bims-imicid 2025-07-13 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2025–07–13
twenty-six papers selected by
Dylan Ryan, University of Cambridge

Lessons from Glucocorticoids, Metformin, and Dimethyl Fumarate: Could Targeting Immunometabolism Lead to Better Anti-Inflammatory Therapies?
Acetyl-CoA subcellular compartmentalization regulates T cell adaptation.
Macrophage respiratory complex III governs immune evasion.
Immune cell metabolism in cancer drug resistance: Advances in target discovery and clinical translation.
Regulation of CD4 + T cell differentiation and function by glucose metabolism.
Succinate Dehydrogenase Regulates Homeostasis and Metabolic Integrity of Alveolar Macrophages.
Targeting macrophage glucose metabolism: Polysaccharide-iron nanozyme-mediated reactive oxygen species/iron homeostasis restoration ameliorates inflammatory bowel disease with anemia comorbidity.
Controlling mitochondrial membrane architecture via MIC60 determines viral replication to promote anti-viral immunity.
Aberrant glucose metabolism drives dysfunction of CD4+ T cells in systemic lupus erythematosus and disease flares.
Waste as an antibacterial weapon.
Aging impairs peroxisome biogenesis in human B cells.
Aging modulates the immunosuppressive, polarizing and metabolic functions of blood-derived myeloid-derived suppressor cells (MDSCs).
Serum tryptophan-kynurenine metabolites served as biomarkers of disease activity in rheumatoid arthritis and linked to immune imbalance.
Triglyceride metabolism controls inflammation and microglial phenotypes associated with APOE4.
Exercise-induced microbiota metabolite enhances CD8 T cell antitumor immunity promoting immunotherapy efficacy.
Rerouting glucose metabolism of therapeutic T-cells for cancer: live longer, perform better.
Upregulated Hexokinase-2 in Airway Epithelium Regulates Apoptosis and Drives Inflammation in Asthma via Peptidylprolyl Isomerase F.
Global transcriptome characterization of peripheral blood mononuclear cells in individuals with chronic HIV infection.
Fucosylated chondroitin sulfate exerts in vitro anti-tumor property through manipulating the metabolism related polarization of macrophages.
Interleukin-17A signaling promotes CD8+ T cell cytotoxicity against West Nile virus infection through enhancing PI3K-mTOR-mediated metabolism.
The microbial metabolite butyrate enhances the effector and memory functions of murine CD8+ T cells and improves anti-tumor activity.
CD4 + T cells promote fibrosis during metabolic dysfunction-associated steatohepatitis.
Mitochondrial control of macrophage polarity in tumors.
ICOS regulates IL-10 production in group 2 innate lymphoid cells via cholesterol and cortisol biosynthesis.
Myocardial pyruvate dehydrogenase kinase 4 drives sex-specific cardiac responses to endotoxemia.
Metabolite derived from green tea polyphenol increases and activates plasmacytoid dendritic cells.

Annu Rev Pharmacol Toxicol. 2025 Jul 09.

Lessons from Glucocorticoids, Metformin, and Dimethyl Fumarate: Could Targeting Immunometabolism Lead to Better Anti-Inflammatory Therapies?

Victoria A Evans, Luke A J O'Neill.

Emerging evidence suggests that alterations in immunometabolism contribute to pathogenesis of inflammatory diseases, providing potential therapeutic targets. Anti-inflammatory drugs such as glucocorticoids, metformin, and dimethyl fumarate (DMF) modulate key immunometabolic pathways. Glucocorticoids boost itaconate production, which exerts anti-inflammatory effects via multiple targets, including by modification of cysteines on inflammatory proteins. Metformin, known for inhibiting gluconeogenesis in type 2 diabetes, also blocks mitochondrial Complex I and increases GDF-15, a regulator of food intake with anti-inflammatory properties, which may explain effects of metformin on inflammation. DMF, like itaconate, modifies cysteines on target proteins, notably KEAP1, leading to Nrf2 activation, which induces antioxidant enzymes and suppresses inflammatory gene expression. These immunometabolic actions suggest that targeting immune cell metabolism could provide new strategies for treating autoimmune diseases. This review explores recent advances in itaconate, GDF-15, and Nrf2 signaling and how harnessing these pathways may lead to novel anti-inflammatory therapies for patients with inflammatory diseases.

DOI: https://doi.org/10.1146/annurev-pharmtox-062624-013520
Cell Immunol. 2025 Jun 28. pii: S0008-8749(25)00086-3. [Epub ahead of print]414 105000

Acetyl-CoA subcellular compartmentalization regulates T cell adaptation.

Annefien Tiggeler, Paul J Coffer.

  Upon activation, naïve T cells undergo rapid proliferation and differentiation, giving rise to clonally expanded populations specifically tailored for an effective immune response. To meet the heightened bioenergetic and biosynthetic demands associated with activation, T cells adapt and reprogram both their metabolism and transcriptome. Beyond this, T cells are also able to dynamically adapt to fluctuations in the microenvironmental nutrient levels. While the adaptability of T cells is a well-established hallmark of their functionality, the molecular mechanisms by which metabolic responses underpin this flexibility remain incompletely defined. Acetyl-CoA, with its role as a central metabolite in mitochondrial ATP production, and a substrate for nuclear histone acetylation reactions, emerges as a key player in a metabolic-epigenetic axis. Recent evidence indicates that enzymes responsible for generating acetyl-CoA can translocate to the nucleus, supporting sub-cellular local acetyl-CoA production. Here, we explore the impact of acetyl-CoA metabolism on T cell functionality within different subcellular compartments and highlight the potential for intervention in acetyl-CoA metabolic pathways in T cell-driven autoimmune diseases and cancers.

Keywords:  Acetyl-CoA; Epigenetic remodelling; Metabolic reprogramming; Nuclear metabolism; T cells

DOI:  https://doi.org/10.1016/j.cellimm.2025.105000
Immunometabolism (Cobham). 2025 Jul;7(3): e00065

Macrophage respiratory complex III governs immune evasion.

Marie Anne-Catherine Neumann, Christian Frezza.

  The intricate interplay between cellular metabolism and immune function has emerged as a pivotal area of research in immunology. Macrophages, as central players in the innate immune system, exhibit remarkable metabolic flexibility that influences their activation states and functional outputs, with important implications for the pathophysiology of inflammatory diseases and cancer. A recent study by Zotta and colleagues provides new insights into the role of mitochondrial complex III (CIII) in regulating the anti-inflammatory cytokine interleukin-10 (IL-10) and its implications for tumor immunity.

Keywords:  IL-10; ROS; immune evasion; inflammation; metabolism; mitochondria

DOI:  https://doi.org/10.1097/IN9.0000000000000065
Chin J Cancer Res. 2025 Jun 30. 37(3): 432-445

Immune cell metabolism in cancer drug resistance: Advances in target discovery and clinical translation.

Liangjie Sun, Guo Zhao, Shuhang Wang, Ning Li.

  Drug resistance continues to be the principal limiting factor in achieving a cure for patients with cancer, significantly hindering the long-term efficacy of novel cancer drugs. Accumulating evidence has shown that metabolites derived from tumor cells regulate immune cell metabolism via tumor microenvironment crosstalk. However, as immunometabolic research has deepened, the leading role played by the intrinsic metabolic regulation of immune cells in the drug resistance of tumor cells has been discovered. Immune metabolites have been shown to cause immune resistance, target therapy resistance, and chemotherapy resistance, and drugs that target immune metabolism have great potential. To date, researchers have not fully explored the impact of immune-derived metabolites on tumor cells and their influence on the responsiveness to cancer drugs. In this review, we focus on the lactate, fatty acid, glucose, and nucleotide metabolic alterations that take place in T cells and macrophages and how these changes can impair anti-tumor immunity, ultimately promoting tumor cell survival and decreasing responsiveness to the corresponding therapeutic approaches. We present the current developments in drugs targeting immunometabolic pathways and propose constructive suggestions, such as precise delivery to immune cell targets to enhance efficacy and safety, offering novel perspectives for cancer drug development.

Keywords:  Cancer; cancer immunity; drug resistance; immunometabolism; metabolism

DOI:  https://doi.org/10.21147/j.issn.1000-9604.2025.03.11
Genes Immun. 2025 Jul 05.

Regulation of CD4 + T cell differentiation and function by glucose metabolism.

Yubo Liu, Yiwen Zhou, Ji Zhang, Jingyi Li, Liyun Zou.

The long-term persistence of naive T lymphocytes is maintained by a state of relative quiescence. Upon antigenic stimulation, these naive T cells undergo rapid activation and proliferation, differentiating into effector cells with specific clonal expansion. Recently, in-depth studies have revealed a fundamental difference in the metabolic requirements of distinct T cell subsets. The fate of CD4 + T cells is influenced by glucose-mediated glycolysis and oxidative phosphorylation (OXPHOS). In this context, key enzymes and various glycolytic intermediates, in conjunction with transcription factors and cytokines, play a crucial role in CD4 + T cell differentiation and function. In our study, we investigated the mechanisms underlying glycolytic reprogramming in CD4 + T cells, with a particular focus on the role of glycolytic enzymes in modulating cytokines and transcription factors that govern T cell differentiation.Our aim is to provide novel insights into the treatment of clinically relevant immune diseases by thoroughly elucidating the characteristics and potential regulatory mechanisms of glucose metabolism in CD4 + T cells.

DOI: https://doi.org/10.1038/s41435-025-00340-8
Immune Netw. 2025 Jun;25(3): e16

Succinate Dehydrogenase Regulates Homeostasis and Metabolic Integrity of Alveolar Macrophages.

Seung Geun Song, Ein Lee, Jaemoon Koh, Doo Hyun Chung.

  Lung tissue-resident macrophages, including alveolar macrophages (AMs) and interstitial macrophages (IMs), are pivotal in maintaining both immune defense and tissue homeostasis. Although the distinct functional roles of these macrophage populations are well recognized, the specific metabolic pathways that support their functions are not fully understood. Comparative RNA sequencing analysis identified Sdha, a key enzyme in mitochondrial metabolism, as one of the most highly expressed and differentially regulated genes involved in metabolic pathways in AMs relative to IMs. This finding led us to investigate the role of succinate dehydrogenase complex subunit A (SDHA) in regulating AM metabolism and function. Here, we demonstrated that SDHA is crucial for maintaining AM homeostasis. Deletion of SDHA resulted in a significant reduction in AM populations without affecting IMs, highlighting an AM-specific requirement for SDHA. In the absence of SDHA, AMs underwent metabolic reprogramming towards glycolysis compared with IMs, along with significant transcriptional changes and cell death. Furthermore, SDHA-deficient AMs showed lipid accumulation and increased endoplasmic reticulum stress. These findings establish SDHA as a crucial regulator of AM metabolism and underscore the importance of maintaining metabolic integrity for AM function and survival within the lung microenvironment.

Keywords:  Alveolar macrophages; Homeostasis; Metabolic reprogramming; Mitochondria; Succinate dehydrogenase

DOI:  https://doi.org/10.4110/in.2025.25.e16
J Colloid Interface Sci. 2025 Jul 04. pii: S0021-9797(25)01748-5. [Epub ahead of print]700(Pt 1): 138357

Targeting macrophage glucose metabolism: Polysaccharide-iron nanozyme-mediated reactive oxygen species/iron homeostasis restoration ameliorates inflammatory bowel disease with anemia comorbidity.

Peng Li, Qi Xia, Hui Zhang, Runyang Hong, Yisen Wang, Ying Huang, Hua Dai, Gen Wei, Yanfeng Zhang, Lei Fan, Juqun Xi.

  Inflammatory bowel disease (IBD) is a chronic immune-mediated disorder characterized by intestinal inflammation, with frequent progression to complications including intestinal stenosis, obstruction, and perforation. The sustained inflammatory burden and gastrointestinal bleeding in IBD culminate in systemic iron depletion, predisposing patients to iron deficiency anemia (IDA). Here, we report a rationally engineered nanozyme, Radix Paeoniae Alba polysaccharide‑iron complexes (PPFeCs), designed to integrate superoxide dismutase-/catalase-mimicking antioxidase activities with bioavailable iron delivery for simultaneous management of IBD and its IDA comorbidity. Experimental results demonstrated that PPFeCs alleviated dextran sulfate sodium-induced colonic inflammation, strengthened epithelial barrier integrity through upregulation of tight junction proteins, and ameliorated systemic iron deficiency by restoring hemoglobin levels, thereby confirming their therapeutic potential for treating IBD-IDA comorbidity. Mechanistically, PPFeCs reprogrammed macrophage glucose metabolism by shifting the balance from glycolysis to oxidative phosphorylation through Phosphoinositide 3-kinas/Protein kinase B (PI3K/Akt) pathway modulation. This metabolic switch synergized with Nuclear factor-kappa B (NF-κB) signaling inhibition to drive macrophage polarization from pro-inflammatory M1 to anti-inflammatory M2 phenotypes, thereby breaking the vicious cycle of inflammation and oxidative stress. Our findings not only elucidate the multifaceted therapeutic mechanisms of PPFeCs but also lay the groundwork for developing polysaccharide-metal-based nanozymes for treating IBD and its associated complications.

Keywords:  Glucose metabolism; IBD; Macrophage polarization; Polysaccharide-metal nanozymes; anemia

DOI:  https://doi.org/10.1016/j.jcis.2025.138357
Cell Rep. 2025 Jul 01. pii: S2211-1247(25)00693-X. [Epub ahead of print] 115922

Controlling mitochondrial membrane architecture via MIC60 determines viral replication to promote anti-viral immunity.

Ichiro Katahira, Nina Liebrand, Michal Gorzkiewicz, Niklas Paul Klahm, Džiuljeta Abromavičiūtė, Julia Werner, Karina Stephanie Krings, Sarah Orywol, Tobias Lautwein, Karl Köhrer, Diran Herebian, Ertan Mayatepek, Max Anstötz, Ann Kathrin Bergmann, Arun Kumar Kondadi, Haifeng C Xu, Aleksandra A Pandyra, Takumi Kobayashi, Dirk Brenner, Thomas Floss, Ulrich Kalinke, Andreas S Reichert, Philipp A Lang.

  Virus-infected cells often exhibit dramatic cellular changes accompanied by altered mitochondrial function. The contribution of factors shaping the inner mitochondrial membrane (IMM) and cristae architecture to viral replication is insufficiently understood. Single-cell transcriptomics applying vesicular stomatitis virus infection suggests involvement of factors determining IMM architecture following infection. Consistently, inhibition of the F1FO adenosine triphosphate (ATP) synthase reduces viral replication, which is associated with oligomerization of this complex and altered IMM structure. Moreover, deletion of mitochondrial contact site and cristae organizing system (MICOS) complex by targeting MIC60 results in reduced viral replication. Generation of Mic60inv/invCD11c-Cre+ mice uncovers reduced crista junctions and viral replication in bone marrow-derived dendritic cells. Consequently, reduced viral replication in CD11c-expressing cells limits prolonged immune activation. Altogether, by linking the F1FO ATP synthase and the MICOS complex to viral replication and immune activation, we describe links between the mitochondrial structure-metabolism and the immune response against viral infection.

Keywords:  BMDC; CP: Cell biology; CP: Microbiology; MIC60; MICOS; immunometabolism; innate immunity; inner mitochondrial membrane; itaconate; mitochondria; viral infection

DOI:  https://doi.org/10.1016/j.celrep.2025.115922
Cent Eur J Immunol. 2025 ;50(1): 13-23

Aberrant glucose metabolism drives dysfunction of CD4+ T cells in systemic lupus erythematosus and disease flares.

Lu Jin, Meng Ding, Shaoxin Cui, Lin Yang, Jinwen Zhao, Jingjing He, Xiaoping Wang, Fei Chang, Xue Liu, Qun Wang, Hongtao Jin, Jun Ma, Aijing Liu.

   Introduction: T cell immuno-metabolic regulation plays a key role in the development of systemic lupus erythematosus (SLE). This study aimed to analyze the role of CD4+ T cell glucose metabolism in SLE development.
Material and methods: Clinical data and blood samples were collected from 20 untreated SLE patients and healthy controls (HCs) matched for age, sex, and body mass index. After being isolated by magnetic sorting and cultured with anti-CD3/CD28 for 72 h, CD4+ T cells were subjected to real-time metabolic analysis. CD4+ T cell proliferation and cytokines were measured with cell counting kit-8 and Luminex liquid chip assay, respectively.
Results: Compared to HCs, SLE-CD4+ T cells exhibited significantly higher glycolytic capacity and mitochondrial oxidative phosphorylation (OXPHOS) (both p < 0.001). Additionally, SLE-CD4+ T cells demonstrated increased proliferation rates and elevated cytokine levels in both plasma and culture supernatants (both p < 0.05). OXPHOS and glycolysis of SLE-CD4+ T cells were positively correlated with SLE disease activity index-2000 (SLEDAI-2K) and cytokines, and negatively correlated with SLE-CD4+ T cell numbers (all p < 0.05).
Conclusions: CD4+ T cells from SLE patients showed higher glucose metabolic activity than those from HCs, and the enhanced glucose metabolism of SLE-CD4+ T cells was strongly correlated with disease activity, suggesting that glucose metabolic reprogramming plays an essential role in the pathogenesis of SLE.

Keywords:  CD4+ T cells; SLEDAI-2K; cytokines; glucose metabolism; systemic lupus erythematosus

DOI:  https://doi.org/10.5114/ceji.2025.149252
Cell Host Microbe. 2025 Jul 09. pii: S1931-3128(25)00240-9. [Epub ahead of print]33(7): 1045-1047

Waste as an antibacterial weapon.

M Maria Elgrail, Michael S Glickman.

Intracellular pathogens neutralize and evade macrophage-intrinsic host defenses. In this issue of Cell Host & Microbe, Anaya-Sanchez et al. show that methylglyoxal, a metabolic byproduct of glycolysis, is part of the macrophage arsenal limiting L. monocytogenes and M. tuberculosis infections but is countered by pathogen expression of methylglyoxal detoxification enzymes.

DOI: https://doi.org/10.1016/j.chom.2025.06.011
J Gerontol A Biol Sci Med Sci. 2025 Jul 09. pii: glaf148. [Epub ahead of print]

Aging impairs peroxisome biogenesis in human B cells.

Jacinta Correia, Promit Sinha Roy, Kaitlyn G Holden, Marian L Kohut, Hua Bai.

  Emerging evidence highlights the critical role of cellular metabolism in immune cell activation, development, and function. Peroxisomes, key metabolic organelles, maintain metabolic homeostasis, yet their role in immune cells remains underexplored. While animal studies show age-related declines in peroxisome biogenesis, this process is unconfirmed in human aging. We investigated peroxisome biogenesis in human peripheral blood mononuclear cells (PBMCs) and found a significant decline in aged CD19+ B cells compared to CD4+ T cells, CD8+ T cells, and CD14+ monocytes. B cell aging also reduces peroxisomal matrix enzyme import, evidenced by decreased SKL-containing enzymes and mature ACOX1, alongside downregulation of PEX19 and E3 ubiquitin ligases PEX2, PEX10, and PEX12. These findings confirm an evolutionarily conserved and age-related decline in peroxisome biogenesis. Further, our work unveils cell type-specific changes in aging human PBMCs, and provides new insights into peroxisome-mediated immunometabolism and B cell aging.

Keywords:  B cell aging; B cell metabolism; Peroxisomal enzyme import; Peroxisome biogenesis

DOI:  https://doi.org/10.1093/gerona/glaf148
Immun Ageing. 2025 Jul 08. 22(1): 29

Aging modulates the immunosuppressive, polarizing and metabolic functions of blood-derived myeloid-derived suppressor cells (MDSCs).

Emma Keltsch, Jennifer Greiner, Lena Wahl, Ingrid Knape, Daniel Tews, Michael Denkinger, Klaus-Michael Debatin, Gudrun Strauss.

   BACKGROUND: Immunosenescence describes the gradual remodeling of immune responses, leading to disturbed immune homeostasis and increased susceptibility of older adults for infections, neoplasia and autoimmunity. Decline in cellular immunity is associated with intrinsic changes in the T cell compartment, but can be further pushed by age-related changes in cells regulating T cell immunity. Myeloid-derived suppressor cells (MDSCs) are potent inhibitors of T cell activation and function, whose induction requires chronic inflammation. Since aging is associated with low grade inflammation (inflammaging) and increased myelopoiesis, age-induced changes in MDSC induction and function in relation to T cell immunity were analyzed.
RESULTS: MDSC numbers and functions were compared between "healthy" young and old adults, who were negatively diagnosed for severe acute and chronic diseases known to induce MDSC accumulation. MDSCs were either isolated from peripheral blood or generated in vitro from blood-derived CD14 cells. Aging was associated with significantly increased MDSC numbers in the monocytic- (M-) and polymorphonuclear (PMN-) MDSC subpopulations. MDSCs could be induced more efficiently from CD14 cells of old donors and these MDSCs inhibited CD3/28-induced T cell proliferation significantly better than MDSCs induced from young donors. Serum factors of old donors supported MDSC induction comparable to serum factors from young donors, but increased immunosuppressive activity of MDSCs was only achieved by serum from old donors. Elevated immunosuppressive activity of MDSCs from old donors was associated with major metabolic changes and increased intracellular levels of neutral and oxidized lipids known to promote immunosuppressive functions. Independent of age, MDSC-mediated suppression of T cell proliferation required direct MDSC- T cell contact. Besides their increased ability to inhibit activation-induced T cell proliferation, MDSCs from old donors strongly shift the immune response towards Th2 immunity and might thereby further contribute to impaired cell-mediated immunity during aging.
CONCLUSIONS: These results indicate that immunosenescence of innate immunity comprises accumulation and functional changes in the MDSC compartment, which directly impacts T cell functions and contribute to age-associated impaired T cell immunity. Targeting MDSCs during aging might help to maintain functional T cell responses and increase the chance of healthy aging.

Keywords:  Immunosenescence; Myeloid-derived suppressor cells; T cell immunity

DOI:  https://doi.org/10.1186/s12979-025-00524-w
Arthritis Res Ther. 2025 Jul 05. 27(1): 136

Serum tryptophan-kynurenine metabolites served as biomarkers of disease activity in rheumatoid arthritis and linked to immune imbalance.

Ruihe Wu, Baochen Li, Rui Su, Xiaoyang Liu, Anqi Gao, Jing Luo, Chong Gao, Xiaofeng Li, Caihong Wang.

   BACKGROUND: Immune imbalance caused by imbalanced helper T(Th)17/regulatory T (Treg) and follicular helper T (Tfh)/follicular regulatory T (Tfr) cells drives the onset of rheumatoid arthritis (RA) fundamentally. Tryptophan (Trp) metabolism is crucial in regulating immune and altered Trp metabolism has been reported in RA. However, the potential of altered Trp metabolites to serve as RA-related biomarkers and their relationship to immune balance in RA remains undetermined.
METHODS: We explored the Trp metabolic characteristics in RA by comparing the targeted quantitative Trp metabolomics between 29 new-onset RA patients and 19 healthy controls (HCs). The RA-related disease biomarkers from Trp metabolites were identified to construct a classification model through machine learning algorithms. Their association with immune imbalance in RA was analyzed.
RESULTS: Differential analysis exhibited significant alterations in serum Trp metabolites and metabolic pathways between RA and HCs. There were 7 differential metabolites of serum Trp, which were all decreased in RA (P < 0.05). Trp metabolic pathways analysis indicated that the Trp-Kynurenine(Kyn) pathway was downregulated in RA(P < 0.05). And the key enzyme of the Trp-Kyn pathway, indoleamine-2,3-dioxygenase1 (IDO1), was reduced in RA (P < 0.05). Altered Trp metabolites especially those from the Trp-Kyn pathway exhibited a negative correlation with the clinical indicators and autoantibody expression. 4 Trp metabolites from the Trp-Kyn pathway including Trp, xanthurenic acid (XA), cinnabarinic acid (CA) and kynurenic acid (KynA) were identified as RA-related disease biomarkers to construct RA-HC classification model, which exhibited good ability to distinguish RA from HCs (AUC = 0.951, 95%CI = 0.897-1.000) and stratify disease activity of RA. In addition, these Trp-Kyn pathway metabolites were also associated with the immune imbalance of RA. Specifically, reduced Trp and XA were negatively related to the imbalanced Th17/Treg cells, and reduced KynA was negatively associated with the imbalanced Tfh/Tfr cells. And the reduced IDO1 was also negatively correlated to the imbalanced Tfh/Tfr cells.
CONCLUSIONS: Altered Trp-Kyn metabolism might contribute to the pathogenesis of RA. We highlighted the association of the Trp-Kyn metabolic pathway with immune imbalance in RA and its potential value in clinical practice, particularly in early diagnosis, disease activity monitoring, and personalized treatment.

Keywords:  Immune imbalance; Rheumatoid arthritis; Tryptophan metabolism; Tryptophan-kynurenine metabolic pathway

DOI:  https://doi.org/10.1186/s13075-025-03596-7
Cell Rep. 2025 Jul 10. pii: S2211-1247(25)00732-6. [Epub ahead of print]44(7): 115961

Triglyceride metabolism controls inflammation and microglial phenotypes associated with APOE4.

Roxan A Stephenson, Jordy Sepulveda, Kory R Johnson, Adrian Lita, Jaanam Gopalakrishnan, Dominic J Acri, Alexandra Beilina, Linling Cheng, Linda G Yang, Jessica T Root, Michael E Ward, Christian Combs, William C Skarnes, Mark R Cookson, Han-Yu Shih, Mioara Larion, G William Rebeck, Priyanka S Narayan.

  Changes to cellular lipids accompany shifts in microglial cell state, but the functional significance of these metabolic changes remains poorly understood. In human induced pluripotent stem cell-derived microglia, we observed that both extrinsic activation (by lipopolysaccharide treatment) and intrinsic triggers (the Alzheimer's disease-associated APOE4 genotype) result in accumulation of triglyceride-rich lipid droplets. We demonstrate that lipid droplet accumulation is not simply concomitant with changes in the cell state. In fact, both triglyceride biosynthesis and catabolism are critical for the activation-induced transcription and secretion of inflammatory cytokines and chemokines, as well as changes in phagocytosis. In microglia harboring the Alzheimer's disease risk APOE4 genotype, inhibiting triglyceride biosynthesis attenuates disease-associated transcriptional states. Triglyceride biosynthesis inhibition also rescues microglial surveillance defects observed in slices from APOE4 humanized transgenic mice. Together, our findings establish that modulating triglyceride metabolism can tune microglial immune activity in response to extrinsic activation and in APOE4-associated disease.

Keywords:  APOE; Alzheimer's; CP: Neuroscience; activation; disease; iPSCs; lipid droplets; lipid metabolism; microglia; motility; neuroinflammation; triglycerides

DOI:  https://doi.org/10.1016/j.celrep.2025.115961
Cell. 2025 Jul 04. pii: S0092-8674(25)00684-1. [Epub ahead of print]

Exercise-induced microbiota metabolite enhances CD8 T cell antitumor immunity promoting immunotherapy efficacy.

Catherine M Phelps, Nathaniel B Willis, Tingting Duan, Amanda H Lee, Yue Zhang, Daphne M Rodriguez J, Surya P Pandey, Colin R Laughlin, Aaron B I Rosen, Alex C McPherson, Jake H Shapira, Simran K Randhawa, Lee Hedden, Tanner G Richie, Hallie M Wiechman, Mackenzie J Bender, Ina Nemet, Patrick A Zöhrer, Rachel A Gottschalk, Kathryn H Schmitz, Steven J Mullett, Stacy L Gelhaus, Diwakar Davar, Hassane M Zarour, Reinhard Hinterleitner, Thomas Mossington, Jonathan H Badger, Richard R Rodrigues, John A McCulloch, Sonny T M Lee, Karl-Heinz Wagner, Maria G Winter, Sebastian E Winter, Jishnu Das, Joseph F Pierre, Giorgio Trinchieri, Marlies Meisel.

  Exercise improves immune checkpoint inhibitor (ICI) efficacy in cancers such as melanoma; however, the mechanisms through which exercise mediates this antitumor effect remain obscure. Here, we identify that the gut microbiota plays a critical role in how exercise improves ICI efficacy in preclinical melanoma. Our study demonstrates that exercise stimulates microbial one-carbon metabolism, increasing levels of the metabolite formate, which subsequently enhances cytotoxic CD8 T cell (Tc1)-mediated ICI efficacy. We further establish that microbiota-derived formate is both sufficient and required to enhance Tc1 cell fate in vitro and promote tumor antigen-specific Tc1 immunity in vivo. Mechanistically, we identify the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) as a crucial mediator of formate-driven Tc1 function enhancement in vitro and a key player in the exercise-mediated antitumor effect in vivo. Finally, we uncover human microbiota-derived formate as a potential biomarker of enhanced Tc1-mediated antitumor immunity, supporting its functional role in melanoma suppression.

Keywords:  CD8 T cells; FMT; Nrf2; exercise; formate; immune checkpoint inhibitor; melanoma; microbiota; microbiota metabolite

DOI:  https://doi.org/10.1016/j.cell.2025.06.018
Immunometabolism (Cobham). 2025 Jul;7(3): e00063

Rerouting glucose metabolism of therapeutic T-cells for cancer: live longer, perform better.

Zhongyi Dong, Jianmei W Leavenworth.

  A significant barrier to the success of adoptive cell therapies (ACTs) in cancer treatment is the inadequate persistence of T-cells following infusion. In vitro T-cell expansion is a crucial component of ACTs; therefore, preconditioning during culture may enhance their in vivo survival and therapeutic efficacy. Here, we discuss a recent article by Greg Delgoffe and colleagues that was published in Cell Metabolism in April 2025, providing evidence that pharmacologic metabolic rewiring of activated T-cells during in vitro expansion enhances their engraftment postinfusion and improves cellular immunotherapies.

Keywords:  adoptive cell therapies; dichloroacetate; epigenetic reprogramming; exhaustion; immune memory; pharmacologic metabolic rewiring; pyruvate dehydrogenase kinase 1

DOI:  https://doi.org/10.1097/IN9.0000000000000063
Cells. 2025 Jul 01. pii: 1004. [Epub ahead of print]14(13):

Upregulated Hexokinase-2 in Airway Epithelium Regulates Apoptosis and Drives Inflammation in Asthma via Peptidylprolyl Isomerase F.

Zhen Tian, Hongyan Zheng, Yan Fan, Boyu Li, Zhenli Huang, Meijia Wang, Jixian Zhang, Jianping Zhao, Shanshan Wang, Jungang Xie.

  Hexokinase catalyzes the first rate-limiting step glycolysis. However, the roles of hexokinase 2 (HK2) in asthma remain incompletely understood. This study aimed to investigate metabolic alterations in asthma, focusing on the expression, function and regulation of HK2. In this study, non-targeted metabolomics analysis of 20 asthma patients and 15 healthy controls identified metabolic alterations in asthma, particularly in the glycolytic pathways. Consistently, HK2 expression was elevated in both asthma individuals and mice with allergic airway inflammation. Airway epithelium-specific HK2 knockdown and pharmacological inhibition with 2-deoxy-D-glucose (2-DG) significantly attenuated airway inflammation and hyperresponsiveness in mice induced by ovalbumin/ lipopolysaccharide. Mechanistic analyses demonstrated that HK2 regulates epithelial apoptosis and inflammation via interaction with peptidylprolyl isomerase F (PPIF), independent of voltage-dependent anion channel 1 (VDAC1). Asthma is associated with metabolic reprogramming, characterized by alterations in lipid and glucose metabolism. These findings establish HK2 plays a crucial role in asthma pathogenesis by promoting airway epithelial apoptosis and inflammation in asthma, suggesting its potential as a therapeutic target.

Keywords:  airway inflammation; apoptosis; asthma; glycolysis; hexokinase 2

DOI:  https://doi.org/10.3390/cells14131004
Genomics. 2025 Jul 08. pii: S0888-7543(25)00098-9. [Epub ahead of print] 111082

Global transcriptome characterization of peripheral blood mononuclear cells in individuals with chronic HIV infection.

Han-Ying Wang, Xi Wang, Qian-Qian Zhang, Xing-Zhong Miao, Liang-Juan Chen, Li-Jun Sun, Hong-Bo Shi.

   BACKGROUND: Acquired Immune Deficiency Syndrome (AIDS), resulting from Human Immunodeficiency Virus (HIV) infection, is one of the most severe infectious diseases worldwide. The current state of prevention and control remains critical. Recent studies have increasingly highlighted the significant role of cellular metabolism in regulating immune responses and managing infections. However, whether distinct immunometabolic profiles exist among different groups infected with HIV remains to be investigated. In this study, we employed RNA-seq technology to explore the differential characterization of immune metabolism across various HIV infections.
METHODS: To investigate the metabolic differences in peripheral blood mononuclear cells (PBMCs) from HIV-infected populations, we obtained PBMCs from 18 individuals diagnosed with HIV. This cohort included four Immune Responders (IRs), five Immune Non-Responders (INRs), five typical progressors (TPs) who maintained high viral loads, and four Elite Controllers (ECs) who sustained low levels of viral replication without treatment. We conducted single-cell sequencing on the PBMCs derived from these patients and compared the results between IRs and INRs, as well as ECs and TPs.
RESULTS: Our findings revealed significant metabolic dysregulation and altered inflammatory states in INRs compared to IRs. These alterations were primarily observed in purine metabolism, oxidative phosphorylation (OXPHOS) and glycolysis pathways, as well as modifications in amino acid and fatty acid metabolism pathways. Furthermore, we identified variations within a subset of CD8+ T-cell populations characterized by high expression of GNLY, which predominantly exerts cytotoxic effects. Differences in metabolic pathways were also noted between ECs and TPs; however, these changes mainly focused on OXPHOS and pentose phosphate pathways while no significant differences were observed in glycolysis pathway.

Keywords:  HIV-1; Metabolism; Mitochondrion; Purine metabolism

DOI:  https://doi.org/10.1016/j.ygeno.2025.111082
Int J Biol Macromol. 2025 Jul 07. pii: S0141-8130(25)06385-8. [Epub ahead of print]320(Pt 2): 145830

Fucosylated chondroitin sulfate exerts in vitro anti-tumor property through manipulating the metabolism related polarization of macrophages.

Jing Liu, Mengqiu Hu, Yanying Sun, Lei Zhao, Bin Wang, Xiaohui Qi, Jiaojiao Mou, Jie Yang.

  Tumor associated macrophages (TAMs) participate in the development of tumor, which was reported to dominantly be alternatively activated M2 subtype. Metabolic reprogramming of TAMs into tumor-inhibiting M1 type has shown to be a promising treatment strategy. In this study, we firstly demonstrated fucosylated chondroitin sulfate isolated from sea cucumber Stichopus chloronotus (fCS-Sc) exerted anti-tumor effects. fCS-Sc intervened the metabolism-polarization crosstalk of macrophages and reprogrammed M2 RAW264.7 cells to M1 subtype. fCS-Sc converted IL-4 and IL-13 mediated M2-like RAW264.7 cells to M1 subtype and enhanced the M1-like anti-tumor immunity via suppressing STAT6 signaling and promoting TLRs-NF-κB pathway. The reprogramming effect of fCS-Sc on M2 subtype macrophages were closely related to its metabolism. fCS-Sc markedly elevated the glycolytic pathway and down-regulated fatty acid oxidation pathway. Furthermore, the co-culture assay of M2 subtype RAW264.7 cells and 4 T1 cells demonstrated that fCS-Sc reprogrammed the M2 macrophages to M1 subtype and facilitated its tumor-killing ability. This study will contribute to the application of fCS-Sc as an ancillary drug in anti-tumor treatments.

Keywords:  Anti-tumor property; Cell metabolism; Fucosylated chondroitin sulfate; Polarization of macrophages

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.145830
PLoS Pathog. 2025 Jul 09. 21(7): e1013218

Interleukin-17A signaling promotes CD8+ T cell cytotoxicity against West Nile virus infection through enhancing PI3K-mTOR-mediated metabolism.

Farzana Nazneen, Biswas Neupane, Yao Chen, Shazeed-Ul Karim, Zongbing You, Weiguo Cui, Fengwei Bai.

West Nile Virus (WNV), a mosquito-borne neurotropic flavivirus, is a major cause of viral encephalitis in the United States, posing a continuous threat to public health. Unfortunately, no vaccine or specific therapeutic intervention is available against WNV infection. Previous studies, including ours, demonstrated that interleukin-17A (IL-17A) signaling promotes the cytotoxicity of CD8+ T cells to facilitate WNV and parasite clearance; however, the molecular mechanism is not understood. IL-17 receptor C (IL-17RC) is an obligatory co-receptor with IL-17 receptor A (IL-17RA) for signaling induced by IL-17A, IL-17A/F, and IL-17F. In this study, we found that IL-17RC deficient (Il17rc-/-) mice were more susceptible to WNV infection with a higher viral load in the brain than wild-type (WT) control mice. The number of infiltrating WNV-specific CD8+ T cells and the expression levels of cytotoxicity mediators, such as perforin, in the T cells in the brain of Il17rc-/- mice were reduced. In addition, WNV-specific CD8+ T cells from IL-17RA deficient (Il17ra-/-) mice and CD8+ cell-specific Il17ra conditional knockout (cre-KO) mice expressed lower levels of perforin than their counterpart controls. Moreover, supplementing mouse recombinant IL-17A ex vivo increased the perforin production in WNV-specific CD8+ T cells from the WT mice but not Il17rc-/- or cre-KO mice. Interestingly, we found that IL-17A signaling activated the phosphatidylinositol-3-kinase/mammalian target of rapamycin (PI3K-mTOR) signaling pathway in CD8+ T cells, leading to increased metabolism of CD8+ T cells to cope with the higher energy demand for WNV clearance in the brain. In summary, our findings reveal a novel IL-17A-PI3K-mTOR signaling axis in promoting the effector functions of CD8+ T cells, suggesting potential broader implications in stimulating immune responses to combat WNV and other intracellular infections.

DOI: https://doi.org/10.1371/journal.ppat.1013218
Front Med (Lausanne). 2025 ;12 1577906

The microbial metabolite butyrate enhances the effector and memory functions of murine CD8+ T cells and improves anti-tumor activity.

Douglas A Gaskarth, Shujun Fan, Andrew J Highton, Roslyn A Kemp.

   Introduction: CD8+ T cells are vital in the immune control of cancer and a key player in cell-based cancer immunotherapy. Recent studies have shown that microbial short-chain fatty acids (SCFA) can promote both effector and memory phenotypes in CD8+ T cells and may thereby enhance protection against cancer.
Methods: In this study, we determined the effect of SCFA butyrate on mouse CD8+ T cell function in vitro and in vivo, using the OT-I model.
Results: Butyrate co-culture with anti-CD3 + anti-CD28 activated T cells in vitro enhanced the frequency of effector CD8+ IFN-γ-producing cells, and the amount of cytokine produced per cell. Culture with butyrate also enhanced the activation, TCR expression, and levels of phosphorylated mTOR proteins within CD8+ T cells but reduced proliferation rate and increased apoptosis. Butyrate-treated activated cells conferred tumor protection after adoptive transfer. Butyrate-treated cells were present at higher frequencies within the tumor compared to non-butyrate treated cells, and expressed IFN-γ. When analyzed using high dimensional cytometry, the tumors of mice that received butyrate-treated cells were enriched in clusters displaying an effector memory phenotype with high expression of IL-15Rβ and T-bet.
Discussion: Our findings show that butyrate promotes the effector activity of CD8+ T cells in culture, which can persist in vivo while also stimulating memory phenotypes. Consequently, butyrate treatment may have strong application in T cell-based immunotherapies to improve protective cell functions and patient outcomes.

Keywords:   T cell memory; CD8+ T cells; activation; butyrate; cancer; effector function; immunotherapy; short-chain fatty acids

DOI:  https://doi.org/10.3389/fmed.2025.1577906
bioRxiv. 2025 Jul 03. pii: 2025.06.27.660220. [Epub ahead of print]

CD4 + T cells promote fibrosis during metabolic dysfunction-associated steatohepatitis.

Lucía Valenzuela-Pérez, Hyun Se Kim Lee, Rachel L Bayer, Shravan K Mishra, Alexander M Washington, Qianqian Guo, Adam Herman, Rondell P Graham, Malaz M Sidahmed, Edward Ssali, Adna A Hassan, Ece Janet Dinc, Kevin D Pavelko, Gregory J Gores, Patrick Starlinger, Xavier S Revelo, Samar H Ibrahim, Enis Kostallari, Adebowale O Bamidele, Petra Hirsova.

Unresolved inflammation and fibrosis are the two key features of metabolic dysfunction-associated steatohepatitis (MASH), a progressive form of steatotic liver disease that can evolve into cirrhosis and liver cancer. Although innate immunity has been well studied in MASH, the role of CD4⁺ T cells remains underexplored despite their potential to coordinate immune responses by providing help to other immune cells, promoting inflammation, or regulating immune activity through effector and regulatory subsets. To better understand the role of CD4 + T cells in the pathogenesis of MASH, we comprehensively characterized hepatic CD4 + T cells in murine and human MASH at a single-cell protein, transcriptional, and functional level. Mass cytometry and CITE-sequencing revealed a marked shift in intrahepatic CD4⁺ T-cell composition in MASH, with enrichment of Th1, regulatory, and cytotoxic CD4⁺ T cells. Similar phenotypic changes were mirrored in the peripheral blood and validated in human MASH samples. Functional assays demonstrated increased production of IFNγ and TNFα by hepatic CD4⁺ T cells, highlighting their proinflammatory effector activity. Transcriptomic profiling identified Tnfrsf4 (OX40) upregulation in hepatic CD4⁺ T cells during MASH. Therapeutic blockade of the OX40L-OX40 axis reversed hepatic fibrosis and improved histologic disease scores in mice with established MASH, and also decreased inflammatory markers in a human ex vivo liver model. Together, these studies provide a proteogenomic single-cell atlas for hepatic CD4⁺ T cells and uncover a CD4⁺ T cell-dependent immunopathogenic circuit as a promising immunotherapeutic target to alleviate MASH and liver fibrosis.

DOI: https://doi.org/10.1101/2025.06.27.660220
Immunity. 2025 Jul 08. pii: S1074-7613(25)00277-8. [Epub ahead of print]58(7): 1618-1620

Mitochondrial control of macrophage polarity in tumors.

Máté Kiss, Mikael J Pittet.

Macrophages can foster pro- or anti-tumor immune environments. In this issue of Immunity, Clark et al. report that altering the composition of the mitochondrial electron transport chain reprograms macrophages toward a CXCL9hiSPP1lo immunostimulatory phenotype, thus amplifying anti-tumor immunity.

DOI: https://doi.org/10.1016/j.immuni.2025.06.008
J Clin Invest. 2025 Jul 08. pii: e193134. [Epub ahead of print]

ICOS regulates IL-10 production in group 2 innate lymphoid cells via cholesterol and cortisol biosynthesis.

Yoshihiro Sakano, Kei Sakano, Benjamin P Hurrell, Mohammad H Kazemi, Xin Li, Stephen Shen, Omid Akbari.

  Group 2 innate lymphoid cells (ILC2s) play a crucial role in inducing type 2 inflammation in the lungs in response to allergens. Our study investigated the regulatory mechanism of IL-10 production by ILC2s and its impact on airway hyperreactivity (AHR), focusing on the role of ICOS. We found that inhibiting ICOS in pulmonary ILC2s significantly enhances IL-10 production. The absence of ICOS reprograms ILC2 steroid metabolism, leading to increased cholesterol and cortisol biosynthesis, and subsequent Glucocorticoid receptor (GR) activation. This reprogramming regulates MAF and NFIL3 activation, promoting IL-10 production. Notably, in vivo GR inhibition or ILC2-specific GR deficiency exacerbated AHR development in multiple mouse models. We extended these findings to human ILC2s, demonstrating concordant results between murine models and human cells. Our results indicate that ICOS negatively regulates IL-10 production in ILC2s by controlling cholesterol and cortisol biosynthesis. This mechanism provides new insights into the complex interplay between ILC2s, ICOS, and glucocorticoid signaling in the context of allergic airway inflammation.

Keywords:  Allergy; Asthma; Cholesterol; Immunology; Pulmonology

DOI:  https://doi.org/10.1172/JCI193134
JCI Insight. 2025 Jul 08. pii: e191649. [Epub ahead of print]10(13):

Myocardial pyruvate dehydrogenase kinase 4 drives sex-specific cardiac responses to endotoxemia.

John Q Yap, Azadeh Nikouee, Matthew Kim, Quan Cao, David J Rademacher, Jessie E Lau, Ananya Arora, Leila Y Zou, Yuxiao Sun, Luke Szweda, Hesham Sadek, Sharon Elliot, Benjamin Roos, Marilyn K Glassberg, Hong-Long Ji, Xiang Gao, Qunfeng Dong, Qun Sophia Zang.

  Males often experience worse cardiac outcomes than females in sepsis. This study identified pyruvate dehydrogenase kinase 4 (PDK4) as a key mediator of this disparity. PDK4 regulates glucose utilization by inhibiting pyruvate dehydrogenase (PDH) in mitochondria. In a mouse endotoxemia model, a sublethal dose of lipopolysaccharide (LPS, 5 mg/kg) significantly upregulated myocardial PDK4 and induced cardiac dysfunction in males but not females. Cardiac-specific PDK4 overexpression promoted this cardiac dysfunction in both sexes, whereas PDK4 knockout provided protection. In WT males, LPS reduced PDH activity and fatty acid oxidation (FAO) while increasing lactate levels, suggesting a shift toward glycolysis. These effects were exacerbated by PDK4 overexpression but attenuated by knockout. In females, metabolic changes were minimal, aside from reduced FAO in LPS-challenged females overexpressing PDK4. Additionally, a higher LPS dose (8 mg/kg) triggered cardiac dysfunction in females, accompanied by modest upregulation of PDK4, but without changes in PDH or lactate. Dichloroacetate (DCA), restraining PDK-mediated PDH inhibition, improved cardiac function in males but not females during endotoxemia. PDK4 overexpression also exacerbated cardiac mitochondrial damage, reduced mitophagy, and increased oxidative stress and inflammation during endotoxemia - effects that were prevented by PDK4 knockout. These findings suggest that PDK4 drives sex-specific cardiac responses in sepsis.

Keywords:  Cardiovascular disease; Inflammation; Metabolism; Mitochondria; Molecular pathology

DOI:  https://doi.org/10.1172/jci.insight.191649
J Nat Med. 2025 Jul 05.

Metabolite derived from green tea polyphenol increases and activates plasmacytoid dendritic cells.

Motofumi Kumazoe, Misato Nakajima, Reno Kawamoto, Yoshinori Fujimura, Reno Tomioka, Moeto Suzuki, Yuko Tanaka, Hirofumi Tachibana.

  The immune system plays a crucial role in protecting the body from harmful bacterial, viral infections and vital for cancer suppression. Dendritic cells (DCs) are indispensable mediators that facilitate the connection between innate and acquired immunity via antigen presentation and cytokine production. One of the major intestinal microbial metabolites of green tea polyphenols, 5-(3',5'-dihydroxyphenyl)-γ-valerolactone (EGC-M5), enhances T cell activity. However, the detailed underlying mechanisms remain unknown. Here, we revealed that the oral administration of EGC-M5 increases and activates plasma cytoid dendritic cells (pDCs) in the spleen without causing changes in body weight. Consistent with these findings, administration of EGC-M5 increased the gene expression of interleukin-12 in the spleen. Oral administration of EGC-M5 significantly increased type I Interferon (IFN) and IL-6 levels, which are involved in vaccine-induced antibody production. Ex vivo experiments showed that EGC-M5 treatment did not directly enhance pDC differentiation. In conclusion, EGC-M5 indirectly increased pDC levels in vivo, accompanied by an increase in the expression of pDC activation markers and the gene expression of interleukin-12, type I IFN and IL-6 in the spleen.

Keywords:  Dendritic cells; Green tea; Immunity; Metabolites; Plasmacytoid dendritic cells

DOI:  https://doi.org/10.1007/s11418-025-01929-z