bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2026–05–03
fifty-one papers selected by
Dylan Gerard Ryan, Trinity College Dublin
  1. Macronutrient availability and immune cell responses.
  2. Mesenchymal Stromal Cells in Immunometabolic Regulation: A Review of Itaconate-Mediated Mechanisms.
  3. Glycolytic reprogramming and immune responses in macrophages: a crosstalk driven by bacterial infection.
  4. Metabolic reprogramming of Th17/Treg imbalance in autoimmune thyroid diseases.
  5. Phospho-enol pyruvate carboxykinase inhibition limits effector function in inflammatory T cells.
  6. Citraconate preserves T cell stemness and antitumor immunity.
  7. HCMV infection depends on EGLN1-mediated mitochondrial activation to increase dNTP pools for viral DNA replication.
  8. Single-cell analysis identifies CPT1a-associated metabolic remodeling in human NK cells during COVID-19.
  9. Chac1 deficiency confers sepsis resistance by enriching gut microbiota-derived indole-3-carboxylic acid to drive macrophage metabolic shifts.
  10. Postprandial lipid metabolism durably enhances T cell immunity.
  11. An anaerobic pathogen rewires host metabolism to fuel oxidative growth in the inflamed gut.
  12. Dynamic metabolic programming of monocyte-derived cells defines immunity in CNS disease.
  13. Argininosuccinate synthase 1 (ASS1) orchestrates arginine metabolism and ornithine production to modulate CHIKV infection.
  14. Metabolic and transcriptional plasticity supports CD8+ T cell resilience and anti-tumor immunity under nutrient stress.
  15. d-amino acids restrain macrophage IL-1β release through gasdermin D acetylation.
  16. Deficiency of microRNA-10a in CD4+ T cells protects against intestinal infection through mitochondrial oxidation-IL-22 pathway.
  17. Multi-omic analysis reveals nitric oxide dependent remodeling in classically activated macrophages and identifies negative regulation mediated by AKR1A1.
  18. 4-Octyl itaconate blocks STAT3-induced ACE2 expression to reduce uptake of SARS-CoV-2.
  19. Lactate conditioning reprograms mucosal-associated invariant T cell metabolism boosting effector function.
  20. Monocyte Metabolic Plasticity and Cytokine Production Differentiate Latent TB Infection from Active Disease.
  21. Investigating Glycolysis in Primary Microglia Using Extracellular Flux Assay.
  22. Hepatitis C Virus (HCV)-Mediated Activation of Hexokinase Domain-Containing Protein 1 (HKDC1) Promotes Hexokinase Activity and Metabolic Reprogramming.
  23. Loss of immunometabolic adaptability in MASH: gut-derived signals drive macrophage reprogramming and fibrosis.
  24. CD177 Promotes NLR Inflammasome Activation in Acute Respiratory Distress Syndrome by Remodeling Neutrophil Glycolytic Metabolism.
  25. Reactive oxygen species and metabolic checkpoints shape plasmacytoid dendritic cell fate in infection and autoimmunity.
  26. Targeting serine metabolism boosts antimycobacterial immunity during Mycobacterium tuberculosis H37Rv Infection.
  27. The immunoregulatory effect of short-chain fatty acids in type 2 diabetes mellitus.
  28. Untargeted metabolomics reveals bovine viral diarrhea virus infection reprogram host nucleotide and amino acid metabolism in MDBK Cells.
  29. Exercise-induced musclin enhances efferocytosis via metabolic reprogramming to alleviate periprosthetic joint infection.
  30. Lp-PLA2-derived LysoPC drives dendritic cell immunogenic activation and Th17 inflammation in severe asthma.
  31. Therapeutic potential of regulating microglial Glut1 in modulating brain glucose metabolism and neuroinflammation in postoperative delirium.
  32. Mitochondrial Proteomics Uncovers that Myeloid S100A9 Deficiency Promotes Liver Injury and Fibrosis Regression via Mitochondrial Metabolic Reprogramming of Macrophages.
  33. A microbiota-derived bile acid overcomes antibiotic-induced hyporesponsiveness to immune checkpoint therapy by enhancing CD8 + T cell antitumor immunity.
  34. JMJD6-mediated epigenetic silencing of innate immunity promotes pseudorabies virus replication.
  35. Inactivated Klebsiella pneumoniae Induces Metabolic and Hematopoietic Reprogramming to Promote Trained Immunity and Heterologous Antibacterial Protection.
  36. NAD+ augmentation by nicotinamide riboside engages SLIT2/ROBO1 signaling to attenuate Th17 inflammation in psoriasis.
  37. Cytochrome P450 1B1 directs pathogenic Th17 cell generation and autoimmune disease by fine-tuning redox homeostasis and mitochondrial integrity.
  38. Targeted regulation of adipose tissue macrophages from an immunometabolic perspective: a novel therapeutic approach for obesity-related metabolic disorders.
  39. BACH2 controls ILC3 function via PPARγ-dependent mitochondrial metabolism.
  40. Extracellular vesicles inherit lactate from aggregated MSCs to alleviate type 1 diabetes mellitus via H2S-induced CD8+ T cell exhaustion.
  41. SCD2 Alleviates Diabetes-Associated Cognitive Dysfunction by Improving Microglial Lipid Metabolism.
  42. FABP4 Couples Lipid Metabolism to PD-L1 Stabilization in Immunosuppressive Macrophages.
  43. Vincamine attenuates alcoholic liver injury through modulation of a CDK1-glycolysis-NLRP3 immunometabolic axis.
  44. mTORC2 regulates lipid metabolism-driven TAMs via the PPAR-γ/CD36 pathway to promote liposarcoma progression.
  45. Natural killer cell dysregulation in polycystic ovary syndrome: immunometabolic and reproductive implication.
  46. Ketone body metabolism activates the immune response against Staphylococcus aureus infection by fueling the tricarboxylic acid cycle and affecting histone β-hydroxybutyrylation.
  47. Angelica sinensis polysaccharides modulate iron metabolism and macrophage polarization to alleviate rheumatoid arthritis.
  48. Gut-derived metabolic reprogramming drives immune aging and tissue degeneration.
  49. Vancomycin disrupts mitochondrial morphology and function and impairs macrophage fungal killing.
  50. ADAR1 Controls Macrophage Scavenging and Lipid-Buffering Programs in Metabolic Tissues.
  51. Kynurenine-AhR-SLC39A10-Zn2+ signaling reprograms macrophages and enhances pirfenidone efficacy in pulmonary fibrosis.
  1. Semin Immunol. 2026 Apr 27. pii: S1044-5323(26)00014-X. [Epub ahead of print]82 102027
    Macronutrient availability and immune cell responses.
    Paulo Estevão, Ana Júlia Estumano Martins, Pedro M Moraes-Vieira.
      Nutritional status and dietary composition profoundly influence immune responses, with carbohydrates, lipids, and proteins, acting as key regulators of immune cell metabolism, activation, and function. This review synthesizes current evidence on how these macronutrients shape the behavior of innate and adaptive immune cells, including monocytes, macrophages, dendritic cells, neutrophils, T cells, and B cells. We discuss how glucose and fructose differentially modulate inflammatory pathways, trained immunity, and antiviral responses; how saturated and polyunsaturated fatty acids affect immune cell signaling and cytokine production; and how amino acid availability influences metabolic reprogramming, polarization, and effector functions. Emerging findings highlight the complex, context-dependent roles of macronutrients in health and disease, revealing their potential as dietary targets in immune-mediated conditions. Understanding these interactions provides a foundation for nutritional strategies aimed at modulating immunity in metabolic, infectious, and inflammatory diseases.
    Keywords:  Inflammation, immunometabolism, immune cells; Macrophages; Metabolism; Nutrient sensing, fatty acids; Nutrients
    DOI:  https://doi.org/10.1016/j.smim.2026.102027
  2. Stem Cell Rev Rep. 2026 May 01.
    Mesenchymal Stromal Cells in Immunometabolic Regulation: A Review of Itaconate-Mediated Mechanisms.
    Rosana Lopes Rodrigues Amon, Giulia Toscano Giannini, Sumara de Freitas, Ricardo Ambrósio Fock.
      Immunometabolism has emerged as a central regulator of immune responses, linking cellular metabolism to inflammatory signaling and tissue homeostasis. Among tricarboxylic acid (TCA) cycle-derived metabolites, itaconate has gained recognition as an important metabolic feedback regulator promoting inflammatory resolution. Mesenchymal stromal/stem cells (MSCs) are multipotent cells widely recognized for their immunomodulatory and regenerative properties, primarily mediated through paracrine signaling and metabolic adaptation. Increasing evidence indicates that MSC immunoregulatory function is closely associated with metabolic reprogramming involving glycolysis, mitochondrial activity, lipid metabolism, and amino acid pathways. Within this context, itaconate has emerged as a potential metabolic interface linking innate immune activation to MSC function. This narrative review summarizes current evidence supporting both direct and indirect interactions between itaconate signaling and MSC biology. Itaconate and its derivatives influence MSC viability, apoptosis resistance, differentiation potential, and redox balance, while indirectly modulating macrophage polarization and inflammatory microenvironment remodeling through extracellular vesicles and paracrine communication. Despite these advances, critical questions remain regarding endogenous itaconate production by MSCs and its effects on MSC secretome composition and immunoregulatory activity. A deeper understanding of the itaconate-MSC axis may enable metabolic preconditioning strategies aimed at enhancing MSC-based therapies for inflammatory and immune-mediated diseases.
    Keywords:  Immunometabolism; Inflammation; Itaconate; Macrophage; Mesenchymal stromal cells
    DOI:  https://doi.org/10.1007/s12015-026-11142-4
  3. Front Immunol. 2026 ;17 1783266
    Glycolytic reprogramming and immune responses in macrophages: a crosstalk driven by bacterial infection.
    Wei-Ren Wang, Lin Yan, Chuan-Ying Zhao, Cong-Cong He, Xing-Hua Gao.
      Macrophage glycolytic reprogramming during bacterial infection is a recognized metabolic shift with profound yet incompletely defined immunological consequences. This review delineates how this metabolic remodeling extends beyond energy provision to function as an integral immunoregulatory platform. We systematically examine the dual roles of key metabolic components, including the conformational dynamics of pyruvate kinase M2 that couple metabolic flux with inflammatory gene transcription, and the NAD+/NADH ratio that balances inflammasome activation against interferon responses. The review further explores how metabolites like lactate, succinate, and itaconate mediate immunomodulation through novel post-translational modifications, including histone lactylation and protein succinylation. Crucially, we analyze how diverse bacterial pathogens such as Salmonella and Mycobacterium tuberculosis exploit these metabolic networks for immune evasion. By integrating recent advances in host immunometabolism with bacterial pathogenesis, this work not only deciphers critical molecular dialogues at the host-pathogen interface but also identifies novel targetable pathways, offering a conceptual framework for developing innovative therapeutic strategies against persistent and antibiotic-resistant infections.
    Keywords:  bacterial infection; glycolytic reprogramming; immunometabolism; macrophage polarization; metabolic signaling
    DOI:  https://doi.org/10.3389/fimmu.2026.1783266
  4. Cell Commun Signal. 2026 Apr 29.
    Metabolic reprogramming of Th17/Treg imbalance in autoimmune thyroid diseases.
    Mengli Zhou, Weijie Wu, Yingzhao Liu, Shengjun Wang, Huiyong Peng.
      Autoimmune thyroid diseases (AITDs), including Hashimoto's thyroiditis and Graves' disease, arise from thyroid-specific autoimmunity driven by a breakdown of immune tolerance and dysregulated T-cell responses. Within this immune network, imbalance between T helper 17 (Th17) cells and regulatory T (Treg) cells has emerged as a major determinant of persistent inflammation and defective immune restraint. These two subsets are supported by distinct but interconnected metabolic programs. Th17 cells preferentially engage glycolytic and anabolic pathways to sustain inflammatory activity, whereas Treg cells rely more strongly on oxidative metabolism and mitochondrial fitness to preserve lineage stability and suppressive function. In AITDs, these intracellular programs are further reshaped by disease-associated microenvironmental cues, including excess iodine, oxidative stress, lactate accumulation, inflammatory cytokines, and tissue-derived stromal signals. This review summarizes how glucose, lipid, mitochondrial, and amino acid metabolism collectively regulate Th17 and Treg differentiation and function. We further examine how these pathways are altered in AITDs and distorted in thyroid and orbital tissues to amplify immune disequilibrium. Finally, we discuss emerging therapeutic strategies aimed at targeting immune metabolic circuits to restore immune homeostasis.
    Keywords:  Autoimmune thyroid diseases; Immunometabolism; Metabolic reprogramming; Regulatory T cells; T helper 17 cells
    DOI:  https://doi.org/10.1186/s12964-026-02915-y
  5. Front Immunol. 2026 ;17 1706167
    Phospho-enol pyruvate carboxykinase inhibition limits effector function in inflammatory T cells.
    Rebecca J Brownlie, Helen Carrasco Hope, David Wright, Graham P Cook, José C Perales, Robert J Salmond.
       Introduction: Following antigenic stimulation, T cells switch from a catabolic metabolic state maintained by low levels of nutrient uptake to an anabolic metabolism that sustains the biosynthetic and energetic demands of clonal expansion, differentiation, and effector function. Much progress has been made in understanding the transcriptional and enzymatic regulation of activated T cell metabolism. However, less is understood of the role for regulators of anaplerosis and cataplerosis such as phospho-enol pyruvate carboxykinases (PEPCK) in T cells.
    Methods: Assessment of PEPCK expression in mouse T cells was performed. Pharmacological inhibitors were used to assess functional and metabolic roles for PEPCKs in T cell activation.
    Results: We show that mitochondrial PEPCK (PEPCK-M) is upregulated following T cell activation, while cytosolic PEPCK-C was not detected. The PEPCK inhibitors limited CD8+ T cell cytotoxic capacity and both CD4+ and CD8+ T cell inflammatory cytokine production. The suppression of T cell effector functions by PEPCK inhibitors was associated with decreased maximal mitochondrial respiration.
    Discussion: These data suggest that PEPCKs act to modulate mitochondrial metabolism, supporting effector function in T cells.
    Keywords:  PEPCK; T cell; T cell activation; immunometabolism; phospho-enol pyruvate carboxykinases
    DOI:  https://doi.org/10.3389/fimmu.2026.1706167
  6. Sci Immunol. 2026 May;11(119): eadz0348
    Citraconate preserves T cell stemness and antitumor immunity.
    Wenhui Li, Minmin Ge, Ziyi Luo, Minju Ni, Kexin Tang, Chenfeng Han, Jiajia Wang, Yifu Ma, Xiaowei Liu, Kaili Ma, Jingxing Yang, Wenjing Li, Cangang Zhang, Qitai Zhao, Guangcan Shao, Jaeoh Park, Yi Zhang, Yonghong Wan, Baojun Zhang, Gang Wang, Mingjing Shen, Qiang Shan, Feng Guo, Ping-Chih Ho, Liyuan Zhang, Lianjun Zhang.
      Metabolic perturbations in the tumor microenvironment profoundly compromise the stemlike properties and effector functions of CD8 T cells. Deciphering the metabolic circuitry that sustains T cell stemness is critical for reinvigorating tumor-infiltrating lymphocytes and augmenting immunotherapeutic efficacy. Here, we identify citraconate, an itaconate isomer, as a metabolite markedly depleted in CD8 T cells subjected to chronic antigen stimulation or hypoxic conditions. Citraconate supplementation preserves stemlike characteristics, attenuates ferroptosis, and potentiates T cell-mediated antitumor immunity. Mechanistically, citraconate maintains intracellular cyclic adenosine monophosphate (cAMP) concentrations by suppressing phosphodiesterase1A/C (PDE1A/C) expression and preserving mitochondrial integrity, thereby activating protein kinase A (PKA) signaling. This activation transcriptionally represses arachidonate-5-lipoxygenase (ALOX5), consequently reducing arachidonic acid peroxidation. Clinically, diminished ALOX5 or PDE1A expression correlates with reduced T cell exhaustion and improved responses to immune checkpoint blockade (ICB) therapy. Our findings reveal the citraconate-mediated PDE1-cAMP-ALOX5 axis as a potential therapeutic target for enhancing cancer immunotherapy.
    DOI:  https://doi.org/10.1126/sciimmunol.adz0348
  7. Cell Rep. 2026 Apr 29. pii: S2211-1247(26)00407-9. [Epub ahead of print]45(5): 117329
    HCMV infection depends on EGLN1-mediated mitochondrial activation to increase dNTP pools for viral DNA replication.
    Lucas A Simpson, Diana M Dunn, Wyatt Fales, Zachary J Moore, Jessica H Ciesla, Nicole C Waild, Matthew H Raymonda, Isaac S Harris, Joshua Munger.
      Human cytomegalovirus (HCMV) is a leading cause of congenital infection and morbidity in immunosuppressed populations. Like all viruses, HCMV is an obligate intracellular parasite that extensively remodels host cell metabolism to support its replication, yet the precise underlying mechanisms and the potentially associated metabolic vulnerabilities remain poorly understood. Using a metabolism-focused screening platform, we identify EGLN prolyl hydroxylase activity as critical for HCMV infection. Our studies reveal that HCMV infection depends on EGLN1, which accumulates in mitochondria during infection. Inhibition of EGLN1 expression blocks HCMV-mediated mitochondrial activation, which in turn prevents the production of the deoxynucleoside triphosphate (dNTP) precursors necessary for dNTP pool expansion and viral DNA replication. Further, pharmacological EGLN inhibition attenuates viral infection in a humanized mouse model. Collectively, these data establish EGLN1 as a critical determinant of mitochondrial metabolic remodeling and virally-induced dNTP generation during HCMV infection, highlighting EGLN1 as a promising antiviral therapeutic target.
    Keywords:  CP: Metabolism; CP: Microbiology; EGLN; HCMV; HIF PHD; TCA cycle; adaptaquin; cytomegalovirus; metabolism; mitochondria
    DOI:  https://doi.org/10.1016/j.celrep.2026.117329
  8. J Immunol. 2026 Apr 15. pii: vkag036. [Epub ahead of print]215(4):
    Single-cell analysis identifies CPT1a-associated metabolic remodeling in human NK cells during COVID-19.
    Sarah Benezech, Louis Picq, Marine Villard, Noémi Rousseaux, Ameline Hamond, Omran Allatif, Antonin Bal, Alexandre Belot, Sophie Trouillet-Assant, Antoine Marçais, Thierry Walzer.
      Natural killer (NK) cells are critical for early antiviral immunity, yet their metabolic regulation during acute human viral infection remains incompletely understood. We analyzed NK cell activation and metabolic reprogramming in 47 vaccinated individuals with mild breakthrough SARS-CoV-2 infection and 20 matched healthy control subjects. COVID-19 patients exhibited elevated plasma interferon α and NK cell activation markers (CD69, CD38), alongside increased basal STAT5 phosphorylation, consistent with IL-15-mediated signaling. Functionally, NK cells from infected subjects displayed heightened cytotoxicity. Metabolic profiling at the single-cell level revealed increased cell size, translational activity, amino acid and glucose uptake, and mitochondrial membrane potential, indicating a globally activated metabolic state specific to NK cells. Using newly developed spectral cytometry panels targeting metabolic regulators, we identified CPT1a as the most discriminative marker between patient and control NK cells, with elevated expression in both CD56bright and CD56dim subsets. CPT1a levels correlated with CD38 expression and with uptake of the fluorescent palmitate analog BODIPY-FL C16, reflecting enhanced long-chain fatty acid oxidation. These changes were absent in B and T lymphocytes. Our findings support that during SARS-CoV-2 infection, human NK cells undergo coordinated cytokine-driven activation and metabolic remodeling, integrating glycolysis and lipid oxidation to support amplified effector function.
    Keywords:  NK cells; bioenergetic metabolism; cytokine-mediated activation; human; natural killer cells; viral infection
    DOI:  https://doi.org/10.1093/jimmun/vkag036
  9. J Adv Res. 2026 Apr 26. pii: S2090-1232(26)00368-1. [Epub ahead of print]
    Chac1 deficiency confers sepsis resistance by enriching gut microbiota-derived indole-3-carboxylic acid to drive macrophage metabolic shifts.
    Jing-Juan Hu, Si-Yuan Feng, Ling Wu, Shi-Ying He, Xiao-Feng Chen, Ge-Hui Li, Yue Min, Hong-Ling Xu, Qi-Shun Sun, Sun Xie, Jian-Liu, Feng Chen, Ke-Xuan Liu, Fan Deng.
       INTRODUCTION: Sepsis is a life-threatening dysregulated host response to infection, lacks effective therapies. ChaC glutathione-specific γ-glutamylcyclotransferase 1 (CHAC1) is elevated in sepsis and correlates with severity, but its functional role in the pathogenesis of sepsis-induced organ damage is unclear.
    OBJECTIVES: We aimed to define the contribution of CHAC1 to sepsis-induced organ injury and elucidate the underlying mechanisms involving gut microbiota-derived metabolites and host immunity.
    METHODS: Chac1-/- mice were subjected to LPS-induced endotoxemia to evaluate organ injury. The gut microbiota's role was defined by 16S rRNA gene sequencing, microbiota depletion and fecal microbiota transplantation (FMT). The effect of microbiota-derived metabolite indole-3-carboxylic acid (ICA) was assessed in vivo. Underlying mechanisms were investigated via macrophage depletion, AHR pharmacological/genetic inhibition, and in vitro studies with RAW264.7 cells and bone marrow-derived macrophages.
    RESULTS: Serum CHAC1 was elevated in septic patients and mice, correlating with disease severity. Chac1 deficiency protected against sepsis-induced multi-organ injury, an effect that was gut microbiota-dependent. Chac1-/- mice exhibited a remodeled gut microbiota, with enrichment of Akkermansia muciniphila and increased levels of the tryptophan metabolite ICA. Exogenous ICA or A. muciniphila supplementation recapitulated the protective phenotype. ICA treatment improved survival, attenuated inflammation, and reduced organ injury by activating the aryl hydrocarbon receptor (AHR) in macrophages. This was evidenced by AHR nuclear translocation, and siRNA-mediated AHR knockdown abolished ICA's effects. ICA reprogrammed macrophage metabolism, inhibiting glycolysis (reduced lactate) and enhancing oxidative phosphorylation (increased ATP, oxygen consumption rate), leading to suppressed pro-inflammatory responses.
    CONCLUSION: Chac1 deficiency confers sepsis resistance by enriching protective gut microbiota and elevating ICA, which acts as a major downstream effector. ICA activates the AHR in macrophages, driving a metabolic shift from glycolysis to oxidative phosphorylation that dampens inflammation and organ injury. This CHAC1-microbiota-ICA-AHR-macrophage axis identifies ICA as a promising therapeutic candidate and CHAC1 as a potential prognostic biomarker for sepsis.
    Keywords:  CHAC1; Indole-3-carboxylic acid; Macrophage; Metabolic reprogramming; Sepsis
    DOI:  https://doi.org/10.1016/j.jare.2026.04.065
  10. Nature. 2026 Apr 29.
    Postprandial lipid metabolism durably enhances T cell immunity.
    Alok Kumar, Dayana B Rivadeneira, Isha Mehta, Bingxian Xie, Rachel Cumberland, Supriya K Joshi, Jitendra S Kanshana, William G Gunn, Victoria Dean, Angelina Parise, Kristin Morder, Erica S Myers, Steven J Mullett, Richard T Cattley, Stacy L Gelhaus, Abigail E Overacre-Delgoffe, Jishnu Das, William F Hawse, Alison B Kohan, Greg M Delgoffe.
      Although intrinsic metabolic pathways have critical roles in T cell function1,2, systemic nutrient availability is in constant flux. Yet, how postprandial metabolism affects T cell fate has been less studied. Here we show that the short-term nutritional state of an individual has marked effects on T cell immunity. Human or murine T cells from fed hosts had higher metabolic capacity than those from fasted hosts, and this increase in capacity persisted after activation and expansion in vitro or in vivo. Triglyceride-rich chylomicrons in serum were drivers of postprandial immunometabolic reprogramming, and chylomicrons primed mTORC1-dependent translation ex vivo and after activation, which markedly enhanced effector function after priming. Human postprandial CAR-T cells manufactured from the same donor showed a therapeutic advantage over T cells collected while individuals were fasted. Thus, postprandial metabolism imparts durable metabolic and functional advantages to T cells, highlighting the importance of considering nutritional status in immunological analysis, vaccination and generation of cellular therapies.
    DOI:  https://doi.org/10.1038/s41586-026-10432-8
  11. Cell. 2026 Apr 30. pii: S0092-8674(26)00401-0. [Epub ahead of print]
    An anaerobic pathogen rewires host metabolism to fuel oxidative growth in the inflamed gut.
    Luisella Spiga, Ryan T Fansler, Yifan Wu, Alexandra Grote, Madison Langford-Butler, Asia K Miller, Maxwell Neal, Owen F Hale, Deepanshu Singla, M Wade Calcutt, Abigail E Rose, Madeline M Bresson, Alexandra C Schrimpe-Rutledge, Brittany Berdy, Simona G Codreanu, Mary Kay Washington, Benjamin P Bratton, Stacy D Sherrod, John A McLean, Karsten Zengler, Cynthia L Sears, Megan G Behringer, Andreas Gnirke, Lili Tao, Jonathan Livny, Danyvid Olivares-Villagómez, Ashlee M Earl, Wenhan Zhu.
      To colonize their host and cause disease, enteric pathogens must deploy their virulence factors to establish distinct nutrient niches. How anaerobic pathogens construct nutrient niches in the densely populated large intestine remains poorly understood. Enterotoxigenic Bacteroides fragilis (ETBF) is a classically anaerobic bacterium implicated in inflammation-associated diseases, including colitis and colorectal cancer. Here, we show that ETBF uses its virulence factor, Bacteroides fragilis toxin (BFT), to generate and adapt to a localized oxidative niche that supports gut colonization. BFT manipulates colonic epithelial signaling and the bile acid recycling pathway, inducing a metabolic shift in the epithelium from oxidative phosphorylation to glycolysis. This shift increases local concentrations of lactate and oxygen, nutrients that support oxidative metabolism in ETBF. These findings reveal an unexpected strategy by which a classically anaerobic pathogen leverages host metabolic remodeling to generate and exploit an oxidative niche in the inflamed gut.
    Keywords:  bile acid recycling; colonocyte metabolism; enterotoxigenic Bacteroides fragilis; obligate anaerobe; oxidative metabolism
    DOI:  https://doi.org/10.1016/j.cell.2026.04.012
  12. Brain. 2026 Apr 29. pii: awag149. [Epub ahead of print]
    Dynamic metabolic programming of monocyte-derived cells defines immunity in CNS disease.
    Claire L Wishart, Jian Tan, Nicholas J C King.
      Monocyte-derived cells (MCs) are highly adaptable innate immune cells that play essential roles in central nervous system (CNS) inflammation. Their functional specialization is closely linked to their metabolic state, which is shaped by local cues such as nutrient availability, oxygen levels, and pro- and anti-inflammatory signals. In this review, we examine the major metabolic pathways that regulate MC behaviour, including glycolysis, oxidative phosphorylation, lipid metabolism, and amino acid metabolism. We assess how these pathways support specific effector functions such as cytokine production, phagocytosis, antigen presentation, and efferocytosis. Moving beyond the traditional M1/M2 framework, we discuss the context-dependent nature of MC metabolism and its role in driving diverse functional states. We then explore how these metabolic programs are engaged across key CNS disease settings, including sterile injury, demyelinating disease, and viral encephalitis. By integrating insights from immunometabolism and neuroinflammation, this review provides a framework for understanding the metabolic regulation of MCs in CNS pathology and highlights potential avenues for therapeutic intervention.
    Keywords:  encephalitis; immunometabolism; monocyte-derived cells; neuroinflammation
    DOI:  https://doi.org/10.1093/brain/awag149
  13. J Virol. 2026 Apr 27. e0209824
    Argininosuccinate synthase 1 (ASS1) orchestrates arginine metabolism and ornithine production to modulate CHIKV infection.
    Nimisha Mishra, Mothe Sravya, Sonali Hanjankar, Anjali Singh, Yash Chaudhary, Ranjan Kumar Nanda, Sujatha Sunil.
      Viruses reprogram the host metabolic machinery to ensure a continuous supply of macromolecules and energy for their own survival. Important cellular pathways are impacted during infection, resulting in changes in key metabolic precursors that influence infection outcomes. The present study was undertaken to evaluate the impact of L-arginine and argininosuccinate synthase 1 (ASS1), an important upstream enzyme of the arginine metabolism pathway, during chikungunya virus (CHIKV) infection in the human liver-derived Huh-7 cells. Using dose-dependent and time-course L-arginine supplementation experiments, we demonstrated that CHIKV exploits cellular arginine for enhanced viral replication. Loss-of-function and gain-of-function studies of ASS1, combined with nitric oxide donor treatments, revealed that arginine metabolism influences multiple downstream pathways, including ornithine synthesis, proline metabolism, and nitric oxide production during CHIKV infection. We further examined the relationship between ASS1 expression and STAT3 signaling in the context of viral infection. Our results demonstrate that exogenous L-arginine supplementation and ASS1 overexpression enhance CHIKV replication in Huh-7 cells. Conversely, ASS1 silencing resulted in >95% reduction in viral titers. Mechanistically, ASS1 modulated arginase 1 activity, affecting ornithine production and downstream metabolites while also influencing the cellular nitroso-redox environment. Additionally, ASS1 expression affected STAT3 levels and its subcellular localization: ASS1 overexpression correlated with reduced nuclear STAT3 accumulation and increased viral replication, whereas ASS1 depletion promoted STAT3 nuclear translocation and restricted viral infection. These findings reveal a complex interplay between arginine metabolism, innate immune signaling, and CHIKV replication, identifying ASS1 as a potential regulatory node in CHIKV-host interactions.
    IMPORTANCE: Metabolic reprogramming of the host is crucial for the virus to establish itself within the cell, and in this process, the virus hijacks several host metabolic pathways. We examined the role of an important arginine metabolizing enzyme, human argininosuccinate synthase (ASS1), during CHIKV infection in liver cells through silencing and overexpressing ASS1 and by L-arginine supplementation. We demonstrate that ASS1 favors CHIKV replication and also plays important roles in several downstream cellular processes during virus infection. This study further deepens our understanding of the significance of the crucial metabolites involved in the arginine metabolism pathway during CHIKV infection and how CHIKV exploits the specific pathway to enhance its replication.
    Keywords:  ASS1; CHIKV; STAT3; antiviral; arginase1; arginine; nitrite; ornithine; polyamines
    DOI:  https://doi.org/10.1128/jvi.02098-24
  14. Immunity. 2026 Apr 29. pii: S1074-7613(26)00144-5. [Epub ahead of print]
    Metabolic and transcriptional plasticity supports CD8+ T cell resilience and anti-tumor immunity under nutrient stress.
    Michael Scaglione, Montana Knight, Krittin Trihemasava, Kelly Rome, Anne-Sophie Archambault, Juhee Oh, Erin Tanaka, Elise Hall, Tran Ngoc Van Le, Caleb L Lines, Brian Goldspiel, Hossein Fazelinia, Clemence Queriault, Lucien Turner, Tanay Parnaik, Jimmy Xu, Morgan Brown, Oishi Bardhan, Jessie Axsom, Frederick C Bennett, Lynn A Spruce, Caroline Bartman, Clementina Mesaros, Ramon I Klein Geltink, Crystal S Conn, Will Bailis.
      CD8+ T cells need to function in complex environments with varied nutrient availability, including the tumor microenvironment and inflamed tissues. The mechanisms that allow CD8+ T cells to maintain immune function in these perturbed settings are poorly understood. Here, we show that CD8+ T cells adapt to nutrient stresses over time, reconfiguring gene-regulatory and metabolic networks to license functional recovery. Under acute stress, T cells reoriented translational programming, which limited nutrient demand and prioritized stress-sensitive metabolic and transcriptional responses. Within these responses, the transcription factors activating transcription factor 4 (ATF4) and CCAAT/enhancer-binding protein gamma (CEBPG) jointly established an adaptive metabolic program, promoting amino acid synthesis and uptake while maintaining mitochondrial metabolism. Despite diminished energetic capacity under environmental stress, this program sustained central carbon metabolism. This subsequently mitigated cellular dysfunction and potentiated anti-tumor immunity. Altogether, we demonstrate that biosynthetic plasticity via translational and metabolic reprioritization confers T cell resilience in unfavorable environments, offering potential strategies to enhance immunotherapies.
    Keywords:  ATF4; CD8(+) T cells; CEBPG; GCN2; HRI; T cell exhaustion; T cells; amino acids; anti-tumor immunity; immunometabolism; integrated stress response; mTOR; nutrient stress; polysome profiling; stress adaptation; translation; tumor-infiltrating lymphocyte
    DOI:  https://doi.org/10.1016/j.immuni.2026.04.004
  15. Sci Adv. 2026 May;12(18): eaed1676
    d-amino acids restrain macrophage IL-1β release through gasdermin D acetylation.
    Zebiao Wu, Qilin Hu, Yinhao Shen, Jian Fu, Bingnan Liu, Meimei Zhang, Ifen Hung, Chunxue Liu, Wenkai Ren.
      d-amino acids have been detected in various tissues; however, whether d-amino acids shape immune cell (e.g., macrophages) function remains undefined. Here, we demonstrated that inflammatory macrophages decrease mRNA expression of d-amino acid oxidase (DAAO) and d-aspartate oxidase (DDO) through nuclear factor κB (NF-κB) signaling. Notably, inhibition of DAAO or DDO increases the concentration of intracellular d-amino acids, consequently suppressing IL-1β release. Mechanistically, d-amino acids inhibit the formation of gasdermin D (GSDMD) oligomer via GSDMD-K146 acetylation. d-amino acids directly bind and increase the enzyme activity of mitochondrial pyruvate dehydrogenase (PDH), resulting in acetyl-coenzyme A production for acetylation. Consistently, d-Ala/d-Glu supplementation or myeloid-specific deletion of DDO attenuates lipopolysaccharides (LPS)-induced sepsis in mice. Collectively, our study reveals a mechanism involving acetylation mediated by d-amino acids in regulation of macrophage function, providing a potential therapeutic strategy for treating macrophage-associated inflammatory diseases.
    DOI:  https://doi.org/10.1126/sciadv.aed1676
  16. J Immunol. 2026 Apr 15. pii: vkag089. [Epub ahead of print]215(4):
    Deficiency of microRNA-10a in CD4+ T cells protects against intestinal infection through mitochondrial oxidation-IL-22 pathway.
    Wenjing Yang, Tianming Yu, Suxia Yao, Yingzi Cong.
      Interleukin 22 (IL-22) produced by CD4+ T cells plays an important role in regulating intestinal immune responses during inflammation and infection, but the mechanisms controlling IL-22 expression in T cells remain incompletely understood. MicroRNA-10a (miR-10a) is known to regulate CD4+ T-cell function, but its role in IL-22 production has not been defined. Here, using mouse CD4+ T cell-specific miR-10a knockout models, we examined how miR-10a regulates IL-22 expression and the underlying metabolic mechanisms. MiR-10a deficiency led to increased IL-22 production in CD4+ T cells both in vitro and in vivo, under steady and inflammatory conditions. CD4+ T cell-specific miR-10a knockout mice were resistant to Citrobacter rodentium infection, and the protection was abolished when blocking the IL-22 pathway in mice. Mechanistically, miR-10a-deficient CD4+ T cells exhibited increased mitochondrial oxidative metabolism and membrane potential. Pharmacologic inhibition of mitochondrial complex III with antimycin A suppressed the enhanced IL-22 production in miR-10a-deficient T cells. We further identified Uqcrq, a subunit of mitochondrial complex III, as a direct target of miR-10a, and loss of Uqcrq suppressed IL-22 production in CD4+ T cells. Together, these findings identify miR-10a as a T cell-intrinsic regulator of mitochondrial oxidative metabolism that constrains IL-22 production in the intestine.
    Keywords:   Uqcrq ; IL-22; microRNA-10a; mitochondrial oxidation
    DOI:  https://doi.org/10.1093/jimmun/vkag089
  17. Redox Biol. 2026 Apr 22. pii: S2213-2317(26)00179-5. [Epub ahead of print]93 104181
    Multi-omic analysis reveals nitric oxide dependent remodeling in classically activated macrophages and identifies negative regulation mediated by AKR1A1.
    Nicholas L Arp, Uzziah S Urquiza, Marcel Morgenstern, Jonathan H Schrope, James A Votava, Steven V John, Jack J Stevens, Felicia Deng, Anna Huttenlocher, Joshua J Coon, Jing Fan.
      Nitric oxide (NO•) is an important regulatory molecule in many biological processes, including immune response. During response to classical activation stimuli lipopolysaccharide (LPS) and interferon-γ (IFNγ), macrophages generate NO• via inducible nitric oxide synthase (iNOS). To comprehensively characterize the effects of NO•, we applied a multi-omic strategy integrating proteomics and transcriptomics to profile murine macrophages across conditions with or without LPS/IFNγ-activation, with or without iNOS expression or exogenous NO• donor treatment. The results showed NO• has broad, yet selected and controlled, regulatory effects, playing a key role in coordinating the systematic remodeling during macrophage classical activation. Among the proteins that are most suppressed in a NO•-dependent manner, electron transport chain (ETC) is the most enriched. NO• drives complex-specific remodeling of ETC, causing selected downregulation of complex I, II, and IV, through a different combination of transcriptional and post-transcriptional mechanisms for each complex. Among the most consistently NO•-dependent upregulated proteins are many enzymes involved in redox defense, and AKR1A1 was identified as a top hit. We found Akr1a1 induction requires both NO• and LPS/IFNγ stimulation. The S-nitroso-CoA reductase activity of AKR1A1 mitigates NO•-driven inhibition of pyruvate dehydrogenase complex by limiting the inhibitory modifications targeting its lipoyl cofactor. Knocking out Akr1a1 causes accelerated remodeling of TCA cycle, dysregulated immunoregulatory metabolite level, and altered functional gene expression and cytokine production at later stage of immune response. Thus, the NO•-dependent upregulation of AKR1A1 forms a negative regulatory loop to fine-tune NO•-mediated metabolic and functional remodeling during immune response. Together, this work provided a systems-level map of NO•-dependent regulation, revealed the crosstalk between NO• and immune signaling, and demonstrated mechanisms providing adaptation and precise control of NO•'s effects.
    Keywords:  Macrophage immune response; Metabolism; Multi-omics; Nitric oxide; Regulation
    DOI:  https://doi.org/10.1016/j.redox.2026.104181
  18. Biochem Pharmacol. 2026 Apr 25. pii: S0006-2952(26)00340-0. [Epub ahead of print] 118007
    4-Octyl itaconate blocks STAT3-induced ACE2 expression to reduce uptake of SARS-CoV-2.
    Hauke J Weiss, Alexander Hooftman, Clarisse Salgado-Benvindo, Robbert Boudewijns, Laurens Liesenborghs, Tristram A J Ryan, Demi van der Horst, Madalina E Carter-Timofte, Hossam Gewaid, Andrew Bowie, Hendrik Jan Thibaut, Kai Dallmeier, David Olagnier, Martijn J van Hemert, Luke A J O'Neill.
      Itaconate is a Krebs cycle-derived metabolite with anti-inflammatory and antiviral properties. This particularly applies to derivatives of itaconate, notably 4-octyl itaconate (4-OI), which has been extensively studied in models of inflammation and infection. Itaconate and 4-OI have been shown to exhibit antiviral activity against Zika virus, Influenza A virus (IAV) and Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2). Here we have further analysed the effect of itaconate and 4-OI on SARS-CoV-2 infection. 4-OI inhibited replication of SARS-CoV-2 in vitro and in vivo, in agreement with recent literature. In lung epithelial cells, 4-OI potently blocked expression of the SARS-CoV-2 uptake receptor, Angiotensin-converting enzyme 2 (ACE2), reducing ACE2 dependent uptake of viral pseudo particles. 4-OI inhibited the induction of both a truncated version of ACE2 and signal transducer and activator of transcription 3 (STAT3)-dependent full-length ACE2, possibly because of its inhibitory effect on Janus kinase 1 (JAK1). Inhibition of JAK1 by 4-OI will therefore block ACE2 expression as well as other effects driven by JAK1, highlighting a dual capability of itaconate derivatives such as 4-OI for having antiviral and anti-inflammatory effects, which could have therapeutic utility in COVID-19.
    Keywords:  ACE2; Antiviral response; Immuno metabolism; Itaconate; JAK-STAT-pathway; SARS-CoV-2
    DOI:  https://doi.org/10.1016/j.bcp.2026.118007
  19. J Immunol. 2026 Apr 15. pii: vkag073. [Epub ahead of print]215(4):
    Lactate conditioning reprograms mucosal-associated invariant T cell metabolism boosting effector function.
    Ardena Berisha, Benjamin J Jenkins, Nidhi Kedia-Mehta, Eimear K Ryan, Shauna Mayock, Odhran Ryan, Cian Davis, Helen Heneghan, Donal O'Shea, Nicholas Jones, Andrew E Hogan.
      Mucosal-associated invariant T (MAIT) cells are unconventional T cells, which upon activation can display potent cytotoxic and cytokine-producing capabilities. Together, these features make MAIT cells promising candidates for cancer immunotherapy. In this study, we show that MAIT cells can be efficiently amplified in vitro, and these amplified MAIT cells are armed with potent anticancer functions, including the ability to produce significant amounts of effector molecules such as IFNγ and granzyme B. Excitingly, we demonstrate that MAIT cells can be redirected to potently kill cancerous cells using a clinically relevant bispecific monoclonal antibody. Furthermore, in an attempt to metabolically condition MAIT cells to improve function, we demonstrate that MAIT cells possess the molecular machinery to transport and metabolize lactate, an abundant metabolite within the solid tumor microenvironment. Activating MAIT cells in the presence of exogenous sodium lactate remodels their cellular metabolism, with a significant increase in mitochondrial metabolism. Functionally, this supports elevated production of effector molecules (IFNγ, granzymes A and B), leading to boosted engager mediated MAIT cell cytotoxicity. These data collectively show that MAIT cells can be pharmacologically directed to target cancer cells and in vitro conditioning using sodium lactate can enhance their anticancer capabilities through reprogrammed cellular metabolism. Our findings represent a novel strategy for a potential new adoptive cancer immunotherapy.
    Keywords:  BiTEs; immunotherapy; lactate; mucosal associated invariant T cells
    DOI:  https://doi.org/10.1093/jimmun/vkag073
  20. J Infect. 2026 Apr 26. pii: S0163-4453(26)00080-0. [Epub ahead of print] 106755
    Monocyte Metabolic Plasticity and Cytokine Production Differentiate Latent TB Infection from Active Disease.
    Gráinne Jameson, Isabella Batten, Adam H Dyer, Caoimhe Geoghegan, Moninne Murray, Niamh McDonnell, Dearbhla M Murphy, Sarah A Connolly, Anne Marie McLaughlin, Cilian Ó Maoldomhnaigh, Laura E Gleeson, Joseph Keane, Sharee A Basdeo.
       RATIONALE: Monocytes are central to host defence against Mycobacterium tuberculosis (Mtb), yet their functional and metabolic profiles during latent TB infection (TBI) and active TB disease (TBD) remain poorly defined. Immunometabolic dysfunction may underlie ineffective responses in TB, but cell-specific mechanisms are unclear.
    OBJECTIVES: To compare the phenotypic, functional, and metabolic profiles of circulating monocytes from individuals with TBI, TBD, and healthy controls (HC), and assess the impact of treatment.
    MEASUREMENTS: Peripheral blood monocytes were profiled using high-dimensional flow cytometry, Luminex cytokine/chemokine assays, and SCENITH™, a flow-based metabolic assay. Unstimulated and Mtb-stimulated monocytes from treatment-naïve and treated individuals were analysed.
    MAIN RESULTS: Monocytes from TBI and TBD showed distinct phenotypes from HC, marked by elevated CD14. HLA-DR was reduced in classical monocytes from TBD compared with both TBI and HC. TNF receptors were downregulated in TBI but unchanged in TBD. Baseline cytokine and chemokine profiles in TBI and TBD were similar (yet distinct from HC), but Mtb stimulation elicited a stronger cytokine response in TBI. Metabolically at baseline, TBI and TBD monocytes exhibited increased glycolysis and reduced mitochondrial dependence versus HC. Treatment partially restored mitochondrial function. Upon Mtb challenge, TBI monocytes had higher glycolytic capacity than HC and TBD.
    CONCLUSIONS: Monocyte metabolic plasticity and cytokine production distinguish TBI from TBD and are partially reversible with treatment. Circulating monocyte metabolism reflects TB immune status and may serve as a biomarker or therapeutic target. Reprogrammed glycolytic profiles in TBI contrast with impaired adaptability in TBD, suggesting dysfunctional myeloid activation during disease.
    Keywords:  Innate Immunity; Mycobacterium tuberculosis; metabolism; monocyte
    DOI:  https://doi.org/10.1016/j.jinf.2026.106755
  21. J Vis Exp. 2026 Apr 10.
    Investigating Glycolysis in Primary Microglia Using Extracellular Flux Assay.
    Aysika Das, Deepak K Kaushik.
      Microglia, the resident macrophage cells of the central nervous system, dynamically alter their metabolic programs in response to physiological and pathological cues. Understanding these metabolic shifts is crucial for elucidating their roles in inflammation. Here, we present a detailed protocol for assessing the glycolytic profile of primary microglia isolated from neonatal mouse brain cortices using a glycolysis stress test on an extracellular flux analyzer. This assay enables real-time measurement of ECAR, an indicator of glycolytic activity associated with low pH, such as lactate. Our approach involves treating cultured microglia under different conditions to examine how metabolic pathways are altered in response to various stimuli, including pro-inflammatory stimuli. Uniquely, our lab prepares fresh stock solutions of different reagents, including glucose, oligomycin, and 2-deoxyglucose (2DG), to target the different aspects of the pathway, with careful adjustment of pH for each reagent to ensure experimental accuracy and reproducibility. This method provides a robust platform for investigating glycolysis in primary microglia and offers insight into their functional states under inflammatory or disease-relevant conditions.
    DOI:  https://doi.org/10.3791/69638
  22. Viruses. 2026 Mar 31. pii: 423. [Epub ahead of print]18(4):
    Hepatitis C Virus (HCV)-Mediated Activation of Hexokinase Domain-Containing Protein 1 (HKDC1) Promotes Hexokinase Activity and Metabolic Reprogramming.
    Hope K Fiadjoe, Amani Doyle, In-Woo Park, Pankaj Chaudhary.
      Hepatitis C virus (HCV) infection is a significant contributor to the development of hepatocellular carcinoma (HCC). One mechanism by which HCV promotes HCC is the remodeling of host cell metabolism; however, the molecular mediators of this process are not yet fully understood. In this study, we identified Hexokinase Domain-Containing Protein 1 (HKDC1) as a crucial effector that links HCV infection to glycolytic reprogramming in hepatoma cells. HCV-positive APC140 cells showed selective upregulation of HKDC1, accompanied by enhanced cytoplasmic localization of the protein. Moreover, these cells exhibited increased total hexokinase activity and elevated pyruvate and lactate production, while the classical hexokinases HK1, HK2, HK3, and HK4 remained unchanged. Depleting HKDC1 led to a reduction in hexokinase activity, glycolytic flux, and HCV subgenomic replicon-associated reporter activity, with no compensatory changes noted in other members of the hexokinase family. These findings indicate that HCV-induced HKDC1 creates a metabolic environment conducive to viral replication and may contribute to HCC development. Therefore, HKDC1 acts as a virus-responsive metabolic mediator that links chronic HCV infection to oncogenic metabolic reprogramming, positioning it as a potential therapeutic target in HCV-associated HCC.
    Keywords:  HCV; HKDC1; glycolysis; hexokinase; metabolic reprogramming
    DOI:  https://doi.org/10.3390/v18040423
  23. Front Immunol. 2026 ;17 1793092
    Loss of immunometabolic adaptability in MASH: gut-derived signals drive macrophage reprogramming and fibrosis.
    Yan Li, Yuyuan Hu, Yuan He, Yuhang Yang, Dingwen Xue, Erkui Xue, Jinghan Jia, Wei Zhang, Jinxi Wang.
      Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive inflammatory subtype of metabolic dysfunction-associated steatotic liver disease (MASLD), characterized by hepatocellular steatosis, persistent inflammation, and varying degrees of fibrosis. Although multiple therapeutic strategies targeting inflammatory or metabolic pathways have entered clinical development, their overall efficacy remains limited, suggesting that the mechanisms driving sustained disease progression remain incompletely understood. Previous studies have largely focused on inflammatory cascades, whereas the role of immune cell energy metabolism in sustaining inflammation and promoting fibrosis has received comparatively less attention. Recent work has increasingly shifted toward immunometabolic reprogramming, indicating that metabolic signals derived from the gut microbiota may contribute to the establishment and maintenance of the hepatic immune microenvironment. In this context, reductions in short-chain fatty acids and secondary bile acids, together with increased succinate and endotoxin levels, may alter the energy metabolism of Kupffer cells and infiltrating macrophages through signaling pathways involving FXR/TGR5 and mTOR/AMPK, thereby favoring a pro-inflammatory phenotype. This metabolic shift is associated with enhanced inflammatory signaling linked to HIF-1α, increased NLRP3 inflammasome activity, and paracrine effects that may promote hepatic stellate cell activation during fibrotic progression. Overall, current evidence supports a model in which MASH progression is associated with a gradual loss of immunometabolic adaptability in the setting of metabolic dysregulation along the gut-liver axis. Reduced metabolic flexibility may limit the ability of immune cells to transition between functional states, thereby hindering resolution of inflammation and contributing to pathological tissue remodeling. Within this framework, single-target interventions may be insufficient to fully restore immunometabolic homeostasis, whereas strategies that concurrently address gut microbial function and key metabolic signaling pathways may be more mechanistically sound. Considering MASH as a model of systemic immunometabolic dysregulation may also provide insight into other metabolism-associated inflammatory diseases, although extrapolation should remain cautious.
    Keywords:  gut–liver axis; immunometabolism; inflammasome activation; macrophage metabolic reprogramming; metabolic dysfunction–associated steatohepatitis (MASH)
    DOI:  https://doi.org/10.3389/fimmu.2026.1793092
  24. J Leukoc Biol. 2026 Apr 21. pii: qiag051. [Epub ahead of print]
    CD177 Promotes NLR Inflammasome Activation in Acute Respiratory Distress Syndrome by Remodeling Neutrophil Glycolytic Metabolism.
    Dongfeng Shen, Yuejiao Sun, Yixin Xu, Yahong Sun, Xiaolong Ma.
      Acute respiratory distress syndrome (ARDS) is a high-mortality lung disorder driven by excessive neutrophil activation. While neutrophils are central to ARDS, the metabolic pathways fueling their inflammatory response remain unclear. This study identifies CD177 as a critical regulator of neutrophil glycolysis and NLRP3 inflammasome activation. Bioinformatics and animal models show that elevated CD177 correlates strongly with increased lactate and IL-1β levels. In vitro experiments demonstrate that CD177 knockdown reduces glycolytic flux and suppresses IL-1β release, a process reversed by lactate supplementation. Furthermore, treating ARDS mice with anti-CD177 antibodies significantly reduces pulmonary edema and tissue injury. These results establish the CD177-glycolysis-NLRP3 axis as a major driver of lung inflammation. Targeting this metabolic checkpoint provides a promising strategy for treating ARDS.
    Keywords:  Acute respiratory distress syndrome; CD177; Glycolysis; Neutrophils
    DOI:  https://doi.org/10.1093/jleuko/qiag051
  25. Redox Biol. 2026 Apr 22. pii: S2213-2317(26)00183-7. [Epub ahead of print]93 104185
    Reactive oxygen species and metabolic checkpoints shape plasmacytoid dendritic cell fate in infection and autoimmunity.
    Lena Rueschpler, Sebastian Schloer.
      Plasmacytoid dendritic cells (pDCs) are innate immune sentinels uniquely specialised in the rapid and potent production of type I interferons (IFN-I) during viral infection. While this capacity is essential for antiviral defence, sustained pDC activation is a central feature of numerous autoimmune and inflammatory disorders. Although the molecular pathways governing nucleic acid sensing and IFN-I induction have been extensively characterised, the metabolic and redox mechanisms that support, and limit pDC function remain incompletely understood. Emerging studies reveal that pDC activity is tightly linked to a specialised redox-metabolic programme involving mitochondrial respiration, reactive oxygen species (ROS), and endolysosomal signalling networks. In this review, we integrate current evidence to propose that pDCs operate within a tightly regulated redox window that permits effective acute antiviral responses but renders them vulnerable to metabolic stress and dysregulation upon chronic stimulation. We examine how mitochondrial fitness, NAD+ homeostasis, ROS dynamics, and endolysosomal redox control collectively influence pDC activation, resolution of inflammation, and pathogenic persistence. By reframing pDC biology through a redox-metabolic perspective, we highlight new conceptual insights into IFN-I-driven disease and identify potential therapeutic strategies to selectively modulate pathogenic pDC responses.
    Keywords:  Autoimmunity; Immunometabolism; Interferons; Mitochondria; NAD(+); Plasmacytoid dendritic cells; Redox signalling; Viral infection
    DOI:  https://doi.org/10.1016/j.redox.2026.104185
  26. Mol Cells. 2026 Apr 26. pii: S1016-8478(26)00057-9. [Epub ahead of print] 100366
    Targeting serine metabolism boosts antimycobacterial immunity during Mycobacterium tuberculosis H37Rv Infection.
    Sang-Hun Son, Ji-Ae Choi, Jaewhan Kim, Tam Doan Nguyen, Junghwan Lee, Doyi Son, Seoyeon Jo, Chang-Hwa Song.
      Serine metabolism is pivotal in regulating immune cell function and molding the host microenvironment during infection, yet its impact on antimycobacterial immunity remains elusive. Here, we probe the role of serine metabolism in Mycobacterium tuberculosis (Mtb)-infected macrophages. We reveal that Mtb infection induces enzymes associated with the serine synthesis pathway (SSP) and serine transporters. Moreover, inhibition of the key SSP enzyme or restriction of exogenous serine boosts antimycobacterial immunity in both in vitro and in vivo. Depletion of serine reduces reactive oxygen species (ROS) levels by diminishing the levels of reduced nicotinamide adenine dinucleotide. This ROS reduction destabilizes hypoxia-inducible factor 1 alpha, impairing glucose uptake and ATP production. Consequently, reduced ATP production activates AMP-activated protein kinase, which inhibits mTOR and induces autophagy, thereby exerting antimycobacterial effect. These findings underscore serine's role as a crucial immune metabolite during Mtb infection and propose that manipulating serine metabolism holds therapeutic promise against mycobacterial infections.
    Keywords:  AMP-activated protein kinase; Autophagy; Phosphoglycerate dehydrogenase; Reactive oxygen species; Tuberculosis
    DOI:  https://doi.org/10.1016/j.mocell.2026.100366
  27. Front Nutr. 2026 ;13 1807302
    The immunoregulatory effect of short-chain fatty acids in type 2 diabetes mellitus.
    Jiaxin Li, Zhongmin Lv, Qi Fan, Peinan Fu, Ning Zhou, Jiefang Deng, Huimin Qi, Meng Yang.
      Short-chain fatty acids (SCFAs) are the primary metabolites of dietary fiber fermented by intestinal flora. They play a systemic role in the immune regulation of type 2 diabetes mellitus (T2DM) by integrating receptor-mediated signaling and epigenetic regulatory mechanisms. At the receptor pathway level, SCFAs activate G protein-coupled receptors such as GPR41/43/109 A, initiate downstream signaling cascades including MAPK, NF-κB, and mTOR/STAT3, and thereby achieve rapid modulation of immune cell function; at the epigenetic regulatory level, SCFAs induce chromatin remodeling and gene expression reprogramming by inhibiting histone deacetylase (HDAC) activity, giving immune cells long-term functional memory. These two pathways act coordinately to broadly regulate the functional status of innate and adaptive immune cells. In innate immune cells, SCFAs influence macrophage polarization, neutrophil activation, dendritic cell antigen presentation, mast cell degranulation, and eosinophil-mediated immune homeostasis; in adaptive immune cells, SCFAs regulate the differentiation of CD4 + T cell subsets, CD8 + T cell effector function, regulatory T cell stability, B cell antibody production and cytokine secretion of congenital lymphocytes (ILCs). These immunomodulatory effects are integrated in multiple metabolic organs such as adipose tissue, liver, islet and intestine to collectively improve T2DM-related chronic inflammation and insulin resistance. Investigation of SCFAs reveals the molecular basis of the interaction between intestinal flora and host immune metabolism, and provides a theoretical foundation for the prevention and treatment of T2DM based on dietary intervention or microecological regulation.
    Keywords:  GPCR; HDAC; SCFAs; T2DM; adaptive immunity; innate immunity
    DOI:  https://doi.org/10.3389/fnut.2026.1807302
  28. Res Vet Sci. 2026 Apr 23. pii: S0034-5288(26)00177-3. [Epub ahead of print]207 106223
    Untargeted metabolomics reveals bovine viral diarrhea virus infection reprogram host nucleotide and amino acid metabolism in MDBK Cells.
    Ting Xiao, Sen Gao, Xiayu Zhang, Fei Teng, Yuxin Wei, Wei Wu, Chenyu Zheng, Xinyuan Qiao, Wenlong Zhang, Yingying Ma.
      Bovine viral diarrhea virus (BVDV) is a highly adapted intracellular parasite that depends entirely on the host cell's metabolic resources and energy for the synthesis of viral components. However, the mechanisms by which BVDV remodels host lipid metabolism remain unclear. In this study, we explored the metabolic impact of BVDV infection in MDBK cells using untargeted metabolomics. The differential metabolite (DEMs) analysis identified 249 and 147 differential metabolites in positive and negative ion modes. These DEMs have been demonstrated to be considerably enriched in a number of critical metabolic pathways, including purine metabolism, ABC transporters, alanine, aspartate, and glutamate metabolism, according to KEGG enrichment analysis. The up-regulated DEMs (Guanine, Xanthine, Xanthosine 5'-monophosphate and Uric acid) were notably focused on purine metabolism, indicating that BVDV infection triggers the host purine de novo and remedial synthesis pathways. In contrast to the up-regulated metabolites supporting viral replication, the down-regulated DEMs (Adenosine 5'-monophosphate, Guanosine 5'- monophosphate and Adenosine) were primarily involved in metabolism and the cGMP-PKG signaling pathway. The down-regulation of several important metabolites demonstrated how BVDV achieves immune escape and persistent infection by undermining the host defense system. However, more experimental confirmation is needed to determine the molecular mechanism by which BVDV uses host metabolic resources to support its own replication. Our metabolomics data provide crucial insights into the infection-induced metabolic perturbations, thereby serving as a valuable data resource for elucidating the mechanism of BVDV-driven host metabolic reprogramming.
    Keywords:  ABC transporters; Bovine viral diarrhea virus; Purine metabolism; Untargeted metabolomics
    DOI:  https://doi.org/10.1016/j.rvsc.2026.106223
  29. J Sport Health Sci. 2026 Apr 29. pii: S2095-2546(26)00024-4. [Epub ahead of print] 101143
    Exercise-induced musclin enhances efferocytosis via metabolic reprogramming to alleviate periprosthetic joint infection.
    Zhiwei Fu, Jintao Wu, Shutao Zhang, Juyang Jiao, Qimin Hong, Yihan Wang, Liangjun Zheng, Xinhua Qu, Bing Yue.
       BACKGROUND: In periprosthetic joint infection (PJI), impaired macrophage efferocytosis limits bacterial clearance and sustains inflammation. Clinical therapies for restoring macrophage efferocytosis in the infectious microenvironment are limited. Here, we elucidate the mechanistic links between regular exercise, musclin release, and macrophage efferocytosis.
    METHODS: We established a murine PJI model to investigate the therapeutic potential of regular exercise. Agar plate colony counting, histological assessment, immunofluorescence staining, radiographic evaluation, and micro-CT were employed to assess bacterial burden, inflammation, tissue fibrosis, and the extent of osteolysis. Bulk RNA sequencing was performed to identify key exercise-responsive molecules. Flow cytometry, immunoprecipitation coupled with mass spectrometry, Seahorse metabolic analysis, and genetic overexpression and inhibition techniques were used to reveal the impacts on macrophage efferocytosis and metabolism. Finally, we evaluated the synergistic therapeutic effects of a key exercise-associated secretory protein combined with antibiotics in PJI mice.
    RESULTS: Regular exercise significantly alleviated bacterial burden and inflammatory osteolysis in PJI mice. The exogenous administration of musclin-identified as a key exercise-responsive myokine-replicated the protective effects of exercise, with the core mechanism involving restoration and enhancement of macrophage efferocytosis. Mechanistically, musclin bound to formyl peptide receptor 2 (FPR2) on macrophages to reprogram their metabolic phenotype, significantly suppressing the glycolytic pathway while restoring oxidative phosphorylation. Therefore, FPR2-mediated metabolic reprogramming was crucial for enhancing efferocytotic capacity. Furthermore, combination therapy of musclin and oxacillin synergistically reduced bone destruction and tissue fibrosis, while being associated with partial restoration of adaptive immunity.
    CONCLUSION: Musclin mitigates PJI by enhancing macrophage efferocytosis via FPR2-mediated metabolic reprogramming. By revealing the mechanism through which exercise ameliorates PJI and establishing musclin as a promising therapeutic candidate, this study provides new strategies for the prevention and treatment of PJI.
    Keywords:  Efferocytosis; Metabolic reprogramming; Musclin; Periprosthetic joint infection; Regular exercise
    DOI:  https://doi.org/10.1016/j.jshs.2026.101143
  30. Inflamm Res. 2026 Apr 28. pii: 105. [Epub ahead of print]75(1):
    Lp-PLA2-derived LysoPC drives dendritic cell immunogenic activation and Th17 inflammation in severe asthma.
    Fang Wang, Zhihui Min, Yuhao Qian, Jiameng Gao, Zhenlin Yang, Zhilong Jiang, Zhihong Chen.
      Severe asthma (SA) is associated with dysregulated phospholipid metabolism, yet the underlying immunometabolic mechanisms remain poorly understood. Our metabolomic profiling of SA patients revealed a characteristic remodeling of the phosphatidylcholine (PC)-lysophosphatidylcholine (LysoPC) axis, featuring an accumulation of long-chain PC precursors and a depletion of polyunsaturated lipids. In a murine model of severe neutrophilic asthma, we identified explosive localized generation of pathogenic saturated LysoPC (particularly the 16:0 species) driven by hyperactive PC hydrolysis. Mechanistically, LysoPC acts as an endogenous danger signal that promotes the immunogenic activation of dendritic cells (DCs) by inducing a signaling "seesaw" of concurrent NF-κB activation and p38 MAPK suppression, thereby driving na ïve CD4+ T cells toward a Th17 phenotype. Crucially, the expression of lipoprotein-associated phospholipase A2 (Lp-PLA2) was robustly upregulated in both murine and human monocyte-derived DCs (moDCs) from SA patients. Importantly, pharmacological inhibition of Lp-PLA2 with darapladib reduced Th17-mediated neutrophilic inflammation in a steroid-resistant asthma model and suppressed DC immunogenicity in vitro. Collectively, our findings define the Lp-PLA2/LysoPC axis as a novel driver of DC-mediated Th17 inflammation, highlighting this pathway as a promising therapeutic target for severe asthma.
    Keywords:  Dendritic cells; Lp-PLA2; LysoPC; Severe asthma; Th17 cells
    DOI:  https://doi.org/10.1007/s00011-026-02246-1
  31. Exp Neurol. 2026 Apr 25. pii: S0014-4886(26)00158-5. [Epub ahead of print]402 115794
    Therapeutic potential of regulating microglial Glut1 in modulating brain glucose metabolism and neuroinflammation in postoperative delirium.
    Huikai Yang, Qingzu Liu, Chongyang Liu, Min Liu, Danyang Geng, Mengyao Qu, Yanan He, Yanhong Liu, Miao Sun, Yulong Ma, Weidong Mi.
       BACKGROUND: Postoperative delirium (POD) is a common and serious complication of surgery, driven in part by neuroinflammation mediated by microglial activation. However, the molecular mechanisms underlying this process remain poorly defined. This study investigates the role of glucose transporter 1 (Glut1) in microglial activation and the pathogenesis of POD.
    METHODS: A mouse model of POD-like behaviour was established via partial hepatectomy. Microglia were depleted using PLX3397 and isolated to confirm their role, and that of Glut1, in POD pathogenesis. Glut1 function was inhibited pharmacologically with BAY-876, and its expression in microglia was modulated using microglia-specific adeno-associated viruses (AAV-mir-Glut1+/+ and AAV-mir-Glut1-/-). In vitro, BV2 microglial cells and BV2-HT22 neuron co-cultures were stimulated with lipopolysaccharide (LPS) to assess how inflammatory activation alters glucose metabolism and affects neuronal glucose uptake. Regulatory effects of microglial Glut1 were evaluated using PET-CT imaging, biodistribution analysis, histology, and biochemical assays.
    RESULTS: An increase in brain glucose metabolism was observed during POD-like behaviour, corresponding with microglial activation following anesthesia and surgery. Inhibition of Glut1 with BAY-876 reduced cerebral glucose uptake, suppressed microglial activation, and improved cognitive performance. Critically, microglia-specific modulation of Glut1 expression attenuated neuroinflammation, corrected metabolic abnormalities, and mitigated POD-like behaviour.
    CONCLUSIONS: Glut1-mediated glucose hypermetabolism in microglia contributes to POD through a metabolic-inflammatory cascade. These findings reveal a key role for microglial Glut1 in linking energy metabolism to neuroinflammation and suggest that targeting this pathway may offer a novel strategy for the prevention and treatment of POD and related perioperative neurocognitive disorders.
    Keywords:  Glucose metabolism; Glucose transporter 1; Microglia; Neuroinflammation; Postoperative delirium
    DOI:  https://doi.org/10.1016/j.expneurol.2026.115794
  32. J Proteome Res. 2026 Apr 28.
    Mitochondrial Proteomics Uncovers that Myeloid S100A9 Deficiency Promotes Liver Injury and Fibrosis Regression via Mitochondrial Metabolic Reprogramming of Macrophages.
    Jinfang Liu, Ruixi Liu, Yunwei Shi, Yi Sun, Zhenpeng Zhang, Mingsong Mao, Lei Chang, Tao Zhang, Chunguang Han, Junzhu Wu, Ping Xu.
      Macrophage-mediated inflammation has been implicated in the pathogenesis of liver fibrosis. Metabolic reprogramming involves the transition of macrophages from a proinflammatory M1 phenotype toward an anti-inflammatory M2 phenotype. S100A9 is highly expressed in activated macrophages and promotes M1 polarization; however, it is unknown whether S100A9 alters the polarization state of macrophages by regulating metabolism. This study revealed enhanced oxidative phosphorylation (OXPHOS) in S100a9-deficient bone marrow-derived macrophages (BMDMs) based on mitochondrial proteomics, characterized by increased mitochondrial fusion and elevated ATP production. Further phenotypic analysis showed that S100a9-deficient peritoneal macrophages and BMDMs exhibited an M2-like phenotype at the basal state and enhanced M2 polarization with IL-4/IL-13 stimulation, reflected by higher CD206 expression. Using the OXPHOS inhibitor oligomycin, we demonstrated that suppressing OXPHOS completely rescued the M2 polarization bias of the S100a9-deficient macrophages. Finally, we found that genetic deletion of S100A9 in myeloid cells protected against liver injury and fibrogenesis through increasing the proportion of hepatic CD206-positive M2-like anti-inflammatory macrophages in a mouse model. Our study uncovers a novel role of S100A9 in macrophage mitochondrial metabolism and phenotype reprogramming during liver fibrosis, and targeting macrophage S100A9 may be considered as a potential therapeutic strategy against liver fibrosis.
    Keywords:  S100A9; liver fibrosis; macrophage polarization; mitochondria metabolism
    DOI:  https://doi.org/10.1021/acs.jproteome.5c01019
  33. bioRxiv. 2026 Apr 19. pii: 2026.04.15.718788. [Epub ahead of print]
    A microbiota-derived bile acid overcomes antibiotic-induced hyporesponsiveness to immune checkpoint therapy by enhancing CD8 + T cell antitumor immunity.
    Wenling Li, Christina M Zarek, Hesuiyuan Wang, Shuheng Gan, Parastoo Sabaiefard, Priscilla Del Valle, Jiwoong Kim, Nicole Poulides, Laura A Coughlin, Jake N Lichterman, Cheng Zhang, Rebecca Suet-Yan Chiu, Tarun Srinivasan, Mauricio J Velasquez, Indu Raman, Vanessa J Maddox, Jeffrey McDonald, Ralf Kittler, Prithvi Raj, Xin V Li, Xiaowei Zhan, Chen Liao, Joao B Xavier, Andrew Y Koh.
      Gut microbiota are critical determinants of effective immune checkpoint therapy (ICT), yet the microbial mediators and host mechanisms that enhance antitumor immunity remain poorly understood. Here, we identify the microbiota-derived bile acid taurodeoxycholic acid (TDCA) as a metabolite associated with immune checkpoint therapy (ICT) response. TDCA administration alone is sufficient to overcome antibiotic-induced ICT hyporesponsiveness across multiple murine tumor models. Mechanistically, TDCA directly enhances CD8⁺ T cell-mediated antitumor immunity, increasing cytotoxicity. These effects required signaling through the bile acid receptor TGR5. Together, these findings reveal TDCA as a gut microbial metabolite that restores ICT efficacy after antibiotic disruption by directly augmenting CD8⁺ T cell anti-tumor activity. This work supports metabolite replacement as a therapeutic strategy to mitigate antibiotic-associated loss of cancer immunotherapy response.
    Significance: TDCA is a microbiota-derived metabolite that restores immune checkpoint therapy efficacy after antibiotic disruption by directly enhancing CD8⁺ T-cell-mediated anti-tumor immunity through bile acid receptor TGR5 signaling. Our findings suggest that supplementation with defined microbial metabolites can mitigate antibiotic-associated loss of immunotherapy response without requiring broader microbiome reconstitution.
    DOI:  https://doi.org/10.64898/2026.04.15.718788
  34. J Virol. 2026 Apr 29. e0002826
    JMJD6-mediated epigenetic silencing of innate immunity promotes pseudorabies virus replication.
    Sheng-Li Ming, Ya-Jing Chai, Jia-Ming Yang, Jia-You Xing, Shi-Jun Zhang, Sai-Nan He, Qing-Xia Lu, Jiang Wang, Jia-Jia Pan, Wei-Fei Lu, Lei Zeng, Bei-Bei Chu.
      Jumonji domain-containing protein 6 (JMJD6) has been implicated in epigenetic regulation. Here, we demonstrated that JMJD6 was upregulated during pseudorabies virus (PRV) infection and critically enhanced viral replication by promoting virion release. Mechanistically, JMJD6 suppressed PRV-induced histone H4K16 acetylation, a modification associated with chromatin relaxation and DNA damage response activation. This epigenetic modulation attenuated the cGAS-STING-mediated innate immune signaling pathway, leading to reduced interferon production and enhanced viral propagation. Furthermore, we identified METTL23 as a nuclear interactor of JMJD6 upon viral infection, revealing a cooperative role between these proteins in facilitating immune evasion. Importantly, administration of the JMJD6-specific inhibitor JMJD6-IN-1 potently activated innate immunity and restricted PRV replication in mice. Our findings unveil a novel epigenetic strategy employed by PRV to evade host antiviral responses and highlight JMJD6 as a potential therapeutic target for combating herpesvirus infections.IMPORTANCEThe ongoing conflict between viruses and host antiviral defenses is central to viral pathogenesis. Pseudorabies virus (PRV), a highly contagious alphaherpesvirus, causes severe economic losses in the global swine industry and poses an emerging zoonotic threat to humans. This study identifies the epigenetic modulator, the JMJD6, as a critical host factor exploited by PRV to evade antiviral immunity. Our work uncovers a previously unrecognized epigenetic strategy employed by herpesviruses and establishes JMJD6 as a promising target for developing broad-spectrum antivirals against PRV and related pathogenic herpesviruses.
    Keywords:  JMJD6; METTL23; cGAS–STING pathway; epigenetic regulation; pseudorabies virus; viral immune evasion
    DOI:  https://doi.org/10.1128/jvi.00028-26
  35. Vaccines (Basel). 2026 Mar 27. pii: 300. [Epub ahead of print]14(4):
    Inactivated Klebsiella pneumoniae Induces Metabolic and Hematopoietic Reprogramming to Promote Trained Immunity and Heterologous Antibacterial Protection.
    Xiang Cheng, Shaoqiong Huang, Zhidong Hu, Xiaoyong Fan.
       BACKGROUND: Infections caused by multidrug-resistant bacteria and inadequate vaccine coverage against opportunistic pathogens highlight the need for interventions that broadly and durably enhance host defense beyond antigen-specific adaptive immunity. Trained immunity, driven by metabolic and epigenetic reprogramming of innate immune cells, has been predominantly characterized using Bacille Calmette-Guérin and β-glucan, whereas its induction by Gram-negative bacteria remains poorly defined. To address this gap, we aimed to determine whether heat-killed Klebsiella pneumoniae (HK Kp) induces trained immunity through metabolic and hematopoietic reprogramming to confer heterologous antibacterial protection.
    METHODS: HK Kp-trained murine bone marrow-derived macrophages and HK Kp-immunized C57BL/6 mice were employed to interrogate functional, metabolic, and transcriptomic reprogramming in vitro, hematopoietic progenitor remodeling in vivo, and protective efficacy against systemic Salmonella Typhimurium and Staphylococcus aureus infection.
    RESULTS: HK Kp-trained macrophages showed markedly enhanced IL-1β secretion across all restimulation conditions, stimulus-dependent amplification of TNF-α responses, increased phagocytosis, and improved intracellular control of S. typhimurium, together with sustained upregulation of the glycolytic enzymes-encoding genes Hk2 and Pfkfb3. Transcriptomic profiling revealed extensive reprogramming enriched in glycolysis/gluconeogenesis and hematopoietic cell lineage pathways. In vivo, HK Kp immunization shifted bone marrow stem/progenitor compartments toward a myeloid-biased state. HK Kp-trained mice challenged with lethal S. typhimurium or S. aureus exhibited less weight loss, improved survival rates, and reduced bacterial burdens.
    CONCLUSIONS: Inactivated K. pneumoniae orchestrates metabolic and hematopoietic reprogramming to establish enhanced innate immune responsiveness and confer heterologous protection in murine S. typhimurium and S. aureus sepsis models, supporting its potential as a potent inducer of trained immunity. These findings establish HK Kp-based trained immunity as a promising strategy for combating multidrug-resistant and vaccine-evading pathogens.
    Keywords:  Klebsiella pneumoniae; hematopoietic stem and progenitor cells; heterologous antibacterial protection; metabolic reprogramming; trained immunity
    DOI:  https://doi.org/10.3390/vaccines14040300
  36. JCI Insight. 2026 Apr 28. pii: e203826. [Epub ahead of print]
    NAD+ augmentation by nicotinamide riboside engages SLIT2/ROBO1 signaling to attenuate Th17 inflammation in psoriasis.
    Kim Han, Rachael J Klein, Thomas C Recupero, Anna Chiara Russo, Rahul Sharma, Anand K Gupta, Shahin Hassanzadeh, Rebecca D Huffstutler, Pradeep K Dagur, Bryan Fisk, Neelam R Redekar, Michael N Sack.
      Enhancing NAD+ levels with nicotinamide riboside (NR) confers anti-inflammatory effects in human disease, although immunoregulatory mechanisms remain poorly characterized. We previously showed that ex vivo NR supplementation of primary CD4+ T cells from psoriatic individuals dampened immune responsiveness. To validate this in vivo, we performed a randomized, placebo-controlled NR supplementation study in individuals with mild-to-moderate psoriasis. Participants received oral NR (500 mg twice daily) or matching placebo for 4 weeks, with blood samples collected at baseline and after supplementation. NR reduced Th17 immune responsiveness. Bulk CD4+ T cell RNA-seq identified induction of the SLIT-ROBO signaling pathway. NR supplementation increased circulating SLIT2 levels and enhanced SLIT2 production in dermal fibroblasts. Pharmacologic and genetic interrogation in CD4+ T cells and fibroblasts demonstrated that SLIT2, acting through the ROBO1 receptor, inhibited Rho GTPase signaling, thereby attenuating canonical Th17 polarization and fibroblast inflammatory activation. These findings indicate that NAD+ augmentation exerts anti-inflammatory effects in psoriasis through SLIT2-ROBO1-mediated crosstalk between dermal fibroblasts and circulating CD4+ T cells, leading to suppression of Th17-driven inflammation.
    Keywords:  Adaptive immunity; Clinical trials; Dermatology; Immunology; Signal transduction
    DOI:  https://doi.org/10.1172/jci.insight.203826
  37. Proc Natl Acad Sci U S A. 2026 May 05. 123(18): e2527753123
    Cytochrome P450 1B1 directs pathogenic Th17 cell generation and autoimmune disease by fine-tuning redox homeostasis and mitochondrial integrity.
    Wenhao Hu, Yunqing Sun, Jie Sun, Yue Liang, Suoqin Jin, Jing Liu, Bing Wu.
      Th17 cell function is highly context-dependent and can be categorized into pathogenic and nonpathogenic Th17 cell subsets. Understanding the molecule control of pathogenic Th17 (pTh17) cell immunity will benefit the treatment for related autoimmune diseases. Here, we revealed that cytochrome P450 1B1 (CYP1B1) is highly upregulated during mice and human colitis. CYP1B1 promoted both colon inflammatory diseases and colitis-associated colorectal cancer via pTh17-dependent but microbiota-independent manner. Notably, CYP1B1 specifically dictated the differentiation and pathogenicity of pTh17 cells, while having no effects on nonpathogenic Th17 cell generation. Mechanistically, CYP1B1 deficiency disrupted intracellular redox homeostasis via decreased glutathione synthetase, leading to increased ROS and mitochondrial dysfunction of pTh17 cells. ROS elimination by N-acetylcysteine or ectopic glutathione synthetase expression restored mitochondrial fitness and promoted pTh17 cell survival and generation. Taken together, our findings uncover a T cell intrinsic CYP1B1-ROS-mitochondrial axis in driving pTh17 cell generation, interfering with this hub may be beneficial for pTh17 cell-related immunopathology.
    Keywords:  CYP1B1; ROS; colitis; mitochondrial; pathogenic Th17
    DOI:  https://doi.org/10.1073/pnas.2527753123
  38. Front Immunol. 2026 ;17 1803488
    Targeted regulation of adipose tissue macrophages from an immunometabolic perspective: a novel therapeutic approach for obesity-related metabolic disorders.
    Chen Jia, Enfang Wu, Chenjia Zhu, Xiyuan Guan, Yuqi Cheng, Feng Zhao, Xin Jin, Dan Cao, Xueyu Li.
      The global prevalence of obesity and its associated metabolic syndromes, characterized by chronic inflammation and metabolic disorders, poses a major health threat worldwide. This makes it urgent to gain a deeper understanding of its pathogenesis and to develop new therapeutic strategies. Adipose tissue macrophages (ATMs), as central regulators of the adipose tissue immune microenvironment, exhibit functional polarization closely linked to obesity-associated chronic low-grade inflammation and insulin resistance. This review systematically elucidates the mechanisms of metabolic reprogramming in adipose tissue microenvironment under obesity, focusing on how profound alterations in their glucose, lipid, and amino acid metabolic networks drive their shift toward a pro-inflammatory phenotype. Building on this, we review the mechanisms of action and latest research advances in emerging therapeutic strategies, including mitochondrial-targeted interventions, extracellular vesicle (EV)-mediated molecular delivery, probiotic/prebiotic modulation, probiotic extracellular vesicles, and nanotechnology-enabled precision interventions. Finally, this review outlines the challenges and future directions for treating obesity-related diseases by precisely regulating the EV-ATMs metabolic axis.
    Keywords:  adipose tissue macrophages; extracellular vesicles; immunometabolism; metabolic reprogramming; nanotechnology; probiotic extracellular vesicles
    DOI:  https://doi.org/10.3389/fimmu.2026.1803488
  39. J Exp Med. 2026 Jun 01. pii: e20251918. [Epub ahead of print]223(6):
    BACH2 controls ILC3 function via PPARγ-dependent mitochondrial metabolism.
    Jianye Wang, Ying Wang, Gaoyu Liu, Jinhao Yang, Houjia Hu, Hailong Cao, Shuo Wang, Xuanlin Liu, Jingyi Wu, Meng Yao, Xiaolei Pan, Pan Zhou, Ying Yu, Zuoqing Song, Qiang Liu, Jie Zhou.
      Group 3 innate lymphoid cells (ILC3s) play an essential role in maintaining intestinal barrier immunity. Dysfunction of ILC3s contributes to the pathogenesis of inflammatory bowel disease (IBD), whereas the mechanisms underlying ILC3 regulation remain incompletely understood. Here, we report that the transcription factor BTB domain and CNC homolog 2 (BACH2) represents an important regulator of intestinal ILC3s. ILC3s from IBD patients exhibited reduced BACH2 expression compared with those from healthy donors. Conditional ablation of BACH2 in ILC3s impaired their function, thereby exacerbating the severity of murine colitis. Mechanistically, BACH2 enhanced mitochondrial oxidative phosphorylation in ILC3s in a peroxisome proliferator-activated receptor γ (PPARγ)-dependent manner. PPARγ was identified as a direct transcriptional target of BACH2 in ILC3s. Notably, pharmacological activation of PPARγ with rosiglitazone restored ILC3 function and ameliorated colitis in BACH2-deficient mice. These observations demonstrate that the presence of BACH2-PPARγ signaling in ILC3s protects against colitis.
    DOI:  https://doi.org/10.1084/jem.20251918
  40. J Nanobiotechnology. 2026 Apr 28.
    Extracellular vesicles inherit lactate from aggregated MSCs to alleviate type 1 diabetes mellitus via H2S-induced CD8+ T cell exhaustion.
    Qianhui Ren, Qianmin Ou, Zhengshi Li, Luhan Niu, Deqian Tang, Xinyu Liu, Xueli Mao, Songtao Shi.
      Aggregated mesenchymal stromal cells (MSCs) show enhanced anaerobic glycolysis and elevated lactate production when compared to conventional adherent MSCs. It is unknown whether their extracellular vesicles (EVs) inherit lactate from parent cells and regulate anaerobic glycolysis in recipient cells. Here we show that aggregated MSC-derived EVs (agg-EVs) have superior therapeutic effects on type 1 diabetes mellitus (T1DM) with significantly reduced hyperglycemia, improved pancreatic islets, and elevated CD8+ T cell exhaustion. Mechanistically, we found that agg-EVs inherited lactate from aggregated MSCs to enhance L-cysteine decomposition in CD8+ T cells. Non-targeted metabolomics analysis revealed that agg-EV-treated CD8+ T cells showed elevated L-cysteine metabolism as well as reduced L-cysteine, glutathione (GSH) and GSH/GSSG (glutathione disulfide) ratio, resulting in an increased hydrogen sulfide (H2S) level. H2S can activate β-catenin to upregulate programmed cell death protein 1 (PD-1) expression and, therefore, suppress CD8+ T cell proliferation and function. Blockage of L-cysteine decomposition by knockdown pyruvate kinase M2 (PKM2) in aggregated MSCs or knockout of cystathionine γ-lyase to reduce H2S level in CD8+ cells diminished agg-EV-mediated therapeutic effects. These findings identify a previously unknown mechanism by which agg-EVs induce CD8+ T cell exhaustion via H2S/β-catenin/PD-1 axis in T1DM immunotherapy.
    Keywords:  Aggregated mesenchymal stromal cells; CD8+ T cell exhaustion; Extracellular vesicles; Hydrogen sulfide; L-cysteine metabolism; Lactate
    DOI:  https://doi.org/10.1186/s12951-026-04466-3
  41. Cell Prolif. 2026 Apr 30. e70221
    SCD2 Alleviates Diabetes-Associated Cognitive Dysfunction by Improving Microglial Lipid Metabolism.
    Yang Yang, Juan He, Jing Zheng, Bing Shao, Lixin Shi, Miao Zhang.
      The mechanisms underlying diabetes-associated cognitive dysfunction (DACD) are not fully understood, and microglial metabolic dysfunction is emerging as a key contributor. This study investigates whether stearoyl-CoA desaturase 2 (SCD2) alleviates cognitive impairment by modulating microglial lipid metabolism and function. Bioinformatics analysis of a single-cell RNA-seq dataset (GSE201644) identified SCD2 downregulation in diabetic (db/db) microglia. A T2D mouse model underwent hippocampal overexpression of SCD2 via AAV injection. In vitro, high glucose (HG)-treated BV2 microglia-like cells were subjected to SCD2 overexpression or oleic acid (OA) supplementation. Mitochondrial function (OCR, ATP, ETC complexes), lipid droplet accumulation (BODIPY, PLIN2), and inflammation (TNF-α, IL-6) were assessed. Cognitive behaviour (MWM, NOR) and neurophysiology (synaptic markers, neuronal survival) were evaluated. Diabetic microglia exhibited reduced SCD2 expression, impaired oxidative phosphorylation and lipid droplet accumulation (LDAM). SCD2 overexpression or OA rescued mitochondrial function, mitigated lipid droplet accumulation and attenuated inflammation. In vivo, hippocampal SCD2 overexpression attenuated neuroinflammation, preserved synaptic integrity and improved cognition in diabetic mice. SCD2 is essential for maintaining microglial lipid and mitochondrial homeostasis in diabetes. Restoring SCD2 function alleviates neuroinflammation and synaptic deficits, thereby rescuing cognitive impairment, highlighting its therapeutic potential for DACD.
    Keywords:  SCD2; diabetes‐associated cognitive dysfunction; lipid droplet accumulation; microglia; neuroinflammation; oxidative phosphorylation
    DOI:  https://doi.org/10.1111/cpr.70221
  42. bioRxiv. 2026 Apr 13. pii: 2026.04.09.717546. [Epub ahead of print]
    FABP4 Couples Lipid Metabolism to PD-L1 Stabilization in Immunosuppressive Macrophages.
    Jianyu Yu, Jonathan Shilyansky, Jiaqing Hao, Anthony Avellino, Yanwen Sun, Xingshan Jiang, Zhaohua Wang, Xiaochun Han, Melissa A Curry, Sonia L Sugg, Bing Li.
      Metabolic dysregulation in obesity reshapes immune function, but how lipid signals drive immune suppression remains unclear. Here, we identify a FABP4-PD-L1 axis that links lipid metabolism to immune checkpoint regulation in monocytes and macrophages. Single-cell transcriptomics revealed a distinct FABP4 high immunosuppressive macrophage subset enriched under high-fat diet (HFD) conditions, characterized by impaired antigen presentation and elevated PD-L1 expression. Mechanistically, palmitic acid (PA) induces FABP4 and promotes PD-L1 palmitoylation, leading to its stabilization on the cell surface independent of transcriptional regulation. FABP4 is essential for this process, which enables PD-L1 surface stabilization, immunosuppression and mammary tumor progression. In humans, a conserved CD14 int CD16⁺ monocyte population exhibits elevated FABP4-PD-L1 signaling and correlates with obesity and invasive breast cancer. These findings establish PD-L1 as a metabolically regulated protein and reveal a mechanism by which lipid excess drives immune evasion, suggesting that targeting FABP4 may enhance responses to immune checkpoint blockade.
    Highlights: FABP4 defines a lipid-responsive, immunosuppressive monocyte/macrophage subsetFABP4 links lipid sensing to PD-L1 expression in macrophagesFABP4 enables palmitic acid-dependent PD-L1 palmitoylation and stabilizationFABP4-PD-L1 signaling correlates with obesity and invasive breast cancer in humans.
    DOI:  https://doi.org/10.64898/2026.04.09.717546
  43. Int Immunopharmacol. 2026 Apr 27. pii: S1567-5769(26)00560-6. [Epub ahead of print]181 116714
    Vincamine attenuates alcoholic liver injury through modulation of a CDK1-glycolysis-NLRP3 immunometabolic axis.
    Xinran Xin, Jiaxiu Li, Dehao Ji, Youli Yao, Jinbin Li, Bin Liu.
       BACKGROUND: Alcoholic liver disease (ALD) is the major immunometabolic disorder characterized by dysregulated lipid metabolism and persistent activation of hepatic innate immune responses. Vincamine (Vin), isolated from Vinca minor, has been reported to exhibit diverse pharmacological activities. Nevertheless, the immunomodulatory effects and underlying mechanisms of Vin on ALD remain poorly understood.
    PURPOSE: This study aimed to explore the protective effects of Vin against alcohol-induced hepatic injury, with a particular focus on immunometabolic regulation of inflammasome activation.
    METHODS: An acute ethanol-fed mouse model was established using male C57BL/6 mice. In vitro experiments were performed using ethanol-stimulated AML12 and HepG2 hepatocytes, as well as LPS/ATP-activated murine peritoneal macrophages.
    RESULTS: Vin significantly attenuated hepatic steatosis in ethanol-fed mice through modulation of lipid metabolism-associated genes, notably SREBP1 and PPARα. Vin also modulated glycolysis-related pathways through regulation of CDK1, GLUT1, and HIF-1α. In vivo, Vin markedly reduced alcohol-induced immune cell infiltration and suppressed activation of the TLR4-NLRP3 inflammasome pathway. In hepatocytes, Vin alleviated ethanol-induced lipid accumulation, accompanied by downregulation of CDK1 and GLUT1 and reduced NLRP3 activation and IL-1β secretion. In macrophages, Vin inhibited LPS/ATP-induced IL-1β and Caspase-1 expression. Mechanistically, CDK1 deficiency impaired glycolytic activity, as reflected by reduced expression of GLUT1, HIF-1α, and LDHA, and subsequently alleviated lipid accumulation and inflammatory responses under ethanol exposure.
    CONCLUSION: Vin exerts protective effects against alcohol-induced hepatic steatosis and inflammation by modulating a CDK1-associated metabolic-inflammatory axis involving glycolysis and NLRP3 inflammasome activation.
    Keywords:  Alcoholic liver disease; CDK1; Glycolysis; Immunometabolism; NLRP3 inflammasome; Vincamine
    DOI:  https://doi.org/10.1016/j.intimp.2026.116714
  44. Adipocyte. 2026 Dec;15(1): 2665903
    mTORC2 regulates lipid metabolism-driven TAMs via the PPAR-γ/CD36 pathway to promote liposarcoma progression.
    Weihua Xiao, Jingdan Sheng, Chunjiao Liu, Junqiang Li, Peng Shu, Maofen Jiang, Min Wang, Ji He, Haifen Ma, Yaxin Ding.
      Tumour-associated macrophages (TAMs) exert a pivotal function in tumour progression, and M2-type TAMs are closely linked to tumour-promoting functions. Mechanistic target of rapamycin complex 2 (mTORC2) may mediate TAM polarization and subsequent tumour development, yet their roles in liposarcoma (LPS) remain unclear. Macrophage polarization was assessed via flow cytometry for CD206. Western blot for Arg-1, Rictor, PPAR-γ, CD36, ACSL1 and CPT2, qPCR for IL-10, Arg-1 and Ym1, and ELISA for IL-10 secretion. Fatty acid metabolism was evaluated using free fatty acid (FFA) uptake assays and Oil Red O staining for intracellular lipid droplets. A Transwell assay was established to assess the effect of treated macrophages on LPS cell biology, and EdU assays were used for proliferation assessment. Transwell migration and invasion assays were utilized for assessing cellular motility. IL-4 induced RAW264.7 macrophages to undergo M2 polarization, characterized by upregulated CD206, Arg-1, and IL-10. During this process, mTORC2 was activated, promoting FFA uptake, lipid droplet accumulation, and fatty acid oxidation via the PPAR-γ/CD36 axis. Co-culture experiments showed that IL-4-polarized M2 macrophages enhanced LPS cell proliferation, migration, and invasion; these effects were inhibited by JR-AB2-011 and restored by LPA, confirming mTORC2-PPAR-γ/CD36-mediated TAMs drive LPS progression. mTORC2 regulates M2 TAM polarization and metabolic reprogramming via the PPAR-γ/CD36 pathway, thereby promoting LPS cell proliferation, migration, and invasion.
    Keywords:  PPAR-γ/CD36 pathway; fatty acid metabolism; liposarcoma; mTORC2; tumour-associated macrophages
    DOI:  https://doi.org/10.1080/21623945.2026.2665903
  45. Front Immunol. 2026 ;17 1781451
    Natural killer cell dysregulation in polycystic ovary syndrome: immunometabolic and reproductive implication.
    Ningxiao Jiang, Jun Liu, Chanyu Li, Xiuju Wang, Yiwei Pang, Xianghui Zhang, Yixuan Ma, Shinan Zhang, Yingjiang Xu, Qingchun Li, Qinglei Sun, Peiyi Tang, Lei Han.
      Polycystic ovary syndrome (PCOS), a complex endocrine and metabolic disorder, involves significant dysregulation of the immune system. Natural killer (NK) cells, as key components of innate immunity, demonstrate notable phenotypic and functional alterations in women with PCOS. These changes include not only an elevated proportion in peripheral blood but also dynamic shifts within the local microenvironments of the ovary and endometrium. The increased level of peripheral NK cells correlates with a chronic low-grade inflammatory state, potentially serving as a predictive marker in infertile PCOS patients. Within the endometrium, uterine NK (uNK) cells exhibit reduced numbers and impaired function, accompanied by dysregulation of cytokine networks such as IL-15 and IL-18, which disrupts the immune equilibrium essential for embryo implantation. Abnormal NK cell function further involves alterations in killer immunoglobulin-like receptor (KIR) repertoires and dysregulated secretion of angiogenic factors, thereby compromising endometrial receptivity and vascular remodeling. Hyperandrogenemia modulates the distribution and activity of NK cells in reproductive tissues by influencing their surface activation markers, while insulin resistance promotes the generation of myeloid-feature NK (myNK) cell subsets via the IL-6/Stat3 signaling pathway, collectively exacerbating metabolic inflammation and reproductive dysfunction. Deciphering the role of NK cells in the immunometabolic interplay of PCOS reveals their position as a critical link between. May represent a potential cutoff requiring validation in larger cohorts reproductive impairment and metabolic disturbances, opening new avenues for targeted immunomodulatory interventions. Collectively, NK cells appear to present an important immunometabolic link between reproductive dysfunction and metabolic disturbance in PCOS, highlight their potential relevance as therapeutic targets.
    Keywords:  chronic inflammation; hyperandrogenism; immunometabolism; insulin resistance; natural killer cell; polycystic ovary syndrome; uterine NK cells
    DOI:  https://doi.org/10.3389/fimmu.2026.1781451
  46. Cell Insight. 2026 Jun;5(3): 100321
    Ketone body metabolism activates the immune response against Staphylococcus aureus infection by fueling the tricarboxylic acid cycle and affecting histone β-hydroxybutyrylation.
    Huanhuan Cai, Xin Yue, Yingbo Chen, Xiaoyu Chen, Renbo Qiao, Gechang Zhong, Shuo Rong, Lin Zhang, Zelong Li, Aihua Liao, Wei Xiong, Cihang Guo, Yanfang Zhu, Keqiong Deng, Li Zhou, Ying Zhu, Zhibing Lu, Xiangtai Zeng, Shi Liu.
      Staphylococcus aureus (S. aureus) is a prominent human pathogen that causes persistent inflammation and is notoriously difficult to treat. Fasting is one of host adaptations to infection, and the induction of ketogenesis and ketolysis is a well-described host metabolic adaptation in response to fasting. However, more information about the energy substrates required to meet the immune response to S. aureus infection demands is needed. This study shows that the production of β-hydroxybutyrate (BHB) is enhanced in individuals with S. aureus, and BHB levels correlate with inflammatory cytokines and fibrotic biomarkers. We found that treatment with BHB or a ketogenic diet promotes the production of interferon and inflammatory cytokines, protecting mice from S. aureus infection and disease. Further studies demonstrated that ketogenesis and ketolysis were required for immune responses to S. aureus infection. Mechanistically, ketone bodies, including BHB and acetoacetate, fuel the tricarboxylic acid cycle. On the other hand, BHB also regulates immune response via effects on histone β-hydroxybutyrylation. These findings suggest ketogenesis and ketolysis are metabolic and epigenetic drivers of immune responses during S. aureus infection.
    DOI:  https://doi.org/10.1016/j.cellin.2026.100321
  47. Int J Biol Macromol. 2026 Apr 23. pii: S0141-8130(26)02108-2. [Epub ahead of print]364 152182
    Angelica sinensis polysaccharides modulate iron metabolism and macrophage polarization to alleviate rheumatoid arthritis.
    Yuxue Zhan, Hengqi Zhang, Tingting Guo, Hailong Qin, Lei Huang, Nire Wu, Jingyi Wang, Xu Mu, Jinglin Wang, Mingming Li, Kaiping Wang, Yu Zhang.
      Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint inflammation and systemic complications. Recent evidence has indicated that disrupted iron metabolism, notably elevated hepcidin expression and excessive iron accumulation in tissues, contributes to RA progression. In RA, Macrophages, which play a central role in both immune regulation and iron homeostasis, are often polarized toward the proinflammatory M1 phenotype. In this study, we investigated the therapeutic effects of Angelica sinensis polysaccharides (ASP, 100-400 mg/kg) in a collagen-induced arthritis (CIA) mouse model. ASP significantly alleviated joint swelling, histopathological damage, and iron deposition in the liver and spleen. It also downregulated hepcidin expression and restored the M1/M2 macrophage balance. Furthermore, immunofluorescence and western blotting confirmed increased ferroportin (FPN) and decreased ferritin levels in splenic macrophages. In an in vitro coculture model mimicking inflammation, ASP indirectly modulated macrophage iron handling and polarization by suppressing hepatocyte-derived hepcidin. RNA-seq analysis revealed that ASP treatment downregulated HIF-1α and NF-κB pathways, which link iron metabolism to macrophage activation, whereas the results of reactive oxygen species (ROS) assays supported its role in reducing oxidative stress associated with iron overload. Together, these findings suggest that ASP alleviates RA symptoms by restoring iron homeostasis and modulating macrophage polarization, primarily by targeting the hepcidin-FPN axis and related inflammatory pathways. ASP therefore holds promise as a low-toxicity, immunomodulatory candidate for RA therapy.
    Keywords:  Angelica sinensis polysaccharide; Hepcidin; Iron metabolism; Macrophage polarization; Rheumatoid arthritis
    DOI:  https://doi.org/10.1016/j.ijbiomac.2026.152182
  48. bioRxiv. 2026 Apr 17. pii: 2026.04.14.718497. [Epub ahead of print]
    Gut-derived metabolic reprogramming drives immune aging and tissue degeneration.
    Sayan Ghosh, Victoria Koontz, Ying Xin, Sridhar Bammidi, Dominique Meyer, Haochen Wang, Vishnu Suresh Babu, Puja Dutta, Durgadas Cherukaraveedu, Shreevadsaa A Mohanakrishnan, Anupam K Mondal, Jagannath Das, Jenny Nguyen, Avinash Soundararajan, Idris A Adekale, Dulal Bhaumik, Stacey Hose, Sheldon Rowan, Padmanabhan P Pattabiraman, Rangaramanujam M Kannan, James T Handa, Ji Yi, Srinivasa R Sripathi, Jiang Qian, Debasish Sinha.
      Aging is characterized by changes in gut microbiome, metabolic imbalance and chronic inflammation, yet how these processes integrate to drive tissue degeneration remains poorly defined. Using age-related macular degeneration (AMD) as a model of tissue aging, we identify a diet-induced metabolic-immune axis that promotes systemic and retinal degeneration. In mice, a high-fat, cholesterol-enriched (HFC) diet induced perturbations in the gut structural integrity and microbiome repertoire, as well as systemic metabolic aging signatures, prominently marked by reduced circulating histidine. Plasma histidine levels were similarly decreased in AMD patients and inversely correlated with body mass index (BMI) in control donors. These diet-induced gut microbiome changes and subsequent metabolic alterations promoted peripheral innate immune reprogramming, with expansion of inflammatory neutrophils and monocytes that infiltrated the outer retina in a mouse model. Mechanistically, the gut-derived IGF1R/AKT2 signaling acts as a central regulator of global epigenetic remodeling and systemic immune aging under high-fat conditions in C. elegans . In a mouse model with an age-dependent dry AMD-like pathology, distinct retinal pigment epithelium (RPE) subpopulations exhibited downregulation of the histidine transporter SLC7A5, linking metabolic stress to activation of MIF/CD74-dependent inflammatory signaling between RPE and infiltrating immune cells. Histidine supplementation or AKT2 phospho-state modulation attenuated systemic immune activation and rescued retinal degeneration. These findings identify histidine-axis dysregulation as a mechanistic bridge between diet-induced microbiome changes, metabolic stress, immune aging, and retinal degeneration.
    DOI:  https://doi.org/10.64898/2026.04.14.718497
  49. mBio. 2026 Apr 29. e0058026
    Vancomycin disrupts mitochondrial morphology and function and impairs macrophage fungal killing.
    Ebrima Bojang, Lozan Sheriff, Emma Morris, Sophie Rouvray, Man Shun Fu, Chloe Wellings, Ketema Abdissa, Victoria Stavrou, Callum Clark, Andrew D Southam, Warwick B Dunn, David Bending, Jose R Hombrebueno, Ilse Jacobsen, Sarah Dimeloe, Rebecca A Hall, Rebecca A Drummond.
      Vancomycin is a widely prescribed antibiotic used in the treatment of gram-positive bacterial infections. We previously showed that this antibiotic disrupted protective antifungal immune responses via microbiome dysbiosis, enhancing susceptibility to invasive candidiasis. Antibiotics are an independent risk factor for developing this life-threatening fungal infection, but whether microbiota-independent mechanisms also drive this association is not clear. Here, we show that vancomycin directly impairs macrophage responses to Candida albicans, the main causative agent of invasive candidiasis. Vancomycin-treated macrophages were less able to kill C. albicans despite normal phagocytosis rates and were hyper-inflammatory and more likely to die during infection. Using a fluorescently labeled vancomycin, we observed vancomycin uptake by macrophages in vivo and within close proximity to the mitochondrial outer membrane. Vancomycin treatment led to a significant depolarization, reduced respiratory capacity, and a hyper-fragmented morphology of mitochondria, as well as increased cellular ROS production. Taken together, this work demonstrates direct effects of vancomycin on mammalian immune cells, helping us to understand the pro-inflammatory effects of this drug and how it promotes susceptibility to life-threatening fungal infection.IMPORTANCEAntibiotics are widely prescribed drugs used to treat bacterial infections; however, their use may increase the likelihood of developing life-threatening fungal infections in vulnerable patients. Candida albicans is a commensal fungus in humans but may cause serious disease in patients with defined risk factors, including antibiotic exposure. We find that the antibiotic vancomycin significantly impairs the ability of macrophages to kill C. albicans yeast. Vancomycin-induced defects in fungal killing were associated with changes to mitochondria in antibiotic-exposed macrophages, which also exhibited enhanced oxidative stress and reduced survival during fungal infection. This work identifies a direct mechanism by which antibiotics may impair antifungal immunity.
    Keywords:  Candida albicans; fungi; hospital infections; macrophages; mitochondria; postantibiotic effect; vancomycin
    DOI:  https://doi.org/10.1128/mbio.00580-26
  50. Eur J Immunol. 2026 Apr;56(4): e70189
    ADAR1 Controls Macrophage Scavenging and Lipid-Buffering Programs in Metabolic Tissues.
    Achilleas Fardellas, Emelie Barreby, Madara Brice, Sebastian Nock, Jules Russick, Ana Vankova, Charlotte Edberg, Ida Robertsen, Jens K Hertel, Per Stål, Gunnar Mellgren, Cecilia Karlsson, Jøran S Hjelmesaeth, Hannes Hagström, Erik Näslund, Volker M Lauschke, Johan Fernø, Ping Chen, Cecilia Morgantini, Myriam Aouadi, Niklas K Björkström.
      Adenosine deaminase acting on RNA 1 (ADAR1) regulates mRNA fate and function through adenosine-to-inosine (A-to-I) RNA editing and RNA-binding activities. While its role in innate immunity is established, the broader regulatory functions of ADAR1 in macrophages remain poorly defined. Here, we systematically profiled ADAR1 expression across human immune cells and identified marked enrichment in macrophages, driven by selective usage of an alternative transcription start site during monocyte-to-macrophage differentiation. ADAR1 binds, edits, and modulates key macrophage targets involved in efferocytosis, endocytosis, lysosomal processing, lipid metabolism, and proliferation in an isoform-specific manner. We further demonstrate that ADAR1 levels and activity are dynamically regulated in adipose tissue and liver during the progression of metabolic disease. Linked to this, macrophage-specific ablation of ADAR1 co-cultured in organotypic 3D primary human liver spheroids and exposed to metabolic stress resulted in an exacerbated lipid accumulation phenotype. Finally, we identify a lipid-associated macrophage-specific upregulation of ADAR1 in adipose tissue following weight loss interventions, mechanistically driven by free fatty acids. These findings uncover a previously unrecognized role for ADAR1 in lipid-buffering, scavenging, and proliferative macrophage functions, extending its biological relevance beyond canonical interferon-mediated immunity and establishing ADAR1 as a key regulator of macrophage adaptation in metabolic disease.
    DOI:  https://doi.org/10.1002/eji.70189
  51. Cell Commun Signal. 2026 Apr 30.
    Kynurenine-AhR-SLC39A10-Zn2+ signaling reprograms macrophages and enhances pirfenidone efficacy in pulmonary fibrosis.
    Huihui Yue, Ruihan Dong, Jianhan He, Fengqin Zhang, Yan Fan, Xinran Dou, Qing Zhou, Xuan Li, Long He, Shu Zhang, Qilin Yu, Weikuan Gu, Jianping Zhao, Yi Wang, Cong-Yi Wang, Huilan Zhang.
       BACKGROUND: Pulmonary fibrosis (PF) is an irreversible and lethal lung disease characterized by progressive scarring lacking safe and effective treatment options. Recent studies have underscored the role of macrophage polarization in fibrotic progression, yet the role of kynurenine (Kyn), a metabolite of tryptophan (Trp), in macrophages during PF progression remains elusive.
    METHODS: Liquid Chromatography-tandem Mass Spectrometry (LC-MS) analysis was used to detect tryptophan metabolism changes in the serum of PF patients and control subjects. Macrophage-specific Ido1 or Ahr deletion mice was utilized to explored the role of Kyn in the bleomycin-induced fibrotic mouse model and ChIP sequence was employed to elucidate the mechanism by which Kyn inhibits pro-fibrotic macrophage activation.
    RESULTS: We identified Kyn, Trp levels and Kyn/Trp ratio (KTR) were notably elevated in the serum of patients with different types of PF and these alterations were inversely correlated with lung function. Although such elevation might appear pathogenic, our functional studies demonstrate that Kyn exerts protective effects in PF, akin to brain natriuretic peptide in heart failure. Macrophage-specific deletion of Ido1 or aryl hydrocarbon receptor (AhR, the receptor of Kyn) exacerbated bleomycin-induced PF, while exogenous Kyn supplementation mitigated disease severity. Mechanistically, Kyn bound to the AhR, facilitating its nuclear translocation, where it promoted Slc39a10 transcription to increase the intracellular levels of zinc ion, thereby inhibiting profibrotic macrophage differentiation. Intriguingly, pirfenidone was noted with high potency to suppress Kyn production and our studies demonstrated that administration of Kyn along with pirfenidone effectively enhanced the therapeutic efficacy against PF.
    CONCLUSIONS: In summary, these findings reveal a previously unrecognized Kyn-AhR-SLC39A10-Zn2+ signaling axis that governs macrophage polarization in PF, and unveiled the importance of Trp metabolism in PF pathogenesis, which could be novel therapeutic strategies against PF.
    Keywords:  Kynurenine; Macrophages; Pulmonary fibrosis; Tryptophan metabolism
    DOI:  https://doi.org/10.1186/s12964-026-02900-5
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