acid alleviates DSS-induced colitis in mice through macrophage glycolipid metabolism.
  5. Mitochondrial Regulator CRIF1 Plays a Critical Role in the Development and Homeostasis of Alveolar Macrophages via Maintaining Metabolic Fitness.
  6. OLFML3 Promotes IRG1 Mitochondrial Localization and Modulates Mitochondrial Function in Macrophages.
  7. Metabolic Signaling as a Driver of T Cell Aging.
  8. Unraveling the Complex Nexus of Macrophage Metabolism, Periodontitis, and Associated Comorbidities.
  9. Regulatory T Cell Metabolism: A Promising Therapeutic Target for Cancer Treatment?
  10. Obesity drives dysregulation in DC responses to viral infection.
  11. Impaired fatty acid import or catabolism in macrophages restricts intracellular growth of Mycobacterium tuberculosis.
  12. The role of m6A modification during macrophage metabolic reprogramming in human diseases and animal models.
  13. Tissue-Specific Metabolic Reprogramming in Innate Lymphoid Cells and Its Impact on Disease.
  14. Lipin-1 restrains macrophage lipid synthesis to promote inflammation resolution.
  15. Quantification of intracellular and mitochondrial ATP content in macrophages during lipopolysaccharide-induced inflammatory response.
  16. Modulation of Immune Responses by Metabolic Reprogramming: The Key Role of Immunometabolism.
  17. Decoding Microglial Polarization and Metabolic Reprogramming in Neurodegenerative Diseases: Implications for Disease Progression and Therapy.
  18. Quantitative assessment of mitochondrial membrane potential in macrophages in sepsis.
  19. SENP1-SIRT3 axis mediates glycolytic reprogramming to suppress inflammation during Listeria monocytogenes infection.
  20. Interferon-driven Metabolic Reprogramming and Tumor Microenvironment Remodeling.
  21. Interleukin-16 enhances anti-tumor immune responses by establishing a Th1 cell-macrophage crosstalk through reprogramming glutamine metabolism in mice.
  22. Esketamine attenuates traumatic brain injury by modulating STAT3-mediated Glycolysis and immune responses.
  23. GPR171 restrains intestinal inflammation by suppressing FABP5-mediated Th17 cell differentiation and lipid metabolism.
  24. Mitochondrial dynamics and metabolism in macrophages for cardiovascular disease: A review.
  25. The Jieduquyuziyin Prescription alleviates systemic lupus erythematosus by modulating B cell metabolic reprogramming via the AMPK/PKM2 signaling pathway.
  26. RORγ bridges cancer-driven lipid dysmetabolism and myeloid immunosuppression.
  27. Inflammation and metabolic dysfunction underly anhedonia-like behavior in antidepressant resistant male rats.
  28. Dietary succinate supplementation alleviates DSS-induced colitis via the IL-4Rα/Hif-1α Axis.
  29. Aromatic Amino Acid Metabolites: Molecular Messengers Bridging Immune-Microbiota Communication.
  30. Metabolic shifts in tryptophan pathways during acute pancreatitis infections.
  31. Lactate: A key regulator of the immune response.
  32. Hexokinase 2-mediated metabolic stress and inflammation burden of liver macrophages via histone lactylation in MASLD.
  33. Visualizing mitochondrial electron transport chain complexes and super-complexes during infection of human macrophages with Legionella pneumophila.
  34. Hexokinase 2 Promotes ISGylation of Acyl-CoA Synthetase Long-chain Family Member 4 in Sepsis-Induced Microglia Cells.
  35. Diverse Functions of Macrophages in Obesity and Metabolic Dysfunction-Associated Steatotic Liver Disease: Bridging Inflammation and Metabolism.
  36. Augmenting Macrophages Apoptosis Induced by Carnitine Palmitoyl Transferase 1A Inhibition via Acetyl-CoA-Associated Protein Acetylation.
  37. Caspase-1/11 controls Zika virus replication in astrocytes by inhibiting glycolytic metabolism.
  38. Disrupting cholesterol homeostasis in T cells boosts antitumour responses.
  39. Myeloid Fatty Acid Metabolism Activates Neighboring Hematopoietic Stem Cells to Promote Heart Failure With Preserved Ejection Fraction.
  40. The Role of Lactate and Lactylation in the Dysregulation of Immune Responses in Psoriasis.
  41. CD3+ T-cell: CD14+ monocyte complexes are dynamic and increased with HIV and glucose intolerance.
  42. Mesenchymal stem cell-derived extracellular vesicles alleviate autism by regulating microglial glucose metabolism reprogramming and neuroinflammation through PD-1/PD-L1 interaction.
  43. The glycolytic enzyme PKM2 regulates inflammatory osteoclastogenesis by modulating STAT3 phosphorylation.
  44. Microglia mediate the early-life programming of adult glucose control.
  1. Nat Metab. 2025 Mar 10.
    A functional single-cell metabolic survey identifies Elovl1 as a target to enhance CD8+ T cell fitness in solid tumours.
    Samantha Pretto, Qian Yu, Pierre Bourdely, Sarah Trusso Cafarello, Heleen H Van Acker, Joren Verelst, Elena Richiardone, Lotte Vanheer, Amir Roshanzadeh, Franziska Schneppenheim, Charlotte Cresens, Maria Livia Sassano, Jonas Dehairs, Martin Carion, Shehab Ismail, Patrizia Agostinis, Susana Rocha, Tobias Bald, Johan Swinnen, Cyril Corbet, Sophia Y Lunt, Bernard Thienpont, Mario Di Matteo, Massimiliano Mazzone.
      Reprogramming T cell metabolism can improve intratumoural fitness. By performing a CRISPR/Cas9 metabolic survey in CD8+ T cells, we identified 83 targets and we applied single-cell RNA sequencing to disclose transcriptome changes associated with each metabolic perturbation in the context of pancreatic cancer. This revealed elongation of very long-chain fatty acids protein 1 (Elovl1) as a metabolic target to sustain effector functions and memory phenotypes in CD8+ T cells. Accordingly, Elovl1 inactivation in adoptively transferred T cells combined with anti-PD-1 showed therapeutic efficacy in resistant pancreatic and melanoma tumours. The accumulation of saturated long-chain fatty acids in Elovl1-deficient T cells destabilized INSIG1, leading to SREBP2 activation, increased plasma membrane cholesterol and stronger T cell receptor signalling. Elovl1-deficient T cells increased mitochondrial fitness and fatty acid oxidation, thus withstanding the metabolic stress imposed by the tumour microenvironment. Finally, ELOVL1 in CD8+ T cells correlated with anti-PD-1 response in patients with melanoma. Altogether, Elovl1 targeting synergizes with anti-PD-1 to promote effective T cell responses.
    DOI:  https://doi.org/10.1038/s42255-025-01233-w
  2. Sci Transl Med. 2025 Mar 12. 17(789): eadn2635
    Itaconate restrains acute proinflammatory activation of microglia MG after traumatic brain injury in mice.
    Ning Liu, Yinghua Jiang, Yuwen Xiu, Giovane G Tortelote, Winna Xia, Yingjie Wang, Yadan Li, Samuel Shi, Jinrui Han, Charles Vidoudez, Aim Niamnud, Mitchell D Kilgore, Di Zhou, Mengxuan Shi, Stephen A Graziose, Jia Fan, Prasad V G Katakam, Aaron S Dumont, Xiaoying Wang.
      Traumatic brain injury (TBI) rapidly triggers proinflammatory activation of microglia, contributing to secondary brain damage post-TBI. Although the governing role of energy metabolism in shaping the inflammatory phenotype and function of immune cells has been increasingly recognized, the specific alterations in microglial bioenergetics post-TBI remain poorly understood. Itaconate, a metabolite produced by the enzyme aconitate decarboxylase 1 [IRG1; encoded by immune responsive gene 1 (Irg1)], is a pivotal metabolic regulator in immune cells, particularly in macrophages. Because microglia are macrophages of the brain parenchyma, the IRG1/itaconate pathway likely modulates microglial inflammatory responses. In this study, we explored the role of the IRG1/itaconate pathway in regulating microglial bioenergetics and inflammatory activation post-TBI using a mouse controlled cortical impact (CCI) model. We isolated microglia before and 4 and 12 hours after TBI and observed a swift but transient increase in glycolysis coupled with a prolonged disruption of mitochondrial metabolism after injury. Despite an up-regulation of Irg1 expression, itaconate in microglia declined after TBI. Microglia-specific Irg1 gene knockout (Irg1-Mi-KO) exacerbated metabolic changes, intensified proinflammatory activation and neurodegeneration, and worsened certain long-term neurological deficits. Supplementation with 4-octyl itaconate (OI) reinstated the use and oxidative metabolism of glucose, glutamine, and fatty acid, thereby enhancing microglial bioenergetics post-TBI. OI supplementation also attenuated proinflammatory activation and neurodegeneration and improved long-term neurological outcomes. These results suggest that therapeutically targeting the itaconate pathway could improve microglial energy metabolism and neurological outcomes after TBI.
    DOI:  https://doi.org/10.1126/scitranslmed.adn2635
  3. Front Immunol. 2025 ;16 1514061
    Dexamethasone has profound influence on the energy metabolism of porcine blood leukocytes and prevents the LPS-induced glycolytic switch.
    Wenjuan Ma, Julia Brenmoehl, Nares Trakooljul, Klaus Wimmers, Eduard Murani.
      In farm animals, little is known about the relationship between energy metabolism of immune cells and their activation state. Moreover, there has recently been evidence that dexamethasone, a powerful glucocorticoid-based drug, can exert its anti-inflammatory effects by interfering with the energy metabolism of immune cells, but the mechanisms are not yet fully understood. To address these knowledge gaps, we explored the connection between the energy metabolism of porcine peripheral blood mononuclear cells (PBMCs) and their response to pro- and anti-inflammatory stimulation with lipopolysaccharide (LPS) and dexamethasone (DEX) in vitro. Interventions in the metabolism of PBMCs with the glycolysis inhibitor 2-deoxy-D-glucose or the HIF-1α inhibitor KC7F2 reduced the LPS-induced TNF-α production, but the mitochondrial ATP synthesis inhibitor oligomycin showed no significant effect. The anti-inflammatory action of DEX was not affected by any of the inhibitors. To investigate the metabolic actions of LPS and DEX in PBMCs, we evaluated glycolysis and mitochondrial respiration following 24 hours stimulation using the Seahorse XFe96 flux analyzer. Our results revealed significantly higher glycolysis in LPS-treated PBMCs, but provided no evidence for a change in mitochondrial respiration. In contrast, DEX reduced LPS-induced glycolysis and, especially when administered alone, significantly lowered mitochondrial respiration. Pretreatment with KC7F2 counteracted the effects of LPS and DEX on glycolysis, and reduced mitochondrial respiration regardless of the inflammatory state of the PBMCs. Gene expression analysis identified the glucose transporter SLC2A3, and the tricarboxylic acid cycle genes IDH1 and SDHB as the main switches for the antagonistic metabolic actions of LPS and DEX, which are closely associated with the inflammatory state of PBMCs.
    Keywords:  GLUT3; PBMC; dexamethasone; glucocorticoid receptor; immunometabolism; inflammation; lipopolysaccharide (LPS)
    DOI:  https://doi.org/10.3389/fimmu.2025.1514061
  4. Int Immunopharmacol. 2025 Mar 13. pii: S1567-5769(25)00378-9. [Epub ahead of print]152 114388
    Indole-3-propionic acid alleviates DSS-induced colitis in mice through macrophage glycolipid metabolism.
    Jiahong Li, Peicen Zou, Ruiqi Xiao, Yajuan Wang.
      Ulcerative colitis (UC) is a chronic relapsing inflammatory bowel disease for which current therapeutic approaches still face many dilemmas, and targeting macrophage polarization and metabolism for the treatment of this disease is a potentially effective strategy. The gut microbial metabolite indole-3-propionic acid (IPA) has favorable anti-inflammatory and antioxidant effects and plays a role in a variety of disease models. IPA is effective in the treatment of UC, but the underlying mechanisms have not been well explored. In the present study, we investigated the mechanisms by which IPA ameliorates colitis in mice from the perspective of macrophage polarization and metabolism. In this study, mice colitis was induced by sodium dextran sulfate and treated with oral IPA. RAW264.7 cells were induced by LPS to polarize into M1 macrophages and treated with IPA. The results showed that IPA could improve colitis by inhibiting M1 polarization of colonic macrophages and promoting M2 polarization. The inhibition of IPA on M1 macrophages was verified in vitro through JNK/MAPK pathway, which inhibited the glycolysis of macrophages. IPA promotes macrophage M2 polarization and enhances fatty acid oxidation through upregulating of CPT1A and ACSL1, which may be related to the activation of PPAR-γ. In summary, IPA can improve colitis by regulating macrophage glucose and lipid metabolism, and targeting intestinal macrophage metabolism may be an effective target for the treatment of UC.
    Keywords:  Fatty acid oxidation; Glycolysis; Indole-3-propionic; Macrophage metabolism; Ulcerative colitis
    DOI:  https://doi.org/10.1016/j.intimp.2025.114388
  5. Immune Netw. 2025 Feb;25(1): e9
    Mitochondrial Regulator CRIF1 Plays a Critical Role in the Development and Homeostasis of Alveolar Macrophages via Maintaining Metabolic Fitness.
    Ein Lee, Seung Geun Song, Haaun Moon, Minho Shong, Doo Hyun Chung.
      The importance of mitochondrial function in macrophages is well established. Alveolar macrophages (AMs), the tissue-resident macrophages (TRMs) of the lung, are particularly dependent on mitochondria-driven oxidative phosphorylation (OXPHOS) to support their functions and maintain homeostasis. However, the specific genes and pathways that regulate OXPHOS in AMs remain unclear. In this study, we investigated the role of CR6-interacting factor 1 (CRIF1), a mitochondrial regulator, as a key factor that specifically modulates the metabolic fitness and maintenance of AMs. Using single-cell RNA sequencing and transcriptomic analyses, we found CRIF1 to be highly expressed in AMs compared to TRMs from other tissues, correlating with enhanced OXPHOS activity. Genetic ablation of Crif1 in macrophages resulted in a marked reduction in AM populations exclusively in the lung, while other TRM populations were unaffected. CRIF1-deficient AMs exhibited an altered metabolic profile, including impaired mitochondrial function, increased glycolysis, and aberrant lipid accumulation. These findings underscore the essential role of CRIF1 in regulating mitochondrial functions and metabolic fitness in AMs, distinguishing it from broader mitochondrial regulators like mitochondrial transcription factor A, which operates across multiple TRM populations. Our study provides critical insights into the tissue-specific regulation of macrophage metabolism and suggests potential therapeutic avenues for lung diseases associated with AM dysfunction.
    Keywords:  Alveolar macrophages; Homeostasis; Metabolic reprogramming; Mitochondria; Oxidative phosphorylation
    DOI:  https://doi.org/10.4110/in.2025.25.e9
  6. Int J Biol Sci. 2025 ;21(5): 2275-2295
    OLFML3 Promotes IRG1 Mitochondrial Localization and Modulates Mitochondrial Function in Macrophages.
    Qijun Yu, Hong Mei, Qian Gu, Ran Zeng, Yanan Li, Junjie Zhang, Chenxu Gao, Hai Fang, Jieming Qu, Jia Liu.
      Olfactomedin-like protein 3 (OLFML3), belonging to olfactomedin (OLF) protein family, has poorly defined functions. Recent studies have reported the functions of OLFML3 in anti-viral immunity and tumorigenesis. In this study, we investigated the roles of OLFML3 in macrophages. In LPS- or Pseudomonas aeruginosa-induced acute lung injury (ALI) mouse model, OLFML3 depletion exacerbated inflammatory response, leading to reduced survival. OLFML3 achieved the in vivo activity by regulating macrophage phagocytosis and migration. Mass spectrometry analysis revealed immunoresponsive gene 1 (IRG1) as an OLFML3-interacting protein. IRG1 is a mitochondrial decarboxylase that catalyzes the conversion of cis-aconitate to itaconate, a myeloid-borne mitochondrial metabolite with immunomodulatory activities. Further investigation showed that OLFML3 could prevent LPS-induced mitochondrial dysfunction in macrophages by maintaining the homeostasis of mitochondrial membrane potential (MMP), mitochondrial reactive oxygen species (mtROS) and itaconate-related metabolites. In-depth protein-protein interaction studies showed that OLFML3 could promote IRG1 mitochondrial localization via a mitochondrial transport protein, apoptosis inducing factor mitochondria associated 1 (AIFM1). In summary, our study showed that OLFML3 could facilitate IRG1 mitochondrial localization and prevent LPS-induced mitochondrial dysfunction in macrophages.
    Keywords:  IRG1; OLFML3; acute Lung Injury; macrophage; mitochondria
    DOI:  https://doi.org/10.7150/ijbs.103859
  7. Immune Netw. 2025 Feb;25(1): e14
    Metabolic Signaling as a Driver of T Cell Aging.
    Minju Choi, Sujin Choi, Minkyeong Cho, Chulwoo Kim.
      Aging significantly diminishes T cell immunity, increasing susceptibility to infections and reducing vaccine efficacy in older individuals. Metabolism plays a key role in T cell function, shaping their energy requirements, activation, and differentiation. Recent studies highlight altered metabolic signaling as a pivotal factor in T cell aging, influencing the ability of T cells to maintain quiescence, respond to activation, and differentiate into functional subsets. Aberrant metabolic pathways disrupt the quiescence of aged T cells and skew their differentiation toward short-lived, pro-inflammatory effector T cells while hindering the generation of long-lived memory and T follicular helper cells. These changes contribute to a hyper-inflammatory state, exacerbate chronic low-grade inflammation, and compromise immune homeostasis. In this review, we explore how metabolic signaling is altered during T cell aging and the resulting functional impacts. We also discuss therapeutic approaches aimed at restoring proper T cell differentiation, improving vaccine responses, and rejuvenating immune function in older populations.
    Keywords:  Inflammaging; Memory T cells; Metabolic signaling; T cell aging; T cell differentiation; Vaccine
    DOI:  https://doi.org/10.4110/in.2025.25.e14
  8. J Innate Immun. 2025 Mar 07. 1-21
    Unraveling the Complex Nexus of Macrophage Metabolism, Periodontitis, and Associated Comorbidities.
    Zihan Zhang, Yi Liu, Tian Yu, Zhen Liu.
      Periodontitis stands out as one of the most prevalent oral dysbiotic inflammatory diseases, ultimately leading to the irreversible destruction of periodontal tissue. Macrophages play a pivotal role in the development and progression of periodontitis, and the feasibility of therapeutic targeting has been established. Given that metabolic switching significantly contributes to macrophage regulation, conducting an in-depth review of macrophage metabolism in periodontitis may serve as the foundation for developing innovative treatments. This paper has undergone meticulous review to furnish a comprehensive summary of the roles played by macrophages in periodontitis and associated comorbidities. To start with, detailed presentations on the metabolic reprogramming of macrophages, including glucose, lipid, and amino acid metabolism, were provided. Subsequently, dominating macrophage phenotype and metabolism under lipopolysaccharide (LPS) stimulation or during periodontitis were presented with emphasize on critical molecules involved. Furthermore, in recognition of the close association between periodontitis and several comorbidities, the interaction among macrophage metabolism, periodontitis, and related metabolic diseases, was thoroughly discussed. In conclusion, through the examination of current research on macrophage metabolic reprogramming induced by periodontitis, this review provides potential immunometabolic therapeutic targets for the future and raises many important, yet unstudied, subjects for follow-up.
    DOI:  https://doi.org/10.1159/000542531
  9. Immune Netw. 2025 Feb;25(1): e13
    Regulatory T Cell Metabolism: A Promising Therapeutic Target for Cancer Treatment?
    Jihyoun Kim, Jiaoran Li, Jun Wei, Seon Ah Lim.
      Regulatory T (Treg) cells are essential for maintaining immune homeostasis by suppressing excessive immune responses. In the context of cancer, however, Tregs promote immune evasion and tumor progression, particularly through their unique adaptations within the tumor microenvironment (TME). Recent research has emphasized how metabolic characteristics shape Treg activation, migration, and immunosuppressive function, revealing the impact of metabolic pathways on Treg fitness in homeostasis and within the TME. In this review, we first provide an overview of Tregs in cancer immunology, discussing their immunosuppressive roles and properties specific to the TME. We then examine the metabolic requirements for Treg activation and migration under normal conditions, followed by a discussion of how hypoxia, lactate accumulation, nutrient limitation, oxidative stress, and other TME-specific factors alter Treg metabolism and contribute to cancer immune evasion. Finally, we explore therapeutic strategies that target Treg metabolism within the TME, including pharmacological modulation of specific metabolic pathways to diminish Treg-mediated immunosuppression. Thus, we could suggest future directions and clinical implications for Treg-targeted metabolic modulation as a complementary approach in cancer treatment, setting the stage for novel strategies in immunotherapy.
    Keywords:  Immune evasion; Immunometabolism; Immunotherapy; Regulatory T cell; Tumor microenvironment
    DOI:  https://doi.org/10.4110/in.2025.25.e13
  10. Discov Immunol. 2025 ;4(1): kyaf001
    Obesity drives dysregulation in DC responses to viral infection.
    Andrea Woodcock, Ronan Bergin, Nidhi Kedia-Mehta, Cathriona Foley, John C Stephens, Donal O'Shea, Mary Canavan, Andrew E Hogan.
       Introduction: Obesity is a worldwide epidemic, with over 1 billion people worldwide living with obesity. It is associated with an increased risk of over 200 chronic co-morbidities, including an increased susceptibility to infection. Numerous studies have highlighted the dysfunction caused by obesity on a wide range of immune cell subsets, including dendritic cells (DCs). DCs are innate immune sentinels that bridge the innate and adaptive immune systems. DCs provide critical signals that instruct and shape the immune response. Our group has previously reported that DCs from people with obesity display defective cytokine production; however, the mechanisms underpinning these defects are unclear.
    Methods: We investigated the functional responses of DCs using a murine-specific single-stranded RNA virus, Sendai virus, in mice on a standard diet and in a model of diet-induced obesity.
    Results: Here, we demonstrate that GM-CSF cultured bone marrow-derived DCs (GM-DCs) from mice on a high-fat diet (HFD) have reduced cytokine production following viral challenge. This was associated with a dysfunctional metabolism through reduced translation in the HFD GM-DCs.
    Conclusions: We propose that obesity-mediated effects on DCs have downstream consequences on their ability to effectively mediate subsequent immune responses, especially during viral infection.
    Keywords:  Sendai virus; dendritic cells; immunometabolism; metabolism
    DOI:  https://doi.org/10.1093/discim/kyaf001
  11. Elife. 2025 Mar 13. pii: RP102980. [Epub ahead of print]13
    Impaired fatty acid import or catabolism in macrophages restricts intracellular growth of Mycobacterium tuberculosis.
    Nelson V Simwela, Eleni Jaecklein, Christopher M Sassetti, David G Russell.
      Mycobacterium tuberculosis (Mtb) infection of macrophages reprograms cellular metabolism to promote lipid retention. While it is clearly known that intracellular Mtb utilize host-derived lipids to maintain infection, the role of macrophage lipid processing on the bacteria's ability to access the intracellular lipid pool remains undefined. We utilized a CRISPR-Cas9 genetic approach to assess the impact of sequential steps in fatty acid metabolism on the growth of intracellular Mtb. Our analyses demonstrate that macrophages that cannot either import, store, or catabolize fatty acids restrict Mtb growth by both common and divergent antimicrobial mechanisms, including increased glycolysis, increased oxidative stress, production of pro-inflammatory cytokines, enhanced autophagy, and nutrient limitation. We also show that impaired macrophage lipid droplet biogenesis is restrictive to Mtb replication, but increased induction of the same fails to rescue Mtb growth. Our work expands our understanding of how host fatty acid homeostasis impacts Mtb growth in the macrophage.
    Keywords:  infectious disease; lipid metabolism; macrophage; microbiology; mouse; mycobacterium; tuberculosis
    DOI:  https://doi.org/10.7554/eLife.102980
  12. Front Immunol. 2025 ;16 1521196
    The role of m6A modification during macrophage metabolic reprogramming in human diseases and animal models.
    Huiling Wang, Peiqi Xu, Kai Yin, Shengjun Wang.
      Macrophage metabolic reprogramming refers to the process by which macrophages adjust their physiological pathways to meet survival and functional demands in different immune microenvironments. This involves a range of metabolic pathways, including glycolysis, the tricarboxylic acid cycle, oxidative phosphorylation, fatty acid oxidation, and cholesterol transport. By modulating the expression and activity of key enzymes and molecules within these pathways, macrophages can make the transition between pro- and anti-inflammatory phenotypes, thereby linking metabolic reprogramming to inflammatory responses and the progression of several diseases, such as atherosclerosis, inflammatory bowel disease (IBD), and acute lung injury (ALI). N6-methyladenosine (m6A) modification has emerged as a critical regulatory mechanism during macrophage metabolic reprogramming, broadly affecting RNA stability, translation, and degradation. Therapeutic strategies targeting m6A modification can regulate the onset of metabolic diseases by influencing macrophage metabolic changes, for instance, small molecule inhibitors of methyltransferase-like 3 (METTL3) can affect glucose metabolism and inhibit IBD. This review systematically explores recent findings on the role and molecular mechanisms of m6A modification during macrophage metabolic reprogramming in human diseases and animal models, underscoring its potential as a therapeutic target for metabolic diseases.
    Keywords:  M1/M2 macrophage reprogramming; cholesterol transport; fatty acid oxidation; glycolysis; oxidative phosphorylation; tricarboxylic acid cycle
    DOI:  https://doi.org/10.3389/fimmu.2025.1521196
  13. Immune Netw. 2025 Feb;25(1): e3
    Tissue-Specific Metabolic Reprogramming in Innate Lymphoid Cells and Its Impact on Disease.
    Jongho Ham, Wooseok Yang, Hye Young Kim.
      Recent advances have highlighted the crucial role of metabolic reprogramming in shaping the functions of innate lymphoid cells (ILCs), which are vital for tissue immunity and homeostasis. As tissue-resident cells, ILCs dynamically respond to local environmental cues, with tissue-derived metabolites such as short-chain fatty acids and amino acids directly modulating their effector functions. The metabolic states of ILC subsets-ILC1, ILC2, and ILC3-are closely linked to their ability to produce cytokines, sustain survival, and drive proliferation. This review provides a comprehensive analysis of how key metabolic pathways, including glycolysis, oxidative phosphorylation, and fatty acid oxidation, influence ILC activation and function. Furthermore, we explore the complex interactions between these metabolic pathways and tissue-specific metabolites, which can shape ILC-mediated immune responses in health and disease. Understanding these interactions reveals new insights into the pathogenesis of conditions such as asthma, inflammatory bowel disease, and cancer. A deeper understanding of these mechanisms may not only advance our knowledge of disease pathogenesis but also lead to the development of novel therapeutic strategies targeting metabolic pathways in ILCs to treat tissue-specific immune disorders.
    Keywords:  Fatty acid oxidation; Glycolysis; Immunometabolism; Innate lymphoid cell; Oxidative phosphorylation; Therapeutic targets; Tissue-specific immunity
    DOI:  https://doi.org/10.4110/in.2025.25.e3
  14. J Immunol. 2025 Jan 01. 214(1): 85-103
    Lipin-1 restrains macrophage lipid synthesis to promote inflammation resolution.
    Temitayo T Bamgbose, Robert M Schilke, Oluwakemi O Igiehon, Ebubechukwu H Nkadi, Monika Binwal, David Custis, Sushma Bharrhan, Benjamin Schwarz, Eric Bohrnsen, Catharine M Bosio, Rona S Scott, Arif Yurdagul, Brian N Finck, Matthew D Woolard.
      Macrophages are critical to maintaining and restoring tissue homeostasis during inflammation. The lipid metabolic state of macrophages influences their function and polarization, which is crucial to the resolution of inflammation. The contribution of lipid synthesis to proinflammatory macrophage responses is well understood. However, how lipid synthesis regulates proresolving macrophage responses needs to be better understood. Lipin-1 is a phosphatidic acid phosphatase with a transcriptional coregulatory activity that regulates lipid metabolism. We previously demonstrated that lipin-1 supports proresolving macrophage responses, and here, myeloid-associated lipin-1 is required for inflammation resolution, yet how lipin-1-regulated cellular mechanisms promote macrophage proresolution responses is unknown. We demonstrated that the loss of lipin-1 in macrophages led to increased free fatty acid, neutral lipid, and ceramide content and increased phosphorylation of acetyl-CoA carboxylase. The inhibition of the first step of lipid synthesis, the transport of citrate from the mitochondria, reduced lipid content and restored efferocytosis and inflammation resolution in lipin-1mKO mice and macrophages. Our findings suggest macrophage-associated lipin-1 restrains lipid synthesis, promoting proresolving macrophage function in response to proresolving stimuli.
    Keywords:  citrate carrier; efferocytosis; fatty acid; inflammation resolution; lipin-1
    DOI:  https://doi.org/10.1093/jimmun/vkae010
  15. Methods Cell Biol. 2025 ;pii: S0091-679X(24)00019-0. [Epub ahead of print]194 77-92
    Quantification of intracellular and mitochondrial ATP content in macrophages during lipopolysaccharide-induced inflammatory response.
    Paulraj Kanmani, Guochang Hu.
      Sepsis, a condition characterized by systemic infection that becomes aggravated and dysregulated, is a significant cause of mortality in critically ill patients. Emerging evidence suggests that severe sepsis is often accompanied by alterations in cell metabolism, particularly mitochondrial dysfunction, resulting in multiorgan failure. Normally, metabolically active cells or tissues exhibit higher levels of mitochondrial turnover, respiration, and adenosine triphosphate (ATP) synthesis. However, during sepsis, these processes become overwhelmed or dysregulated, leading to impaired ATP production in mitochondria. Here, we present two straightforward protocols for quantifying ATP production from mitochondria in bone marrow-derived macrophages (BMDMs). Our workflow facilitates the easy isolation of BMDMs and mitochondria from BMDMs treated with lipopolysaccharide (LPS), the major cell wall component of Gram-negative bacteria. We quantified intracellular and mitochondrial ATP production in macrophages in vitro using this protocol. The results indicated a decrease in mitochondrial ATP content in BMDMs in response to LPS. With minimal adjustments, this method can be adapted for use with various human and mouse primary cells and cell lines.
    Keywords:  ATP; Inflammation; Lipopolysaccharide; Macrophage; Mitochondria; Sepsis
    DOI:  https://doi.org/10.1016/bs.mcb.2024.01.006
  16. Immune Netw. 2025 Feb;25(1): e15
    Modulation of Immune Responses by Metabolic Reprogramming: The Key Role of Immunometabolism.
    Sung-Gyoo Park, June-Yong Lee, Hyungseok Seo, Soo Seok Hwang, Chong-Kil Lee, Gap Ryol Lee.
      
    DOI:  https://doi.org/10.4110/in.2025.25.e15
  17. Aging Dis. 2025 Feb 21.
    Decoding Microglial Polarization and Metabolic Reprogramming in Neurodegenerative Diseases: Implications for Disease Progression and Therapy.
    Ran Gao, Ya Gao, Wenting Su, Renxi Wang.
      As the resident macrophages of the brain, microglia are crucial immune cells specific to the central nervous system (CNS). They constantly surveil their surroundings and trigger immunological reactions, playing a key role in various neurodegenerative diseases (ND). As illnesses progress, microglia exhibit multiple phenotypes. Traditionally, microglia have been classified into two main phenotypes upon activation: the pro-inflammatory M1 polarization and the anti-inflammatory M2 polarization. However, this classification is now considered overly simplistic, as it is unable to fully convey the intricacy and diversity of the inflammatory response. Immune regulatory factors, such as chemokines secreted by microglia, are essential for modulating brain development, maintaining the neural milieu, and orchestrating responses to injury, along with the subsequent repair processes. However, in recent years, the significance of metabolic reprogramming in both physiological microglial activity and ND has also become increasingly recognized. Upon activation-triggered by brain injury, infection, or ND-microglia typically modify their metabolic processes by transitioning from oxidative phosphorylation (OXPHOS) phosphorylation to glycolysis. This shift facilitates rapid energy production but may also enhance pro-inflammatory responses. This review seeks to summarize metabolic reprogramming and polarization in the function of microglia and their involvement in ND.
    DOI:  https://doi.org/10.14336/AD.2024.1629
  18. Methods Cell Biol. 2025 ;pii: S0091-679X(24)00017-7. [Epub ahead of print]194 43-58
    Quantitative assessment of mitochondrial membrane potential in macrophages in sepsis.
    Ajaz Ahmad, Paulraj Kanmani, Guochang Hu.
      Sepsis, a life-threatening condition characterized by dysregulated host response to infection, poses a significant public healthcare challenge. Excessive inflammatory responses during sepsis can lead to mitochondrial dysfunctions, resulting in organ damage. One hallmark of mitochondrial dysfunction is the reduction of mitochondrial membrane potential, which disrupts cellular metabolism, bioenergetics, and decreases the production of high-energy ATP through oxidative phosphorylation. In human sepsis, the mitochondrial membrane potential in peripheral blood monocytes has been identified as a marker of disease severity. Here, we present a detailed and widely accepted protocol for the detection of mitochondrial membrane potential using the JC-1 fluorescent dye in murine bone marrow-derived macrophages and J774A.1 macrophages following stimulation with lipopolysaccharides. This protocol is routinely employed and can be easily adapted for various cell types, intact tissues, and isolated mitochondria with minimal modifications. By utilizing this technique, researchers can gain valuable insights into mitochondrial function in different experimental contexts, potentially advancing our understanding of the pathogenesis and treatment of sepsis-related mitochondrial dysfunction.
    Keywords:  Inflammation; JC-1; Lipopolysaccharides; Macrophage; Mitochondrial membrane potential; Reactive oxygen species; Sepsis; p120 catenin
    DOI:  https://doi.org/10.1016/bs.mcb.2024.01.004
  19. mBio. 2025 Mar 12. e0252424
    SENP1-SIRT3 axis mediates glycolytic reprogramming to suppress inflammation during Listeria monocytogenes infection.
    Yan Xiong, Yongliang Du, Feng Lin, Beibei Fu, Dong Guo, Zhou Sha, Rong Tian, Rui Yao, Lulu Wang, Zixuan Cong, Bohao Li, Xiaoyuan Lin, Haibo Wu.
      Listeria monocytogenes, a foodborne pathogen, has the ability to invade intestinal mucosal cells, undergo intracellular proliferation, activate host immune responses, and induce diseases such as colitis. We have demonstrated that sentrin-specific protease 1 (SENP1) functions as a protective gene in the host, suppressing the inflammatory response triggered by Listeria monocytogenes. The host's SENP1-SIRT3 axis plays a critical role in regulating inflammation during Listeria monocytogenes infection. Our findings reveal that overexpression of SENP1, particularly under Listeria monocytogenes infection conditions (MOI = 20), effectively suppresses inflammation through modulation of glycolysis. Mechanistically, during Listeria monocytogenes infection, SENP1 accumulates in the mitochondria, facilitating the de-SUMOylation and activation of sirtuin 3 (SIRT3). Activated SIRT3 then regulates the deacetylation of pyruvate kinase M2 (PKM2), leading to a decrease in glycolytic intermediates, downregulation of glycolysis-related gene expression, and suppression of inflammation. Taken together, our study provides a deeper understanding of the mechanistic role of the SENP1-SIRT3 axis in the regulation of inflammation, offering novel insights, and strategies for the treatment and prevention of inflammatory diseases.
    IMPORTANCE: Sentrin-specific protease 1 (SENP1)-sirtuin 3 (SIRT3) has never been reported in the regulation of bacteria-induced inflammation. Our study demonstrated that SENP1 acted as a protective factor against Listeria-induced inflammation by promoting SIRT3 activation and subsequent metabolic reprogramming. The SENP1-SIRT3 axis served not only as an essential signaling pathway for regulating mitochondrial metabolic responses to metabolic stress but also responds to bacterial invasion and plays a protective role in the organism. Our findings provide a basis for further research into targeting the SENP1-SIRT3 signaling pathway for the treatment of bacterial infections.
    Keywords:  Listeria monocytogenes; PKM2; SENP1-SIRT3 axis; SUMO; glycolysis
    DOI:  https://doi.org/10.1128/mbio.02524-24
  20. Immune Netw. 2025 Feb;25(1): e8
    Interferon-driven Metabolic Reprogramming and Tumor Microenvironment Remodeling.
    Tzu-Hsuan Chang, Ping-Chih Ho.
      IFNs play a critical role in cancer biology, including impacting tumor cell behavior and instructing the tumor microenvironment (TME). IFNs recently have been shown to reprogram tumor metabolism through distinct mechanisms. Furthermore, IFNs shape the TME by modulating immune cell infiltration and function, contributing to the intricate interaction between the tumor and stromal cells. This review summarizes the effects of IFNs on metabolic reprogramming and their impacts on the function of immune cells within the TME, with a particular focus on the dual roles of IFNs in mediating both anti-tumor and pro-tumor immune responses. Understanding the significance of IFNs-mediated processes aids to advise future therapeutic strategies in cancer treatment.
    Keywords:  Antitumor; Interferon; Metabolism; Tumor microenvironment
    DOI:  https://doi.org/10.4110/in.2025.25.e8
  21. Nat Commun. 2025 Mar 10. 16(1): 2362
    Interleukin-16 enhances anti-tumor immune responses by establishing a Th1 cell-macrophage crosstalk through reprogramming glutamine metabolism in mice.
    Zhenzhen Wen, Tong Liu, Xutao Xu, Nandini Acharya, Zhida Shen, Yunkun Lu, Junjie Xu, Ke Guo, Shuying Shen, Yuening Zhao, Pinli Wang, Shumin Li, Weiyu Chen, Hui Li, Yimin Ding, Min Shang, Hongshan Guo, Yu Hou, Bijun Cui, Manlu Shen, Youling Huang, Ting Pan, Wang Qingqing, Qian Cao, Kai Wang, Peng Xiao.
      Overcoming immunosuppression in the tumor microenvironment (TME) is crucial for developing novel cancer immunotherapies. Here, we report that IL-16 administration enhances the polarization of T helper 1 (Th1) cells by inhibiting glutamine catabolism through the downregulation of glutaminase in CD4+ T cells and increases the production of Th1 effector cytokine IFN-γ, thus improving anti-tumor immune responses. Moreover, we find that establishing an IL-16-dependent, Th1-dominant TME relies on mast cell-produced histamine and results in the increased expression of the CXCR3 ligands in tumor-associated macrophages (TAM), thereby improving the therapeutic effectiveness of immune checkpoint blockade (ICB). Cancer patients exhibit impaired production of IL-16, which correlates with poorer prognosis. Additionally, low IL-16 production is associated with unresponsiveness to immunotherapy in cancer patients. Collectively, our findings provided new insights into the biological function of IL-16, emphasizing its potential clinical significance as a therapeutic approach to augment anti-tumor immunity and sensitize ICB-based cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s41467-025-57603-1
  22. BMC Neurosci. 2025 Mar 07. 26(1): 21
    Esketamine attenuates traumatic brain injury by modulating STAT3-mediated Glycolysis and immune responses.
    Yufang Liu, Zheng Gong, Longfei Zhang, Xian Yang, Jie Zhu, Xin Zhou, Xingzhi Liao.
       BACKGROUND: Secondary injury following traumatic brain injury (TBI) involves neuroinflammation, immune cell infiltration, and metabolic dysregulation, leading to progressive neurological damage. This study evaluates the potential of esketamine, an NMDA receptor antagonist, to modulate immune responses, inhibit glycolysis, and mitigate secondary brain injury in a TBI mouse model.
    METHODS: Male C57BL/6J mice were subjected to controlled cortical impact to induce TBI. Mice were treated with esketamine, either alone or combined with the STAT3 activator colivelin, or the glycolysis inhibitor 2-deoxyglucose (2-DG). Neurological function, BBB permeability, immune cell infiltration, macrophage polarization, and glycolytic activity were assessed using immunohistochemistry, flow cytometry, quantitative PCR, and enzyme-linked immunosorbent assay (ELISA).
    RESULTS: Esketamine treatment significantly reduced structural brain tissue damage, including contusions, tissue loss, and edema, while also improving neurological outcomes in TBI mice. Mechanistically, esketamine inhibited CD4 + T cell activation and suppressed Th17 differentiation both in vivo and in vitro. It also promoted a shift in macrophage polarization from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype. Further analysis revealed that esketamine blocked STAT3 activation, which in turn reduced the expression of glycolytic genes (e.g., Hk2, Pgk1, Aldoa) essential for Th17 cell proliferation and M1 polarization. Co-treatment with colivelin reversed esketamine's effects on STAT3-mediated glycolysis, while 2-DG enhanced its anti-inflammatory actions.
    CONCLUSION: Esketamine attenuates TBI-induced neuroinflammation and tissue damage by inhibiting STAT3-mediated glycolysis, thus reducing Th17 and M1 macrophage activity and promoting regulatory and reparative immune responses. These findings highlight esketamine's potential as a therapeutic option for TBI, targeting both immune modulation and metabolic pathways to alleviate secondary injury.
    CLINICAL TRIAL NUMBER: not applicable.
    Keywords:  Esketamine; Glycolysis; Immune modulation; STAT3; Traumatic brain injury
    DOI:  https://doi.org/10.1186/s12868-025-00941-z
  23. Gut. 2025 Mar 12. pii: gutjnl-2024-334010. [Epub ahead of print]
    GPR171 restrains intestinal inflammation by suppressing FABP5-mediated Th17 cell differentiation and lipid metabolism.
    Fushun Kou, Xiao-Yu Li, Zhongsheng Feng, Jinghan Hua, Xiaohan Wu, Han Gao, Jian Lin, Dengfeng Kang, Ai Li, Junxiang Li, Yao Ding, Ting Ban, Qing Zhang, Zhanju Liu.
       BACKGROUND: GPR171 suppresses T cell immune responses involved in antitumour immunity, while its role in inflammatory bowel disease (IBD) pathogenesis remains unclear.
    OBJECTIVE: We aimed to investigate the role of GPR171 in modulating CD4+ T cell effector functions in IBD and evaluate its therapeutic potential.
    DESIGN: We analysed GPR171 expression in colon biopsies and peripheral blood samples from patients with IBD and assessed the impact of GPR171 on CD4+ T cell differentiation through administration of its endogenous ligand (BigLEN). We further determined the role of GPR171 in dextran sulfate sodium (DSS)-induced colitis and CD45RBhighCD4+ T-cell transfer colitis model and deciphered the underlying mechanisms using RNA sequencing (RNA-seq) and lipidomics. We developed a novel BigLEN-based Fc fusion protein (BigLEN-Fc) and evaluated its potential in preventing and treating colitis.
    RESULTS: GPR171 was markedly increased in inflamed mucosa and CD4+ T cells of patients with IBD compared with controls. BigLEN-triggered GPR171 activation inhibited Th17 cell differentiation in vitro. GPR171 deficiency exacerbated DSS- and CD45RBhighCD4+ T cell-induced colitis in mice, characterised by increased Th17 cell responses in intestinal mucosa. Mechanistically, GPR171 deficiency promoted Th17 cell differentiation and altered lipidome profile in Th17 cells via the cAMP-pCREB-FABP5 axis. Blockage of FABP5 reduced Th17 cell differentiation in vitro and ameliorated DSS-induced colitis in Gpr171 -/- mice. Furthermore, BigLEN-mutFc administration potently mitigated colitis in mice.
    CONCLUSIONS: GPR171 deficiency promotes Th17 cell differentiation and causes lipid metabolism perturbation, contributing to intestinal inflammation in a FABP5-dependent manner. Target therapy (eg, BigLEN-Fc) represents a novel therapeutic approach for IBD treatment.
    Keywords:  INFLAMMATORY BOWEL DISEASE; INTESTINAL GENE REGULATION; INTESTINAL T CELLS; MUCOSAL IMMUNITY
    DOI:  https://doi.org/10.1136/gutjnl-2024-334010
  24. Phytomedicine. 2025 Mar 07. pii: S0944-7113(25)00260-0. [Epub ahead of print]140 156620
    Mitochondrial dynamics and metabolism in macrophages for cardiovascular disease: A review.
    Yi-Lang Zhong, Chen-Qin Xu, Ji Li, Zhi-Qiang Liang, Miao-Miao Wang, Chao Ma, Cheng-Lin Jia, Yong-Bing Cao, Jian Chen.
       BACKGROUND: Mitochondria regulate macrophage function, affecting cardiovascular diseases like atherosclerosis and heart failure. Their dynamics interact with macrophage cell death mechanisms, including apoptosis and necroptosis.
    PURPOSE: This review explores how mitochondrial dynamics and metabolism influence macrophage inflammation and cell death in CVDs, highlighting therapeutic targets for enhancing macrophage resilience and reducing CVD pathology, while examining molecular pathways and pharmacological agents involved.
    STUDY DESIGN: This is a narrative review that integrates findings from various studies on mitochondrial dynamics and metabolism in macrophages, their interactions with the endoplasmic reticulum (ER) and Golgi apparatus, and their implications for CVDs. The review also considers the potential therapeutic effects of pharmacological agents on these pathways.
    METHODS: The review utilizes a comprehensive literature search to identify relevant studies on mitochondrial dynamics and metabolism in macrophages, their role in CVDs, and the effects of pharmacological agents on these pathways. The selected studies are analyzed and synthesized to provide insights into the complex relationships between mitochondria, the ER, and Golgi apparatus, and their implications for macrophage function and fate.
    RESULTS: The review reveals that mitochondrial metabolism intertwines with cellular architecture and function, particularly through its intricate interactions with the ER and Golgi apparatus. Mitochondrial-associated membranes (MAMs) facilitate Ca2+ transfer from the ER to mitochondria, maintaining mitochondrial homeostasis during ER stress. The Golgi apparatus transports proteins crucial for inflammatory signaling, contributing to immune responses. Inflammation-induced metabolic reprogramming in macrophages, characterized by a shift from oxidative phosphorylation to glycolysis, underscores the multifaceted role of mitochondrial metabolism in regulating immune cell polarization and inflammatory outcomes. Notably, mitochondrial dysfunction, marked by heightened reactive oxygen species generation, fuels inflammatory cascades and promotes cell death, exacerbating CVD pathology. However, pharmacological agents such as Metformin, Nitazoxanide, and Galanin emerge as potential therapeutic modulators of these pathways, offering avenues for mitigating CVD progression.
    CONCLUSION: This review highlights mitochondrial dynamics and metabolism in macrophage inflammation and cell death in CVDs, suggesting therapeutic targets to improve macrophage resilience and reduce pathology, with new pharmacological agents offering treatment opportunities.
    Keywords:  Cardiovascular diseases; Durgs; Macrophages; Mitochondria
    DOI:  https://doi.org/10.1016/j.phymed.2025.156620
  25. J Ethnopharmacol. 2025 Mar 11. pii: S0378-8741(25)00310-1. [Epub ahead of print] 119626
    The Jieduquyuziyin Prescription alleviates systemic lupus erythematosus by modulating B cell metabolic reprogramming via the AMPK/PKM2 signaling pathway.
    Xiaolong Li, Qingmiao Zhu, Zi Yang, Mengyu Zhu, ZhiJun Xie, Yongsheng Fan, Ting Zhao.
       ETHNOPHARMACOLOGICAL RELEVANCE: The Jieduquyuziyin prescription (JP) is an enhanced formula derived from the "Sheng Ma Bie Jia Tang" in the Golden Chamber. JP is an empirical formula approved for use in the treatment of systemic lupus erythematosus (SLE) in hospitals across China, demonstrating notable therapeutic effects. It has been shown to suppress B cell activation and alleviate symptoms; however, its underlying mechanism remains unclear.
    AIM OF THE STUDY: The aim of this study is to investigate the effect of JP on B cell metabolic reprogramming in the treatment of SLE and to elucidate the underlying regulatory mechanisms.
    MATERIALS AND METHODS: Core targets and pathways regulating B cell activation were identified through sequencing of activated and resting B cells from SLE patients and network pharmacology of JP. Targeted metabolomics was employed to assess JP's effect on B cell metabolism. In vivo experiments evaluated the effects of JP, JP combined with a PKM2 inhibitor, or an AMPK inhibitor on SLE activity, B cell activation and glycolysis.
    RESULTS: Bioinformatics analyses identified PKM as a core target in B cell activation, which was significantly upregulated and linked to the inhibition of AMPK signaling. JP reduced B cell glycolysis and activation, leading to significant improvements in disease pathology. The combination of JP with an AMPK inhibitor diminished the therapeutic effect. Further studies suggested that JP inhibits glycolysis-dependent B cell activation via the AMPK/PKM2 pathway, reducing germinal center responses and effector B cells.
    CONCLUSION: This study reveals that the AMPK/PKM2 pathway is a promising therapeutic target for regulating immune metabolic imbalance in SLE B cells. Additionally, it provides evidence that JP may improve SLE by activating the AMPK/PKM2 pathway to inhibit glycolysis-dependent B cell activation, laying the foundation for further investigation of its therapeutic mechanisms.
    Keywords:  B cell activation; Chinese herbal medicine; Metabolic reprogramming; glycolysis; systemic lupus erythematosus
    DOI:  https://doi.org/10.1016/j.jep.2025.119626
  26. Cancer Discov. 2025 Mar 12.
    RORγ bridges cancer-driven lipid dysmetabolism and myeloid immunosuppression.
    Augusto Bleve, Martina Incerti, Francesca Maria Consonni, Valentina Garlatti, Giulia Ballerini, Chiara Pandolfo, Marta Noemi Monari, Simone Serio, Daniela Pistillo, Marina Sironi, Chiara Alì, Marcello Manfredi, Elettra Barberis, Giovanna Finocchiaro, Marco Antonio Cassatella, Cristina Panico, Gianluigi Condorelli, Antonio Sica.
      Despite well-documented metabolic and hematopoietic alterations during tumor development, the mechanisms underlying this crucial immunometabolic intersection remain elusive. Of particular interest is the connection between lipid metabolism and the retinoic-acid-related orphan receptor (RORC1/RORγ), whose transcriptional activity modulates cancer-related emergency myelopoiesis and is boosted by cholesterol metabolites, while hypercholesterolemia itself is associated with dysregulated myelopoiesis. Here, we show that cancer and hypercholesterolemic diet independently or cooperatively activate RORγ-dependent expansion of myeloid-derived suppressor cells (MDSCs) and M2-polarized tumor-associated macrophages (TAMs), supporting cancer spread. Moreover, we report that tumor-induced expression of IL-1b and IL-6 promotes hepatic expression of proprotein convertase subtilisin/kexin type 9 (PCSK9) in preclinical models and patients. Importantly, lowering cholesterol levels, by genetic or pharmacological inhibition of PCSK9, prevents MDSC expansion, M2 TAM accumulation and tumor progression in a RORγ-dependent manner, unleashing specific anti-tumor immunity. Overall, we identify RORγ as a key sensor of lipid disorders, bridging hypercholesterolemia and pro-tumor myelopoiesis.
    DOI:  https://doi.org/10.1158/2159-8290.CD-24-0199
  27. Brain Behav Immun. 2025 Mar 08. pii: S0889-1591(25)00082-0. [Epub ahead of print]
    Inflammation and metabolic dysfunction underly anhedonia-like behavior in antidepressant resistant male rats.
    Roger B Varela, Heather Macpherson, Adam J Walker, Tristan Houghton, Clarissa Yates, Nathanael J Yates, Dara Daygon, Susannah J Tye.
      Inflammation and metabolic dysfunction impair dopamine neurotransmission, which is thought to serve as a critical mechanism underpinning motivational deficits such as anhedonia across a range of psychiatric and neurological disorders. This difficult-to-treat transdiagnostic symptom has important implications for treatment resistant depression (TRD), and may warrant more targeted therapeutic approaches that address the underlying pathophysiological mechanisms. Using the adrenocorticotrophic hormone (ACTH) model of antidepressant treatment resistance we characterized the relationship between antidepressant-like and anhedonia-like behavioral responses to bupropion, mesocortical tyrosine hydroxylase (TH) expression, chronic low-grade inflammation, and metabolic changes in male rats. We demonstrate that chronic ACTH elicited both an antidepressant resistant- and anhedonia-like phenotype in forced swim and effort-related choice behavioral tasks, respectively. This was associated with decreased TH expression in the brain, increased central and peripheral markers of inflammation, and peripheral metabolic disturbances, including impairment of immune cell insulin action. Multivariate analysis revealed that peripheral interleukin-6 (IL-6) levels, immune cell glucose uptake and disturbance of nucleotide metabolism were strongly associated with anhedonia-like behavior. Post-hoc analyses further confirmed strong correlations between TH expression, inflammation and behavioral performance. These data suggest that stress hormone-induced upregulation of inflammation concurrent with the impairment of insulin-mediated glucose uptake into immune cells is associated with disruption of nucleotide metabolism, and potential impaired central dopamine synthesis contributing to the behavioral expression of anhedonia. These results suggest that immunometabolic perturbations concomitant with impaired insulin action at the level of the immune cell result in a metabolically deficient state that directly impacts nucleotide precursors essential for dopamine synthesis and effortful behavior. These results highlight the potential for immune and metabolic markers for individualized treatment of refractory depression and anhedonia.
    Keywords:  Anhedonia; Dopamine; IL-6; Immunometabolism; Inflammation; Treatment-resistant depression
    DOI:  https://doi.org/10.1016/j.bbi.2025.03.001
  28. Int Immunopharmacol. 2025 Mar 13. pii: S1567-5769(25)00398-4. [Epub ahead of print]152 114408
    Dietary succinate supplementation alleviates DSS-induced colitis via the IL-4Rα/Hif-1α Axis.
    Laiying Liang, Buyun Dang, Xiaomei Ouyang, Xianling Zhao, Yongdong Huang, Ying Lin, Xiaoshen Cheng, Guijing Xie, Junhui Lin, Peng Mi, Zhenyu Ye, Bayasi Guleng, Shih-Chin Cheng.
      Inflammatory bowel disease (IBD) remains a pressing global health challenge, necessitating novel therapeutic strategies. Succinate, a metabolite known for its role in type 2 immunity and tuft cell activation in the small intestine, presents its potential in IBD management. However, its impact on colonic inflammation has not been explored. Here, we demonstrate that succinate administration induces a type 2 immune response, significantly alleviating dextran sulfate sodium (DSS)-induced colonic inflammation. Succinate enhances antibacterial capacity, reduces intestinal permeability, and reshapes the colonic cytokine milieu. Mechanistically, succinate promotes myeloid cell expansion in peripheral blood, mesenteric lymph nodes, and the colonic lamina propria. The protective effects of succinate were abolished in Ccr2-/- mice, confirming the role of monocyte recruitment, but persisted in Rag1-/- mice, indicating independence from adaptive immunity. Adoptive transfer of monocytes from succinate-treated donors mitigated intestinal inflammation in recipient mice. Transcriptomic analysis revealed heightened expression of Il1b and Il6, and higher lactate production in monocytes upon lipopolysaccharide (LPS) stimulation, highlighting a reprogrammed pro-inflammatory trained immunity phenotype. Finally, we identify the IL-4Rα/Hif-1α axis is critical for succinate-mediated protection. These findings reveal the ability of succinate to reprogram monocytes into protective intestinal macrophages via induction of type 2 response, restoring homeostasis through enhanced barrier function and immune modulation. Our study positions thus uncover succinate as a promising therapeutic candidate for IBD.
    Keywords:  Colitis; Hif-1α; IL-4; Succinate; Type 2 immunity
    DOI:  https://doi.org/10.1016/j.intimp.2025.114408
  29. Immune Netw. 2025 Feb;25(1): e10
    Aromatic Amino Acid Metabolites: Molecular Messengers Bridging Immune-Microbiota Communication.
    Hyun-Ki Shin, Ye-Ji Bang.
      Aromatic amino acid (AAA) metabolites, derived from tryptophan, phenylalanine, and tyrosine through coordinated host and microbial metabolism, have emerged as critical modulators of immune function. We examine the complex journey of AAAs from dietary intake through intestinal absorption and metabolic transformation, highlighting the crucial role of host-microbe metabolic networks in generating diverse immunomodulatory compounds. This review provides a unique integrative perspective by mapping the molecular mechanisms through which these metabolites orchestrate immune responses. Through detailed analysis of metabolite-receptor and metabolite-transporter interactions, we reveal how specific molecular recognition drives cell type-specific immune responses. Our comprehensive examination of signaling networks-from membrane receptor engagement to nuclear receptor activation to post-translational modifications- demonstrates how the same metabolite can elicit distinct functional outcomes in different immune cell populations. The context-dependent nature of these molecular interactions presents both challenges and opportunities for therapeutic development, particularly in inflammatory conditions where metabolite signaling pathways are dysregulated. Understanding the complexity of these regulatory networks and remaining knowledge gaps is fundamental for advancing metabolite-based therapeutic strategies in immune-mediated disorders.
    Keywords:  Aromatic amino acids; Gut microbiome; Host-microbe interactions; Immunometabolism; Immunomodulation; Molecular mechanisms
    DOI:  https://doi.org/10.4110/in.2025.25.e10
  30. JCI Insight. 2025 Mar 10. pii: e186745. [Epub ahead of print]10(5):
    Metabolic shifts in tryptophan pathways during acute pancreatitis infections.
    Daosheng Wang, Silei Sun, Qianli Zhao, Bing Zhao, Li Ma, Tongxuan Su, Lili Xu, Menglu Gui, Dan Xu, Wei Chen, Yu Zeng, Yining Shen, Yiyue Liu, Cen Jiang, Qi Ni, Yingchao Cui, Yide Lu, Qiuya Lu, Danfeng Dong, Yibing Peng, Enqiang Mao.
      Infectious complications (ICs) in acute pancreatitis (AP) are primarily driven by intestinal bacterial translocation, significantly increasing mortality and hospital stays. Despite this, the role of the gut microenvironment, particularly its metabolic aspects, in AP remains poorly understood. In this study, we investigated a cohort of patients with AP, and conducted supplemental murine studies, to explore the relationship between the gut metabolome and the development of ICs. Metabolomic analysis revealed that disruptions in gut tryptophan metabolism - especially reductions in serotonin and indole pathways - are key features associated with IC occurrence. Additionally, elevated plasma levels of tryptophan metabolites within the kynurenine pathway were identified as valuable predictive biomarkers for ICs. Mechanistic studies in murine models demonstrated that an impaired intestinal Th17 response, modulated by these tryptophan metabolites, plays a critical role in IC development. Serotonin supplementation enhanced Th17 responses, reducing IC incidence, while administration of kynurenic acid, a kynurenine metabolite, exacerbated pancreatic infections, potentially through immunosuppressive effects. These findings highlight the pivotal role of tryptophan metabolites in AP pathogenesis, emphasizing their potential as both predictive markers and therapeutic targets in IC management.
    Keywords:  Amino acid metabolism; Bacterial infections; Diagnostics; Gastroenterology
    DOI:  https://doi.org/10.1172/jci.insight.186745
  31. Immunity. 2025 Mar 11. pii: S1074-7613(25)00075-5. [Epub ahead of print]58(3): 535-554
    Lactate: A key regulator of the immune response.
    Alba Llibre, Salih Kucuk, Atrayee Gope, Michelangelo Certo, Claudio Mauro.
      Lactate, the end product of both anaerobic and aerobic glycolysis in proliferating and growing cells-with the latter process known as the Warburg effect-is historically considered a mere waste product of cell and tissue metabolism. However, research over the past ten years has unveiled multifaceted functions of lactate that critically shape and impact cellular biology. Beyond serving as a fuel source, lactate is now known to influence gene expression through histone modification and to function as a signaling molecule that impacts a wide range of cellular activities. These properties have been particularly studied in the context of both adaptive and innate immune responses. Here, we review the diverse roles of lactate in the regulation of the immune system during homeostasis and disease pathogenesis (including cancer, infection, cardiovascular diseases, and autoimmunity). Furthermore, we describe recently proposed therapeutic interventions for manipulating lactate metabolism in human diseases.
    Keywords:  immune regulation; lactate; lactate sensing; lactate signaling; lactylation
    DOI:  https://doi.org/10.1016/j.immuni.2025.02.008
  32. Cell Rep. 2025 Mar 11. pii: S2211-1247(25)00236-0. [Epub ahead of print]44(3): 115465
    Hexokinase 2-mediated metabolic stress and inflammation burden of liver macrophages via histone lactylation in MASLD.
    Jinyang Li, Xiancheng Chen, Shiyu Song, Wangjie Jiang, Tianjiao Geng, Tiantian Wang, Yan Xu, Yongqiang Zhu, Jun Lu, Yongxiang Xia, Rong Wang.
      
    DOI:  https://doi.org/10.1016/j.celrep.2025.115465
  33. Methods Cell Biol. 2025 ;pii: S0091-679X(24)00016-5. [Epub ahead of print]194 19-42
    Visualizing mitochondrial electron transport chain complexes and super-complexes during infection of human macrophages with Legionella pneumophila.
    Mariatou Dramé, Daniel Schator, Carmen Buchrieser, Pedro Escoll.
      The ultrastructure of mitochondria is pivotal for their respiratory activity. Thus, the regulation of the assembly of the super-complexes (SCs) of the mitochondrial electron transport chain (ETC) might be a core aspect of macrophage immunometabolism during bacterial infection. In order to study the impact of infection by Legionella pneumophila on the configuration of mitochondrial complexes and SCs in human macrophages, we have adapted and combined different methods such as cell sorting of infected cells, magnetic isolation of highly pure and functional mitochondria, quality control of mitochondrial purity by flow cytometry, and BN-PAGE (Blue-Native Polyacrylamide Gel Electrophoresis) coupled to Western Blot using near-infrared (NIR) fluorescence. The here presented protocol uses infected and non-infected human macrophage-like THP-1 cells and GFP-expressing L. pneumophila, but the method can be used to analyze the configuration of ETC complexes and SCs also in other mammalian cells and infected with different intracellular bacteria expressing a fluorescent protein.
    Keywords:  Blue-native PAGE; Electron transport chain; Human macrophages; Legionella pneumophila; Mitochondria; Mitochondria isolation; OXPHOS; Super-complexes; THP-1
    DOI:  https://doi.org/10.1016/bs.mcb.2024.01.003
  34. J Lipid Res. 2025 Mar 12. pii: S0022-2275(25)00036-7. [Epub ahead of print] 100776
    Hexokinase 2 Promotes ISGylation of Acyl-CoA Synthetase Long-chain Family Member 4 in Sepsis-Induced Microglia Cells.
    Guangyang Bai, Shun Ke, Jun Lu, Shanshan Yu, Shusheng Li, Minghao Fang, Jianmin Ling.
      Metabolic reprogramming is often observed in sepsis-associated microglial cells. However, little is known about the aberrant metabolic genes involved in neuroinflammation and lipid accumulation in microglial cells of sepsis-associated encephalopathy (SAE). Here, we show that hexokinase 2 (HK2) is upregulated and strongly associated with the inflammatory response and lipid metabolism in lipopolysaccharide-induced BV2 cells. Downregulation of HK2 lowered the activation of NOD-like receptor signaling family pyrin domain containing 3, both in BV2 cells and in the hippocampus of cecal ligation and puncture-induced male septic mice. Moreover, the inhibition of HK2 promoted lipid droplet reduction. Mechanistically, HK2 knockdown in microglial cells reduced the ISGylation of Acyl-CoA Synthetase Long-chain Family Member 4 (ACSL4) by interferon-stimulated gene 15 (ISG15). Notably, siISG15 effectively down-regulated the expression of ACSL4 in lipopolysaccharide-induced BV2 cells. Our findings provide new mechanistic insights of HK2 in microglial cells through regulation of ACSL4 ISGylation, suggesting a promising therapeutic strategy for treating SAE by targeting HK2.
    Keywords:  Acyl-CoA Synthetase Long-chain Family Member 4; Hexokinase 2; ISG15; ISGylation; Sepsis-Associated Microglial
    DOI:  https://doi.org/10.1016/j.jlr.2025.100776
  35. Immune Netw. 2025 Feb;25(1): e12
    Diverse Functions of Macrophages in Obesity and Metabolic Dysfunction-Associated Steatotic Liver Disease: Bridging Inflammation and Metabolism.
    Jun Hee Jang, Jin Hyun Sung, Jin Young Huh.
      Macrophages play crucial roles in immune response and tissue homeostasis, with their functions becoming increasingly complex in obesity-mediated metabolic disorders. This review explores the extensive range of macrophage activities within adipose and liver tissues, emphasizing their contribution to the pathogenesis and progression of obesity and its related metabolic dysfunction-associated steatotic liver disease (MASLD). In the context of obesity, macrophages respond adaptively to lipid overloads and inflammatory cues in adipose tissue, profoundly influencing insulin resistance and metabolic homeostasis. Concurrently, their role in the liver extends to moderating inflammation and orchestrating fibrotic responses, integral to the development of MASLD. Highlighting the spectrum of macrophage phenotypes across these metabolic landscapes, we summarize their diverse roles in linking inflammatory processes with metabolic functions. This review advocates for a deeper understanding of macrophage subsets in metabolic tissues, proposing targeted research to harness their therapeutic potential in mitigating MASLD and other metabolic disorders.
    Keywords:  Adipose tissue; Liver; Macrophages; Metabolic dysfunction-associated steatotic liver disease; Obesity
    DOI:  https://doi.org/10.4110/in.2025.25.e12
  36. Immunology. 2025 Mar 12.
    Augmenting Macrophages Apoptosis Induced by Carnitine Palmitoyl Transferase 1A Inhibition via Acetyl-CoA-Associated Protein Acetylation.
    Guochao Shi, Rong Wang, Chunrong Huang.
      Macrophage apoptosis contributes to acute lung injury (ALI). However, the relationship between cell metabolism and the apoptosis of macrophages remains unclear. In our study, murine alveolar macrophages (MH-S) were stimulated by lipopolysaccharide (LPS) to induce an apoptosis model; cell viability, mitochondrial membrane potential (MMP) and apoptosis rate were determined. TCA metabolites and fatty acids were measured; qPCR and western blot were used to detect gene and protein expressions. The LPS-induced ALI mice model was established, and pathological changes, inflammatory cytokines, and protein acetylation were evaluated. The results showed that LPS exposure impaired cell viability and increased apoptosis of alveolar macrophages (AM) in a concentration-dependent manner. LPS also downregulated the expression of the FAO rate-limiting enzyme carnitine palmitoyl transferase 1A (CPT1A), which was accompanied by suppression of fatty acid oxidation (FAO) and alterations of the fatty acid profile. CPT1A inhibitor etomoxir also promoted cell apoptosis of AM and decreased MMP. Overexpression of CPT1A ameliorated cell apoptosis of AM induced by LPS. Etomoxir and LPS decreased acetyl-CoA levels, and supplementation of acetyl-CoA prevented LPS-induced cell apoptosis. In addition, LPS led to the alteration of acetylated protein profiles. In vivo study, excessive cell apoptosis, decreased expression of proteins related to FAO, and decreased acetyl-CoA levels were detected in ALI animal models. Acetyl-CoA could relieve the apoptosis and inflammation in the lung induced by LPS. These findings suggested the essential role of CPT1A and acetyl-CoA in cell apoptosis of AM induced by LPS.
    Keywords:  CPT1A; LPS; acetyl‐CoA; apoptosis; fatty acid
    DOI:  https://doi.org/10.1111/imm.13917
  37. FEBS J. 2025 Mar 12.
    Caspase-1/11 controls Zika virus replication in astrocytes by inhibiting glycolytic metabolism.
    Ingrid S de Farias, Guilherme Ribeiro, Isaú H Noronha, Victoria Weise L Lucena, Jean P S Peron, Pedro M Moraes-Vieira, Jose C Alves-Filho, Karina R Bortoluci.
      Zika virus (ZIKV) poses a significant threat due to its association with severe neurological complications, particularly during pregnancy. Although viruses exhibit tropism for neural cells, including astrocytes, the role of these cells in controlling ZIKV replication remains unclear. In this study, we demonstrated that ZIKV induces caspase-1 activation in primary astrocytes despite the absence of classical signs of inflammasome activation. Caspase-1 and caspase-11 double knockout (caspase-1/11-/-) astrocytes exhibit heightened permissiveness to viral replication, accompanied by overactivation of glycolytic metabolism. Inhibition of glycolysis reversed the susceptibility of caspase-1/11-/- astrocytes to ZIKV infection. Protein network analysis revealed mammalian target of rapamycin complex (mTORC) as a link between proteins involved in glycolysis and caspase-1, and mTORC inhibition also suppressed viral replication. Furthermore, we found that the impact of caspase-1/11 on astrocytes depends on the regulation of pyruvate transport to mitochondria for viral replication. Overall, our findings elucidate a caspase-1/11-dependent microbicidal mechanism in astrocytes that involves the mTORC/glycolytic pathway/pyruvate axis, providing insights into potential therapeutic targets for ZIKV infection.
    Keywords:  Zika virus; astrocytes; caspase‐1/11; glycolysis; pyruvate
    DOI:  https://doi.org/10.1111/febs.70061
  38. Nat Metab. 2025 Mar 10.
    Disrupting cholesterol homeostasis in T cells boosts antitumour responses.
    Kelly T Kennewick, Steven J Bensinger.
      
    DOI:  https://doi.org/10.1038/s42255-025-01240-x
  39. Circulation. 2025 Mar 12.
    Myeloid Fatty Acid Metabolism Activates Neighboring Hematopoietic Stem Cells to Promote Heart Failure With Preserved Ejection Fraction.
    Mallory Filipp, Zhi-Dong Ge, Matthew DeBerge, Connor Lantz, Kristofor Glinton, Peng Gao, Sasha Smolgovsky, Jingbo Dai, You-Yang Zhao, Laurent Yvan-Charvet, Pilar Alcaide, Samuel E Weinberg, Gabriele G Schiattarella, Joseph A Hill, Matthew J Feinstein, Sanjiv J Shah, Edward B Thorp.
       BACKGROUND: Despite the high morbidity and mortality of heart failure with preserved ejection fraction (HFpEF), treatment options remain limited. The HFpEF syndrome is associated with a high comorbidity burden, including high prevalence of obesity and hypertension. Although inflammation is implicated to play a key role in HFpEF pathophysiology, underlying causal mechanisms remain unclear.
    METHODS: Comparing patient samples and animal models, we defined the innate immune response during HFpEF in situ and through flow cytometry and single-cell RNA sequencing. After identifying transcriptional and cell signatures, we implemented a high-fat diet and hypertensive model of HFpEF and tested roles for myeloid and hematopoietic stem cells during HFpEF. Contributions of macrophage metabolism were also evaluated, including through mass spectrometry and carbon labeling. Primary macrophages were studied ex vivo to gain insight into complementary cell-intrinsic mechanisms.
    RESULTS: Here we report evidence that patients with cardiometabolic HFpEF exhibit elevated peripheral blood hematopoietic stem cells. This phenotype was conserved across species in a murine mode of high-fat diet and hypertension. Hematopoietic stem cell proliferation was coupled to striking remodeling of the peripheral hematopoietic stem cell niche and expression of the macrophage adhesion molecule Vcam1. This could be partially inhibited by sodium-glucose cotransporter-2 inhibitors and explained by elevated fatty acid metabolism in macrophage mitochondria, which in turn remodeled the Vcam1 promoter to enhance its expression.
    CONCLUSIONS: These findings identify a significant new stem cell signature of cardiometabolic HFpEF and support a role for myeloid maladaptive fatty acid metabolism in the promotion of systemic inflammation and cardiac diastolic dysfunction.
    Keywords:  heart failure; hematopoiesis; inflammation; macrophages; metabolism; stem cells
    DOI:  https://doi.org/10.1161/CIRCULATIONAHA.124.070248
  40. Clin Rev Allergy Immunol. 2025 Mar 13. 68(1): 28
    The Role of Lactate and Lactylation in the Dysregulation of Immune Responses in Psoriasis.
    Xinxin Wu, Changya Liu, Caiyun Zhang, Le Kuai, Sheng Hu, Ning Jia, Jiankun Song, Wencheng Jiang, Qilong Chen, Bin Li.
      Historically, lactate has been considered merely a metabolic byproduct. However, recent studies have revealed that lactate plays a much more dynamic role, acting as an immune signaling molecule that influences cellular communication, through the process of "lactate shuttling." Lactylation, a novel post-translational modification, is directly derived from lactate and represents an emerging mechanism through which lactate exerts its effects on cellular function. It has been shown to directly affect immune cells by modulating the activation of pro-inflammatory and anti-inflammatory pathways. This modification influences the expression of key immune-related genes, thereby impacting immune cell differentiation, cytokine production, and overall immune response. In this review, we focused on the role of lactate and lactylation in the dysregulation of immune responses in psoriasis and its relapse. Additionally, we discuss the potential applications of targeting lactate metabolism and lactylation modifications in the treatment of psoriasis, alongside the investigation of artificial intelligence applications in advancing lactate and lactylation-focused drug development, identifying therapeutic targets, and enabling personalized medical decision-making. The significance of this review lies in its comprehensive exploration of how lactate and lactylation contribute to immune dysregulation, offering a novel perspective for understanding the metabolic and epigenetic changes associated with psoriasis. By identifying the roles of these pathways in modulating immune responses, this review provides a foundation for the development of new therapeutic strategies that target these mechanisms.
    Keywords:  Lactate; Lactylation; Psoriasis
    DOI:  https://doi.org/10.1007/s12016-025-09037-2
  41. J Immunol. 2025 Feb 28. pii: vkae054. [Epub ahead of print]
    CD3+ T-cell: CD14+ monocyte complexes are dynamic and increased with HIV and glucose intolerance.
    Laventa M Obare, Joshua Simmons, Jared Oakes, Xiuqi Zhang, Cindy Nochowicz, Stephen Priest, Samuel S Bailin, Christian M Warren, Mona Mashayekhi, Heather K Beasley, Jianqiang Shao, Leslie M Meenderink, Quanhu Sheng, Joey Stolze, Rama Gangula, Tarek Absi, Yan Ru Su, Kit Neikirk, Abha Chopra, Curtis L Gabriel, Tecla Temu, Suman Pakala, Erin M Wilfong, Sara Gianella, Elizabeth J Phillips, David G Harrison, Antentor Hinton, Spyros A Kalams, Annet Kirabo, Simon A Mallal, John R Koethe, Celestine N Wanjalla.
      Persistent systemic inflammation is associated with an elevated risk of cardiometabolic diseases. However, the characteristics of the innate and adaptive immune systems in individuals who develop these conditions remain poorly defined. Doublets, or cell-cell complexes, are routinely eliminated from flow cytometric and other immune phenotyping analyses, which limits our understanding of their relationship to disease states. Using well-characterized clinical cohorts, including participants with controlled human immunodeficiency virus (HIV) as a model for chronic inflammation and increased immune cell interactions, we show that circulating CD14+ monocytes complexed to CD3+ T cells are dynamic, biologically relevant, and increased in individuals with diabetes after adjusting for confounding factors. The complexes form functional immune synapses with increased expression of proinflammatory cytokines and greater glucose utilization. Furthermore, in persons with HIV, the CD3+ T cell: CD14+ monocyte complexes had more HIV copies compared to matched CD14+ monocytes or CD4+ T cells alone. Our results demonstrate that circulating CD3+ T-cell: CD14+ monocyte pairs represent dynamic cellular interactions that may contribute to inflammation and cardiometabolic disease pathogenesis. CD3+ T-cell: CD14+ monocyte complexes may originate or be maintained, in part, by chronic viral infections. These findings provide a foundation for future studies investigating mechanisms linking T cell-monocyte cell-cell complexes to developing immune-mediated diseases, including HIV and diabetes.
    Keywords:  CD3+; HIV; T-cell: CD14+; diabetes; doublets; monocyte complexes; reservoir
    DOI:  https://doi.org/10.1093/jimmun/vkae054
  42. J Nanobiotechnology. 2025 Mar 11. 23(1): 201
    Mesenchymal stem cell-derived extracellular vesicles alleviate autism by regulating microglial glucose metabolism reprogramming and neuroinflammation through PD-1/PD-L1 interaction.
    Qian Qin, Linlin Fan, Xin Zeng, Danyang Zheng, Han Wang, Mengyue Li, Yutong Jiang, Hui Wang, Hao Liu, Shengjun Liang, Lijie Wu, Shuang Liang.
      Neuroinflammation triggered by microglia activation is hallmark of autism spectrum disorder (ASD), and this process includes crucial metabolic reprogramming from oxidative phosphorylation to glycolysis, which may cause neuron loss and functional impairment. The inhibitory immune checkpoint programmed cell death protein 1 (PD-1) on immune cells is an important target for tumor immunotherapy. However, the immunomodulatory effects of PD-1 in ASD remains to be elusive. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) exhibit immunomodulatory capabilities in a range of neurological diseases. Our findings indicated the expression of PD-L1 on MSC-EVs, potentially facilitating signaling to PD-1-expressing microglia. Here, we showed how MSC-EVs activated of PD-L1/PD-1 axis and ameliorated glycolysis, neuroinflammation and autism-like behaviors. After first detecting elevated glycolysis and neuroinflammation in prefrontal cortex (PFC) tissue from the maternal immune activation (MIA) mice, we also demonstrated that PD-1 expression level was upregulated in microglia. Following given MSC-EVs carried PD-L1 into adult MIA offspring mice via intranasal administration, which bound with PD-1 on microglia and then the autism-like behaviors were alleviated as well. Further experiments verified that MSC-EVs could decreased the level of glycolysis and neuroinflammation by PD-1/ERK/HIF-1α pathway in the primary microglia in PFC of MIA offspring mice. Pharmacological blockade and genetic inhibition of PD-1 could weaken the effect of MSC-EVs and aggravate microglial dysfunction, glycolysis and autism-like behaviors in MIA offspring mice. Futhermore, PD-L1 deficient weakened the effect of MSC-EVs on neuroinflammation, glycolysis and autism-like behaviors in MIA offspring mice. Our research indicated the significant immunomodulatory capabilities of MSC-EVs, which play an important role in reprogramming microglial glucose metabolism and suppressing neuroinflammation in ASD. By activating the PD-L1/PD-1 axis and inhibiting the downstream ERK/HIF-1α pathway, MSC-EVs were found to alleviate autism-like behaviors, which revealing a novel pathological mechanism and offering promising therapeutic insights into ASD.
    Keywords:  Autism spectrum disorder; Glycolysis; MSC-EVs; Neuroinflammation; PD-L1/PD-1
    DOI:  https://doi.org/10.1186/s12951-025-03250-z
  43. J Biol Chem. 2025 Mar 06. pii: S0021-9258(25)00238-8. [Epub ahead of print] 108389
    The glycolytic enzyme PKM2 regulates inflammatory osteoclastogenesis by modulating STAT3 phosphorylation.
    Mingjuan Li, Feng Li, Chongjie Zhu, Chi Zhang, Yushi Le, Zubing Li, Qilong Wan.
      Periodontitis is a prevalent chronic inflammatory disease characterized by alveolar bone resorption mediated by osteoclasts. Pyruvate kinase M2 (PKM2), a key enzyme in glycolysis and pyruvate metabolism, has recently been recognized for its regulatory roles beyond metabolism, including gene expression and protein kinase activity. However, its exact role in osteoclastogenesis remains unclear. This study investigates the function of PKM2 in inflammatory osteoclastogenesis and explores its potential as a therapeutic target for periodontitis. Using murine bone marrow-derived macrophages (BMMs) stimulated with lipopolysaccharides (LPS) to mimic inflammatory conditions in vitro, we analyzed PKM2 expression and glycolytic activity during osteoclastogenesis through bioinformatics, tartrate-resistant acid phosphatase (TRAP) staining, phalloidin staining, quantitative real-time PCR (RT-qPCR), and Western blotting. Glycolysis was inhibited using 2-deoxy-D-glucose (2-DG), while TEPP-46 was used to activate PKM2. In a mouse model of periodontitis, the effects of TEPP-46 on alveolar bone loss were evaluated using micro-computed tomography, immunohistochemistry, TRAP staining, and hematoxylin-eosin (HE) staining. The results demonstrated that LPS significantly enhanced osteoclastogenesis and glycolysis, increasing PKM2 expression in osteoclasts. Inhibiting glycolysis with 2-DG suppressed osteoclast formation and osteoclast-related gene expression under inflammatory conditions. TEPP-46 treatment reduced nuclear dimeric PKM2 levels, decreased phosphorylated signal transducer and activator of transcription 3 (p-STAT3) expression, and inhibited osteoclastogenesis and osteoclast-related gene expression. Co-immunoprecipitation confirmed an interaction between nuclear dimeric PKM2 and p-STAT3. In vivo, TEPP-46 effectively reduced alveolar bone loss by preventing PKM2 nuclear translocation and STAT3 phosphorylation. These findings reveal that PKM2 regulates inflammatory osteoclastogenesis through modulation of glycolysis and STAT3 signaling, highlighting its potential as a therapeutic target for periodontitis.
    Keywords:  Glycolysis; Inflammation; M2 Type Pyruvate Kinase; Osteoclasts; Periodontitis; p-STAT3
    DOI:  https://doi.org/10.1016/j.jbc.2025.108389
  44. Cell Rep. 2025 Mar 12. pii: S2211-1247(25)00180-9. [Epub ahead of print]44(3): 115409
    Microglia mediate the early-life programming of adult glucose control.
    Martin Valdearcos, Emily R McGrath, Stephen M Brown Mayfield, Melissa G Jacuinde, Andrew Folick, Rachel T Cheang, Ruoyu Li, Tomas P Bachor, Rachel N Lippert, Allison W Xu, Suneil K Koliwad.
      Glucose homeostasis is, in part, nutritionally programmed during early neonatal life, a critical window for synapse formation between hypothalamic glucoregulatory centers. Although microglia prune synapses throughout the brain, their role in refining hypothalamic glucoregulatory circuits remains unclear. Here, we show that the phagocytic activity of microglia in the mediobasal hypothalamus (MBH) is induced following birth, regresses upon weaning from maternal milk, and is exacerbated by feeding dams a high-fat diet while lactating. In addition to actively engulfing synapses, microglia are critical for refining perineuronal nets (PNNs) within the neonatal MBH. Remarkably, transiently depleting microglia before weaning (postnatal day [P]6-16) but not afterward (P21-31) induces glucose intolerance in adulthood due to impaired insulin responsiveness, which we link to PNN overabundance and reduced synaptic connectivity between hypothalamic glucoregulatory neurons and the pancreatic β cell compartment. Thus, microglia facilitate early-life synaptic plasticity in the MBH, including PNN refinement, to program hypothalamic circuits regulating adult glucose homeostasis.
    Keywords:  CP: Metabolism; CP: Neuroscience; glucose homeostasis; hypothalamus; insulin; metabolic programming; microglia; neonatal; perineuronal nets; synaptic plasticity
    DOI:  https://doi.org/10.1016/j.celrep.2025.115409
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