bims-imicid 2025-03-23 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2025–03–23
39 papers selected by
Dylan Ryan, University of Cambridge

AMPK is necessary for Treg functional adaptation to microenvironmental stress during malignancy and viral pneumonia.
Recycling dead bacteria to fuel macrophage immunometabolism.
Do microglia metabolize fructose in Alzheimer's disease?
Differences in glycolytic metabolism between tissue-resident alveolar macrophages and recruited lung macrophages.
Macrophage-specific PHGDH protects against MAFLD by suppressing TAK1.
Mitochondrial reactive oxygen species regulate acetyl-CoA flux between cytokine production and fatty acid synthesis in effector T cells.
Blocking lactate: kick T cells when they are down.
Metabolic mechanisms of immunotherapy resistance.
High fat diet feeding impairs neutrophil phagocytosis, bacterial killing, and neutrophil-induced hematopoietic regeneration.
Crohn's Disease-associated variant in laccase domain containing 1 (LACC1) modulates T cell gene expression, metabolism and T cell function.
Mitochondrial response to fever boosts TH1-driven inflammatory responses.
Immunometabolic effects of β-glucan-trained immunity in newborn goats.
Activated T cells break tumor immunosuppression by macrophage re-education.
CD38-mediated metabolic reprogramming promotes the stability and suppressive function of regulatory T cells in tumor.
VDAC2 loss elicits tumour destruction and inflammation for cancer therapy.
RBM15, an m6A enzyme, suppresses NLRP3 inflammasome activation in rheumatoid arthritis through macrophage metabolism.
Reprogramming aerobic metabolism mitigates Streptococcus pyogenes tissue damage in a mouse necrotizing skin infection model.
Frozen Shoulder as a Metabolic and Immune Disorder: Potential Roles of Leptin Resistance, JAK-STAT Dysregulation, and Fibrosis.
Regulatory T cells in the mouse hypothalamus control immune activation and ameliorate metabolic impairments in high-calorie environments.
Bioengineering the metabolic network of CAR T cells with GLP-1 and Urolithin A increases persistence and long-term anti-tumor activity.
The tumor microenvironment is an ecosystem sustained by metabolic interactions.
The role of n-3-derived specialised pro-resolving mediators (SPMs) in microglial mitochondrial respiration and inflammation resolution in Alzheimer's disease.
Shared and distinct responses of human and murine alveolar macrophages and monocyte-derived macrophages to Mycobacterium tuberculosis.
Gallic acid promotes M2 macrophage polarization through mitochondrial oxidative phosphorylation in periodontitis.
Activation of GPR35 by kynurenic acid inhibits IL-1β secretion in macrophages during CR-hvKP-induced pneumonia.
Impact of oxidized phosphatidylcholine supplementation on the lipidome of RAW264.7 macrophages.
ACOD1-mediated lysosomal membrane permeabilization contributes to Mycobacterium tuberculosis-induced macrophage death.
Human gut microbial aromatic amino acid and related metabolites prevent obesity through intestinal immune control.
Human cytomegalovirus promotes de novo PC synthesis during early virus replication.
Functional regulation of cytotoxic T cells by gut microbial metabolites.
Leishmania major Dihydrolipoyl dehydrogenase (DLD) is a key metabolic enzyme that drives parasite proliferation, pathology and host immune response.
Microbiota-produced immune regulatory bile acid metabolites control central nervous system autoimmunity.
IL-7Rα signaling in regulatory T cells of adipose tissue is essential for systemic glucose homeostasis.
Metabolic stress and age drive inflammation and cognitive decline in mice and humans.
Exploring Human Brain Metabolism via Genome-Scale Metabolic Modeling with Highlights on Multiple Sclerosis.
Bcl-xL overexpression in T cells preserves muscle mitochondrial structure and function and prevents frailty in old mice.
Lactylation orchestrates ubiquitin-independent degradation of cGAS and promotes tumor growth.
Myeloid-derived suppressor cell inhibits T-cell-based defense against Klebsiella pneumoniae infection via IDO1 production.
Multi-platform omics analysis of Nipah virus infection reveals viral glycoprotein modulation of mitochondria.

J Clin Invest. 2025 Mar 18. pii: e179572. [Epub ahead of print]

AMPK is necessary for Treg functional adaptation to microenvironmental stress during malignancy and viral pneumonia.

Manuel A Torres Acosta, Jonathan K Gurkan, Qianli Liu, Nurbek Mambetsariev, Carla Reyes Flores, Kathryn A Helmin, Anthony M Joudi, Luisa Morales-Nebreda, Kathleen Cheng, Hiam Abdala-Valencia, Samuel E Weinberg, Benjamin D Singer.

  CD4+FOXP3+ regulatory T (Treg) cells maintain self-tolerance, suppress the immune response to cancer, and protect against tissue injury during acute inflammation. Treg cells require mitochondrial metabolism to function, but how Treg cells adapt their metabolic programs to optimize their function during an immune response occurring in a metabolically stressed microenvironment remains unclear. Here, we tested whether Treg cells require the energy homeostasis-maintaining enzyme AMPK to adapt to metabolically aberrant microenvironments caused by malignancy or lung injury, finding that AMPK is dispensable for Treg cell immune-homeostatic function but is necessary for full Treg cell function in B16 melanoma tumors and during influenza virus pneumonia. AMPK-deficient Treg cells had lower mitochondrial mass and exhibited an impaired ability to maximize aerobic respiration. Mechanistically, we found that AMPK regulates DNA methyltransferase 1 to promote transcriptional programs associated with mitochondrial function in the tumor microenvironment. During viral pneumonia, we found that AMPK sustains metabolic homeostasis and mitochondrial activity. Induction of DNA hypomethylation was sufficient to rescue mitochondrial mass in AMPK-deficient Treg cells, linking AMPK function to mitochondrial metabolism via DNA methylation. These results define AMPK as a determinant of Treg cell adaptation to metabolic stress and offer potential therapeutic targets in cancer and tissue injury.

Keywords:  Immunology; Intermediary metabolism; Mitochondria; Oncology; Pulmonology; T cells

DOI:  https://doi.org/10.1172/JCI179572
Nat Immunol. 2025 Mar 19.

Recycling dead bacteria to fuel macrophage immunometabolism.

Shane M O'Carroll, Luke A J O'Neill.

DOI: https://doi.org/10.1038/s41590-025-02117-7
J Neuroinflammation. 2025 Mar 15. 22(1): 85

Do microglia metabolize fructose in Alzheimer's disease?

Annalise M Sturno, James E Hassell, Miguel A Lanaspa, Kimberley D Bruce.

  Alzheimer's disease (AD) is an age-associated neurodegenerative disorder with a complex etiology. While emerging AD therapeutics can slow cognitive decline, they may worsen dementia in certain groups of individuals. Therefore, alternative treatments are much needed. Microglia, the brain resident macrophages, have the potential to be novel therapeutic targets as they regulate many facets of AD, including lipid droplet (LD) accumulation, amyloid beta (Aβ) clearance, and neuroinflammation. To carry out such functions, microglia undergo phenotypic changes, which are linked to shifts in metabolism and substrate utilization. While homeostatic microglia are driven by oxidative phosphorylation (OXPHOS) and glycolysis, in aging and AD, microglia shift further towards glycolysis. Interestingly, this "metabolic reprogramming" may be linked to an increase in fructose metabolism. In the brain, microglia predominantly express the fructose transporter SLC2A5 (GLUT5), and enzymes involved in fructolysis and endogenous fructose production, with their expression being upregulated in aging and disease. Here, we review evidence for fructose uptake, breakdown, and production in microglia. We also evaluate emerging literature targeting fructose metabolism in the brain and periphery to assess its ability to modulate microglial function in AD. The ability of microglia to transport and utilize fructose, coupled with the well-established role of fructose in metabolic dysfunction, supports the notion that microglial fructose metabolism may be a novel potential therapeutic target for AD.

Keywords:  Fructose; Immunometabolism; Metabolic reprogramming; Microglia; Neurodegeneration

DOI:  https://doi.org/10.1186/s12974-025-03401-x
Front Immunol. 2025 ;16 1535796

Differences in glycolytic metabolism between tissue-resident alveolar macrophages and recruited lung macrophages.

Parker S Woods, Gökhan M Mutlu.

  Immunometabolism has emerged as a key area of focus in immunology and has the potential to lead to new treatments for immune-related diseases. It is well-established that glycolytic metabolism is essential for adaptation to hypoxia and for macrophage inflammatory function. Macrophages have been shown to upregulate their glycolytic metabolism in response to pathogens and pathogen-associated molecular patterns such as LPS. As a direct link to the external environment, the lungs' distinctive nutrient composition and multiple macrophage subtypes provide a unique opportunity to study macrophage metabolism. This review aims to highlight how the steady-state airway and severely inflamed airway offer divergent environments for macrophage glycolytic metabolism. We describe the differences in glycolytic metabolism between tissue-resident alveolar macrophages, and other lung macrophages at steady-state and during inflammation/injury. We also provide an overview of experimental guidelines on how to assess metabolism at the cellular level using Seahorse-based bioenergetic analysis including a review of pharmacologic agents used to inhibit or activate glycolysis.

Keywords:  alveolar macrophage; bioenergetics; bone marrow-derived macrophage; cytokines; glycolysis; interstitial macrophage; metabolism; monocyte-derived alveolar macrophage

DOI:  https://doi.org/10.3389/fimmu.2025.1535796
Cell Rep. 2025 Mar 16. pii: S2211-1247(25)00197-4. [Epub ahead of print]44(3): 115426

Macrophage-specific PHGDH protects against MAFLD by suppressing TAK1.

Penghui Hu, Xiao Shan, Hongyuan Dong, Sujun Yu, Baochen Wang, Hui Xiong, Zemin Ji, Weijia Jing, Yan Cui, Zihan Li, Yanzhao Zhou, Zhe Wang, Jinrong Wang, Jiuzhou Tang, Ting Wang, Keliang Xie, Qiujing Yu.

  Metabolic dysfunction-associated fatty liver disease (MAFLD) is a progressive disease with only one approved treatment currently available. Hepatic phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme of the serine biosynthesis pathway, regulates MAFLD development. However, the role of macrophage PHGDH in MAFLD progression remains unclear. Here, we demonstrate that the lipotoxicity inducer palmitic acid (PA) significantly increases macrophage PHGDH expression and that PHGDH deficiency in macrophages promotes PA-induced inflammatory responses. Myeloid-specific PHGDH deficiency exacerbates MAFLD in mice. Mechanistically, tetrameric PHGDH binds to transforming growth factor-β-activated kinase 1 (TAK1) to inhibit its interaction with TAK1 binding protein 1 (TAB1), sequentially suppressing the activation of TAK1 and downstream NF-κB and MAPK signaling. Inhibition of TAK1 activation slows the development of metabolic dysfunction-associated steatohepatitis (MASH) caused by myeloid PHGDH knockout. Importantly, adeno-associated virus-mediated PHGDH overexpression in liver macrophages alleviates MAFLD in mice. Collectively, these results identify macrophage PHGDH as a promising therapeutic agent for MAFLD.

Keywords:  CP: Immunology; CP: Metabolism; macrophage; metabolic dysfunction-associated fatty liver disease; phosphoglycerate dehydrogenase; transforming growth factor-β-activated kinase 1

DOI:  https://doi.org/10.1016/j.celrep.2025.115426
Cell Rep. 2025 Mar 13. pii: S2211-1247(25)00201-3. [Epub ahead of print]44(3): 115430

Mitochondrial reactive oxygen species regulate acetyl-CoA flux between cytokine production and fatty acid synthesis in effector T cells.

Beibei Wu, Jin Seok Woo, Spyridon Hasiakos, Calvin Pan, Shawn Cokus, Cristiane Benincá, Linsey Stiles, Zuoming Sun, Matteo Pellegrini, Orian S Shirihai, Aldon J Lusis, Sonal Srikanth, Yousang Gwack.

  Genetic and environmental factors shape an individual's susceptibility to autoimmunity. To identify genetic variations regulating effector T cell functions, we used a forward genetics screen of inbred mouse strains and uncovered genomic loci linked to cytokine expression. Among the candidate genes, we characterized a mitochondrial inner membrane protein, TMEM11, as an important determinant of Th1 responses. Loss of TMEM11 selectively impairs Th1 cell functions, reducing autoimmune symptoms in mice. Mechanistically, Tmem11-/- Th1 cells exhibit altered cristae architecture, impaired respiration, and increased mitochondrial reactive oxygen species (mtROS) production. Elevated mtROS hindered histone acetylation while promoting neutral lipid accumulation. Further experiments using genetic, biochemical, and pharmacological tools revealed that mtROS regulate acetyl-CoA flux between histone acetylation and fatty acid synthesis. Our findings highlight the role of mitochondrial cristae integrity in directing metabolic pathways that influence chromatin modifications and lipid biosynthesis in Th1 cells, providing new insights into immune cell metabolism.

Keywords:  CP: Immunology; CP: Metabolism; EAE; MICOS complex; Th1 cells; cytokine production; histone acetylation; mitochondria; mitochondrial cristae architecture; neutral lipids; reactive oxygen species

DOI:  https://doi.org/10.1016/j.celrep.2025.115430
Immunometabolism (Cobham). 2025 Apr;7(2): e00059

Blocking lactate: kick T cells when they are down.

Veronika Horkova, Bart Everts, Dirk Brenner.

  In the last couple of decades, cancer research has been shifting its focus to the immune system. Cancer cells, with their ability to adapt and evade immune responses, seem to accelerate the evolutionary pressure that has been put on our immune system during evolution. We thus try to aid these natural selection processes and assist our immune system to combat cancer. Here, we are discussing a study by Greg Delgoffe and colleagues that was published in Nature Immunology in December 2024, exploring a new approach to bring the dysfunctional immune cells back to life by blocking their lactate uptake.

Keywords:  MCT11; T cell exhaustion; anti-tumor immunity; hypoxia; immune checkpoint blockade; lactate; metabolism

DOI:  https://doi.org/10.1097/IN9.0000000000000059
Explor Target Antitumor Ther. 2025 ;6 1002297

Metabolic mechanisms of immunotherapy resistance.

Luis Cabezón-Gutiérrez, Magda Palka-Kotlowska, Sara Custodio-Cabello, Beatriz Chacón-Ovejero, Vilma Pacheco-Barcia.

  Immunotherapy has revolutionized cancer treatment, yet its efficacy is frequently compromised by metabolic mechanisms that drive resistance. Understanding how tumor metabolism shapes the immune microenvironment is essential for developing effective therapeutic strategies. This review examines key metabolic pathways influencing immunotherapy resistance, including glucose, lipid, and amino acid metabolism. We discuss their impact on immune cell function and tumor progression, highlighting emerging therapeutic strategies to counteract these effects. Tumor cells undergo metabolic reprogramming to sustain proliferation, altering the availability of essential nutrients and generating toxic byproducts that impair cytotoxic T lymphocytes (CTLs) and natural killer (NK) cell activity. The accumulation of lactate, deregulated lipid metabolism, and amino acid depletion contribute to an immunosuppressive tumor microenvironment (TME). Targeting metabolic pathways, such as inhibiting glycolysis, modulating lipid metabolism, and restoring amino acid balance, has shown promise in enhancing immunotherapy response. Addressing metabolic barriers is crucial to overcoming immunotherapy resistance. Integrating metabolic-targeted therapies with immune checkpoint inhibitors may improve clinical outcomes. Future research should focus on personalized strategies to optimize metabolic interventions and enhance antitumor immunity.

Keywords:  Immune resistance; cancer; metabolism; tumor microenvironment

DOI:  https://doi.org/10.37349/etat.2025.1002297
J Immunol. 2025 Mar 17. pii: vkaf024. [Epub ahead of print]

High fat diet feeding impairs neutrophil phagocytosis, bacterial killing, and neutrophil-induced hematopoietic regeneration.

Emily Bowers, Gabrielle P Entrup, Mohammed Islam, Ramkumar Mohan, Arianna Lerner, Peter Mancuso, Bethany B Moore, Kanakadurga Singer.

  The prevalence of obesity and metabolic diseases have risen significantly over the past decades. Chronic inflammation in obesity is a link between obesity and secondary disease. While macrophages and monocytes are known to contribute to metabolic disease risk during diet exposure, little is known about the contribution of neutrophils. We assessed the impact of obesity on neutrophils using a 16-week model of diet-induced obesity. Bone marrow (BM) neutrophils significantly expanded with chronic high-fat diet (HFD), significantly decreased TNFɑ protein release, and impaired neutrophil regenerative function compared to normal diet (ND) neutrophils. scRNAseq and flow cytometry demonstrated HFD neutrophil heterogeneity and validated that these cells do not have elevated expression of proinflammatory genes without secondary stimulation. HFD neutrophils showed elevated expression of genes associated with lipid metabolism-acyl-CoA thioesterase 1 (Acot1), carnitine palmitoyltransferase 1a (Cpt1a), and perilipin 2 (Plin2). Consistent with the importance of lipid metabolism in driving dysfunction, neutrophils from HFD-fed animals and neutrophils treated with palmitate had impaired bacterial phagocytosis and killing responses. These data shed light on the complex regulation of intracellular lipids and the role of metabolism on neutrophil function during homeostasis and disease.

Keywords:  fatty acid; metabolism; neutrophil function; neutrophils; obesity

DOI:  https://doi.org/10.1093/jimmun/vkaf024
Nat Commun. 2025 Mar 15. 16(1): 2577

Crohn's Disease-associated variant in laccase domain containing 1 (LACC1) modulates T cell gene expression, metabolism and T cell function.

Yingcong Li, Gabriel Ascui, Martina Dicker, Thomas Riffelmacher, Vivek Chandra, Benjamin Schmiedel, Ting-Fang Chou, Pandurangan Vijayanand, Mitchell Kronenberg.

Genome wide association studies (GWAS) identify many risks for Crohn's disease (CD), including a site near the metabolism gene laccase domain containing 1 (LACC1). We previously found this site near LACC1 was associated with decreased LACC1 expression in T lymphocytes, yet the mechanism affecting gene expression and its links to T cell function and inflammatory disease were unknown. Here we identify variants in the promoter region that influence transcription of LACC1. Direct association of disease-risk variants with lower LACC1 pre-mRNA in human CD4+ T cells is confirmed by comparing transcripts from each allele from donors heterozygous for the LACC1 CD-risk allele. Using gene editing, we validate the function of this promoter region in LACC1 expression in T cells. Human CD4+ T cells with LACC1 gene knockdown show altered metabolism, including reduced oxygen consumption rate, and reduced in vitro regulatory T cell differentiation. Therefore, our study provides a mechanism linking these specific LACC1 variants to colitis by attributing promoter region variants to changes in T cell metabolism and function.

DOI: https://doi.org/10.1038/s41467-025-57744-3
Immunometabolism (Cobham). 2025 Apr;7(2): e00058

Mitochondrial response to fever boosts TH1-driven inflammatory responses.

Gillian Dunphy, David Sancho.

  Increased body temperature, both locally and systemically, is a key feature of the inflammatory response. Heat is associated with increased blood flow to affected areas and increased immune infiltrate, yet increased temperature has also been described to have direct effects on immune cell function. In a recent study, Heintzman, et al investigated the effect of febrile temperature (39 °C) on T cell function. They describe increased TH1 function and fitness accompanied by a decrease in regulatory T cell suppressive function. These findings add another important consequence to our understanding of fever responses.

Keywords:  TH1 immunity; fever; inflammation; mitochondria

DOI:  https://doi.org/10.1097/IN9.0000000000000058
Res Vet Sci. 2025 Mar 16. pii: S0034-5288(25)00086-4. [Epub ahead of print]187 105612

Immunometabolic effects of β-glucan-trained immunity in newborn goats.

Miriam Angulo, Carlos Angulo.

  Debaryomyces hansenii CBS 8339 β-glucans induced trained immunity in newborn goats. However, the metabolic shifts and potential signaling pathways have not been described yet. Thus, the present study aims to prove, firstly, modifications in cell metabolism related to trained immunity induction (β-glucans) and inhibition (MCC950) in an in vitro model upon lipopolysaccharide (LPS) re-stimulation; secondly, metabolic changes and possible signaling pathways are related to immune memory induced by β-glucan per os in newborns after ex vivo re-stimulation with a bacterial pathogen. Immune training leads to augmenting glycolysis (glucose and lactate) metabolites. Nevertheless, these changes were unaffected by a NOD-like receptor (NLRP3) inhibitor. In vivo training with oral β-glucan doses also evidenced an increase in glycolysis metabolites mediated by up-regulating AKT/MTOR/HIF1Α genes signaling pathway in monocytes; β-glucan in vivo training up-regulated Dectin1, TLR4, TLR6 RAF1, IL1Β and IL6 gene expressions in monocytes, while TNFΑ gene down-regulated. In conclusion, the results demonstrated that D. hansenii β-glucan induced trained immunity in newborn goat monocytes after LPS re-stimulation through glycolysis shifts, which were not reverted by the MCC950 inhibitor.

Keywords:  Animal health; Functional carbohydrates; Memory in innate leukocytes; Metabolic shift

DOI:  https://doi.org/10.1016/j.rvsc.2025.105612
Cancer Discov. 2025 Mar 18.

Activated T cells break tumor immunosuppression by macrophage re-education.

Rosa Trotta, Silvia Rivis, Shikang Zhao, Marie-Pauline Orban, Sarah Trusso Cafarello, Iris Charatsidou, Joanna Pozniak, Jonas Dehairs, Lotte Vanheer, Carlos A Pulido Vicuna, Veerle Boecxstaens, Oliver Bechter, Francesca M Bosisio, Johannes V Swinnen, Jean-Christophe Marine, Massimiliano Mazzone.

Here, we observe that in human and murine melanomas, T-cell activation abates hematopoietic prostaglandin-D2 synthase (HPGDS) transcription in tumor-associated macrophages (TAMs) through TNFα signaling. Mechanistically, HPGDS installs a Prostaglandin-D2 (PGD2) autocrine loop in TAMs via DP1 and DP2 activation that sustains their pro-tumoral phenotype and promotes paracrine inhibition of CD8+ T cells via a PGD2-DP1 axis. Genetic or pharmacologic HPGDS targeting induces anti-tumoral features in TAMs and favors CD8+ T-cell recruitment, activation, and cytotoxicity, altogether sensitizing tumors to αPD1. Conversely, HPGDS overexpression in TAMs or systemic TNFα blockade sustains a pro-tumoral environment and αPD1-resistance, preventing the downregulation of HPGDS by T cells. Congruently, patients and mice resistant to αPD1 fail to suppress HPGDS in TAMs, reinforcing the evidence that circumventing HPGDS is necessary for efficient αPD1 treatment. Overall, we disclose a mechanism whereby T-cell activation controls the innate immune system, and we suggest HPGDS/PGD2 targeting to overcome immunotherapy resistance.

DOI: https://doi.org/10.1158/2159-8290.CD-24-0415
Sci Adv. 2025 Mar 21. 11(12): eadt2117

CD38-mediated metabolic reprogramming promotes the stability and suppressive function of regulatory T cells in tumor.

Ishita Sarkar, Debashree Basak, Puspendu Ghosh, Anupam Gautam, Arpita Bhoumik, Praveen Singh, Anwesha Kar, Shaun Mahanti, Snehanshu Chowdhury, Lagnajita Chakraborty, Soumya Mondal, Ramanuj Mukherjee, Shikhar Mehrotra, Saikat Majumder, Shantanu Sengupta, Sandip Paul, Shilpak Chatterjee.

In the tumor microenvironment (TME), regulatory T cells (Tregs) adapt their metabolism to thrive in low-glucose, high-lactate conditions, but the mechanisms remain unclear. Our study identifies CD38 as a key regulator of this adaptation by depleting nicotinamide adenine dinucleotide (oxidized form) (NAD+), redirecting lactate-derived pyruvate toward phosphoenolpyruvate and bypassing the tricarboxylic acid (TCA) cycle. This prevents accumulation of α-ketoglutarate, which destabilizes Tregs by inducing hypermethylation at the Foxp3 locus. Restoring NAD+ with nicotinamide mononucleotide reverses this adaptation, pushing Tregs back to the TCA cycle and reducing their suppressive function. In YUMM1.7 melanoma-bearing mice, small-molecule CD38 inhibition selectively destabilizes intratumoral Tregs, sparking robust antitumor immunity. These findings reveal that targeting the CD38-NAD+ axis disrupts Tregs metabolic adaptation and offers a strategy to enhance antitumor responses.

DOI: https://doi.org/10.1126/sciadv.adt2117
Nature. 2025 Mar 19.

VDAC2 loss elicits tumour destruction and inflammation for cancer therapy.

Sujing Yuan, Renqiang Sun, Hao Shi, Nicole M Chapman, Haoran Hu, Cliff Guy, Sherri Rankin, Anil Kc, Gustavo Palacios, Xiaoxi Meng, Xiang Sun, Peipei Zhou, Xiaoyang Yang, Stephen Gottschalk, Hongbo Chi.

Tumour cells often evade immune pressure exerted by CD8+ T cells or immunotherapies through mechanisms that are largely unclear1,2. Here, using complementary in vivo and in vitro CRISPR-Cas9 genetic screens to target metabolic factors, we established voltage-dependent anion channel 2 (VDAC2) as an immune signal-dependent checkpoint that curtails interferon-γ (IFNγ)-mediated tumour destruction and inflammatory reprogramming of the tumour microenvironment. Targeting VDAC2 in tumour cells enabled IFNγ-induced cell death and cGAS-STING activation, and markedly improved anti-tumour effects and immunotherapeutic responses. Using a genome-scale genetic interaction screen, we identified BAK as the mediator of VDAC2-deficiency-induced effects. Mechanistically, IFNγ stimulation increased BIM, BID and BAK expression, with VDAC2 deficiency eliciting uncontrolled IFNγ-induced BAK activation and mitochondrial damage. Consequently, mitochondrial DNA was aberrantly released into the cytosol and triggered robust activation of cGAS-STING signalling and type I IFN response. Importantly, co-deletion of STING signalling components dampened the therapeutic effects of VDAC2 depletion in tumour cells, suggesting that targeting VDAC2 integrates CD8+ T cell- and IFNγ-mediated adaptive immunity with a tumour-intrinsic innate immune-like response. Together, our findings reveal VDAC2 as a dual-action target to overcome tumour immune evasion and establish the importance of coordinately destructing and inflaming tumours to enable efficacious cancer immunotherapy.

DOI: https://doi.org/10.1038/s41586-025-08732-6
Clin Exp Rheumatol. 2025 Mar 05.

RBM15, an m6A enzyme, suppresses NLRP3 inflammasome activation in rheumatoid arthritis through macrophage metabolism.

Mingyu Yu, Jun Wu, Shuo Zhang, Weitian Yan, Sai Kong, Jiangyun Peng.

OBJECTIVES: Rheumatoid arthritis (RA) is a chronic autoimmune disease primarily marked by joint inflammation and systemic damage. This research explored the protective effects of the m6A-related gene RBM15 on RA both in vivo and in vitro, focusing on its impact on NLRP3 inflammasome activation.
METHODS: We identified downregulation of RBM15 in synovial biopsy samples from RA patients through GSE77298 analysis.
RESULTS: Real-time PCR confirmed that RBM15 expression was significantly reduced in RA patients compared to healthy controls (HC). Upon LPS stimulation, M1 markers (CXCL9 and CXCL10) were enhanced, and M2 markers (ARG1 and MRC1) were suppressed, but RBM15 overexpression reversed these effects. Additionally, RBM15 overexpression reversed the increase in glycolysis induced by LPS stimulation in macrophages. Knockdown of RBM15 significantly promoted NLRP3 inflammasome activation, but this was reversed by the glycolysis inhibitor 2-DG. Finally, collagen-induced arthritis (CIA) mice were injected with RBM15-adenovirus (RBM15-Ad) or control adenovirus (Con-Ad). RBM15 overexpression reduced RA symptoms, pathological damage, and inflammatory responses in CIA mice. Moreover, NLRP3 inflammasome activation was suppressed in the RBM15-Ad group.
CONCLUSIONS: The m6A enzyme RBM15 mitigates RA damage by reducing macrophage glycolysis and inhibiting NLRP3 inflammasome activation.

DOI: https://doi.org/10.55563/clinexprheumatol/uecchi
Nat Commun. 2025 Mar 15. 16(1): 2559

Reprogramming aerobic metabolism mitigates Streptococcus pyogenes tissue damage in a mouse necrotizing skin infection model.

Wei Xu, Tara R Bradstreet, Zongsen Zou, Suzanne Hickerson, Yuan Zhou, Hongwu He, Brian T Edelson, Michael G Caparon.

Disease tolerance is a host response to infection that limits collateral damage to host tissues while having a neutral effect on pathogen fitness. Previously, we found that the pathogenic lactic acid bacterium Streptococcus pyogenes manipulates disease tolerance using its aerobic mixed-acid fermentation pathway via the enzyme pyruvate dehydrogenase, but the microbe-derived molecules that mediate communication with the host's disease tolerance pathways remain elusive. Here we show in a murine model that aerobic mixed-acid fermentation inhibits the accumulation of inflammatory cells including neutrophils and macrophages, reduces the immunosuppressive cytokine interleukin-10, and delays bacterial clearance and wound healing. In infected macrophages, the aerobic mixed-acid fermentation end-products acetate and formate from streptococcal upregulate host acetyl-CoA metabolism and reduce interleukin-10 expression. Inhibiting aerobic mixed-acid fermentation using a bacterial-specific pyruvate dehydrogenase inhibitor reduces tissue damage during murine infection, correlating with increased interleukin-10 expression. Our results thus suggest that reprogramming carbon flow provides a therapeutic strategy to mitigate tissue damage during infection.

DOI: https://doi.org/10.1038/s41467-025-57348-x
J Clin Med. 2025 Mar 06. pii: 1780. [Epub ahead of print]14(5):

Frozen Shoulder as a Metabolic and Immune Disorder: Potential Roles of Leptin Resistance, JAK-STAT Dysregulation, and Fibrosis.

Santiago Navarro-Ledesma.

  Frozen shoulder (FS) is a complex and multifactorial condition characterized by persistent inflammation, fibrosis, and metabolic dysregulation. Despite extensive research, the underlying drivers of FS remain poorly understood. Recent findings indicate the coexistence of pro-inflammatory and fibrosis-resolving macrophages within affected tissues, suggesting a dysregulated immune response influenced by metabolic and neuroendocrine factors. This review proposes that leptin resistance, a hallmark of metabolic syndrome and chronic inflammation, may play a central role in FS pathogenesis by impairing macrophage polarization, perpetuating inflammation, and disrupting fibrosis resolution. The JAK-STAT signaling pathway, critically modulated by leptin resistance, may further contribute to immune dysregulation by sustaining inflammatory macrophage activation and interfering with tissue remodeling. Additionally, FS shares pathogenic features with fibrotic diseases driven by TGF-β signaling, mitochondrial dysfunction, and circadian disruption, further linking systemic metabolic dysfunction to localized fibrotic pathology. Beyond immune and metabolic regulation, alterations in gut microbiota, bacterial translocation, and chronic psychosocial stress may further exacerbate systemic inflammation and neuroendocrine imbalances, intensifying JAK-STAT dysregulation and leptin resistance. By examining the intricate interplay between metabolism, immune function, and fibrotic remodeling, this review highlights targeting leptin sensitivity, JAK-STAT modulation, and mitochondrial restoration as novel therapeutic strategies for FS treatment. Future research should explore these interconnections to develop integrative interventions that address both the metabolic and immune dysregulation underlying FS, ultimately improving clinical outcomes.

Keywords:  frozen shoulder; immunology; metabolism; psychology; rehabilitation

DOI:  https://doi.org/10.3390/jcm14051780
Nat Commun. 2025 Mar 20. 16(1): 2744

Regulatory T cells in the mouse hypothalamus control immune activation and ameliorate metabolic impairments in high-calorie environments.

Maike Becker, Stefanie Kälin, Anne H Neubig, Michael Lauber, Daria Opaleva, Hannah Hipp, Victoria K Salb, Verena B Ott, Beata Legutko, Roland E Kälin, Markus Hippich, Martin G Scherm, Lucas F R Nascimento, Isabelle Serr, Fabian Hosp, Alexei Nikolaev, Alma Mohebiany, Martin Krueger, Bianca Flachmeyer, Michael W Pfaffl, Bettina Haase, Chun-Xia Yi, Sarah Dietzen, Tobias Bopp, Stephen C Woods, Ari Waisman, Benno Weigmann, Matthias Mann, Matthias H Tschöp, Carolin Daniel.

The hypothalamus in the central nervous system (CNS) has important functions in controlling systemic metabolism. A calorie-rich diet triggers CNS immune activation, impairing metabolic control and promoting obesity and Type 2 Diabetes (T2D), but the mechanisms driving hypothalamic immune activation remain unclear. Here we identify regulatory T cells (Tregs) as key modulators of hypothalamic immune responses. In mice, calorie-rich environments activate hypothalamic CD4+ T cells, infiltrating macrophages and microglia while reducing hypothalamic Tregs. mRNA profiling of hypothalamic CD4+ T cells reveals a Th1-like activation state, with increased Tbx21, Cxcr3 and Cd226 but decreased Ccr7 and S1pr1. Importantly, results from Treg loss-of function and gain-of-function experiments show that Tregs limit hypothalamic immune activation and reverse metabolic impairments induced by hyper-caloric feeding. Our findings thus help refine the current model of Treg-centered immune-metabolic crosstalk in the brain and may contribute to the development of precision immune modulation for obesity and diabetes.

DOI: https://doi.org/10.1038/s41467-025-57918-z
Cell Rep Med. 2025 Mar 18. pii: S2666-3791(25)00094-1. [Epub ahead of print]6(3): 102021

Bioengineering the metabolic network of CAR T cells with GLP-1 and Urolithin A increases persistence and long-term anti-tumor activity.

Areej Akhtar, Md Shakir, Mohammad Sufyan Ansari, Divya, Md Imam Faizan, Varnit Chauhan, Aashi Singh, Ruquaiya Alam, Iqbal Azmi, Sheetal Sharma, Mehak Pracha, Insha Mohi Uddin, Uzma Bashir, Syeda Najidah Shahni, Rituparna Chaudhuri, Sarah Albogami, Rik Ganguly, Shakti Sagar, Vijay Pal Singh, Gaurav Kharya, Amit Kumar Srivastava, Ulaganathan Mabalirajan, Soumya Sinha Roy, Irfan Rahman, Tanveer Ahmad.

  Constant tumor antigen exposure disrupts chimeric antigen receptor (CAR) T cell metabolism, limiting their persistence and anti-tumor efficacy. To address this, we develop metabolically reprogrammed CAR (MCAR) T cells with enhanced autophagy and mitophagy. A compound screening identifies a synergy between GLP-1R agonist (semaglutide [SG]) and Urolithin A (UrA), which activate autophagy through mTOR (mechanistic target of rapamycin) inhibition and mitophagy via Atg4b activation, maintaining mitochondrial metabolism in CAR T cells (MCAR T-1). These changes increase CD8+ T memory cells (Tm), enhancing persistence and anti-tumor activity in vitro and in xenograft models. GLP-1R knockdown in CAR T cells diminishes autophagy/mitophagy induction, confirming its critical role. We further engineer GLP-1-secreting cells (MCAR T-2), which exhibited sustained memory, stemness, and long-term persistence, even under tumor re-challenge. MCAR T-2 cells also reduce cytokine release syndrome (CRS) risks while demonstrating potent anti-tumor effects. This strategy highlights the potential of metabolic reprogramming via targeting autophagy/mitophagy pathways to improve CAR T cell therapy outcomes, ensuring durability and efficacy.

Keywords:  CAR T cells; GLP-1 peptide; T cell persistence; Urolithin A; anti-tumor activity; autophagy; metabolism; mitochondrial health; mitophagy

DOI:  https://doi.org/10.1016/j.xcrm.2025.102021
Cell Rep. 2025 Mar 13. pii: S2211-1247(25)00203-7. [Epub ahead of print]44(3): 115432

The tumor microenvironment is an ecosystem sustained by metabolic interactions.

Emily Jane Kay, Sara Zanivan.

  Cancer-associated fibroblasts (CAFs) and immune cells make up two major components of the tumor microenvironment (TME), contributing to an ecosystem that can either support or restrain cancer progression. Metabolism is a key regulator of the TME, providing a means for cells to communicate with and influence each other, modulating tumor progression and anti-tumor immunity. Cells of the TME can metabolically interact directly through metabolite secretion and consumption or by influencing other aspects of the TME that, in turn, stimulate metabolic rewiring in target cells. Recent advances in understanding the subtypes and plasticity of cells in the TME both open up new avenues and create challenges for metabolically targeting the TME to hamper tumor growth and improve response to therapy. This perspective explores ways in which the CAF and immune components of the TME could metabolically influence each other, based on current knowledge of their metabolic states, interactions, and subpopulations.

Keywords:  CAFs; CP: Cancer; CP: Metabolism; immune cells; metabolism; stroma immune; tumor microenvironment

DOI:  https://doi.org/10.1016/j.celrep.2025.115432
Mol Neurodegener. 2025 Mar 21. 20(1): 35

The role of n-3-derived specialised pro-resolving mediators (SPMs) in microglial mitochondrial respiration and inflammation resolution in Alzheimer's disease.

Mary Slayo, Christoph Rummel, Pasindu Hansana Singhaarachchi, Martin Feldotto, Sarah J Spencer.

  Alzheimer's disease (AD) is the most common form of dementia globally and is characterised by reduced mitochondrial respiration and cortical deposition of amyloid-β plaques and neurofibrillary tangles comprised of hyper-phosphorylated tau. Despite its characterisation more than 110 years ago, the mechanisms by which AD develops are still unclear. Dysregulation of microglial phagocytosis of amyloid-β may play a key role. Microglia are the major innate immune cell of the central nervous system and are critical responders to pro-inflammatory states. Typically, microglia react with a short-lived inflammatory response. However, a dysregulation in the resolution of this microglial response results in the chronic release of inflammatory mediators. This prolongs the state of neuroinflammation, likely contributing to the pathogenesis of AD. In addition, the microglial specialised pro-resolving mediator (SPM) contribution to phagocytosis of amyloid-β is dysregulated in AD. SPMs are derivatives of dietary n-3 polyunsaturated fatty acids (PUFAs) and potentially represent a strategic target for protection against AD progression. However, there is little understanding of how mitochondrial respiration in microglia may be sustained long term by n-3-derived SPMs, and how this affects their clearance of amyloid-β. Here, we re-evaluate the current literature on SPMs in AD and propose that SPMs may improve phagocytosis of amyloid-β by microglia as a result of sustained mitochondrial respiration and allowing a pro-resolution response.

Keywords:  Alzheimer’s disease; Beta-oxidation; Fatty acids; Inflammation; Microglia; Mitochondria; N-3; Sex differences; Specialised pro-resolving mediators

DOI:  https://doi.org/10.1186/s13024-025-00824-1
bioRxiv. 2025 Mar 05. pii: 2025.02.28.640814. [Epub ahead of print]

Shared and distinct responses of human and murine alveolar macrophages and monocyte-derived macrophages to Mycobacterium tuberculosis.

Kimberly A Dill-McFarland, Glenna Peterson, Pamelia N Lim, Shawn Skerrett, Thomas R Hawn, Alissa C Rothchild, Monica Campo.

Macrophages serve as important sites of bacterial replication and host immune response during Mycobacterium tuberculosis (Mtb) infection with distinct roles for alveolar macrophages (AMs) early in infection and monocyte-derived (MDMs) during later stages of disease. Here, we leverage data from human and mouse models to perform a cross-species analysis of macrophage responses to Mtb infection. Overall, we find that both subsets of human and murine macrophages mount a strong interferon response to Mtb infection. However, AM across both species do not generate as strong a pro-inflammatory response as human MDMs or murine bone marrow-derived macrophages (BMDMs), as characterized by TNFA signaling and inflammatory response pathways. Interestingly, AMs from mice that were previously vaccinated with BCG (scBCG) or from a model of contained TB (coMtb) had Mtb responses that were more similar to human AMs than control mice. We also identify species-specific pathways altered by infection differently in mouse and human macrophages, specifically in pathways related to cholesterol in AMs as well as MYC targets and Hedgehog signaling in MDMs/BMDMs. Lastly, to investigate downstream effects of the macrophage interferon responses, we examine macrophage expression of IL-10, an immunosuppressive cytokine induced by Type I Interferons, and c-Maf, a transcription factor required for IL-10 expression in myeloid cells. We find that c-Maf and IL-10 have significantly lower expression in AMs compared to MDMs in both humans and mice, suggesting one possible mechanism by which AMs mount a stronger interferon response following Mtb infection. Overall, these results highlight the dynamics of innate myeloid responses over the course of Mtb infection and the benefit of a combined analysis across species to reveal conserved and unique responses.

DOI: https://doi.org/10.1101/2025.02.28.640814
Arch Oral Biol. 2025 Mar 15. pii: S0003-9969(25)00065-2. [Epub ahead of print]174 106237

Gallic acid promotes M2 macrophage polarization through mitochondrial oxidative phosphorylation in periodontitis.

Ruobing Zhang, Wenjing Yang, Kai Li, Xiaolong Zhang, Jie Liu, Lin Ai.

   OBJECTIVE: This in vitro investigation assessed the role of gallic acid in regulating macrophage polarization.
DESIGN: In this study, RAW264.7 macrophages were treated with P. gingivalis lipopolysaccharide (LPS) to mimic inflammatory conditions in periodontitis. Immunofluorescence staining, enzyme‑linked immunosorbent (ELISA) assay, RNA sequencing, and seahorse metabolic profile assay were used to assess the effects of gallic acid on macrophage polarization, cytokine release, underlying mechanism and metabolic profile.
RESULTS: The study demonstrated that treatment with gallic acid could induce M2 polarization of macrophages (P < 0.01) and increase the production of anti-inflammatory cytokines (P < 0.01). Analysis of RNA sequencing data showed enrichment of mitochondrial oxidative phosphorylation, regulation of metabolic processes, and the PI3K-Akt signaling pathway in LPS-treated macrophages treated with gallic acid. Furthermore, gallic acid was found to enhance mitochondrial oxidative phosphorylation activity through the PI3K-Akt signaling pathway in RAW264.7 cells.
CONCLUSIONS: Gallic acid treatment has the potential to promote M2 polarization of macrophages by modulating mitochondrial oxidative phosphorylation via the PI3K-Akt signaling pathway.

Keywords:  Gallic acid; Macrophage; Mitochondria; Periodontitis

DOI:  https://doi.org/10.1016/j.archoralbio.2025.106237
Int Immunopharmacol. 2025 Mar 18. pii: S1567-5769(25)00406-0. [Epub ahead of print]153 114416

Activation of GPR35 by kynurenic acid inhibits IL-1β secretion in macrophages during CR-hvKP-induced pneumonia.

Qingyue Zhang, Bao Meng, Mingyang Tang, Chengcheng Li, Yuexin Xu, Jinjin Pan, Liang Yu, Yasheng Li, Yi Yang, Yanyan Liu, Hongru Li, Lifen Hu, Ting Wu, Jiabin Li.

  Carbapenemase-resistant hypervirulent Klebsiella pneumoniae (CR-hvKP) is a common pathogen that can cause severe pneumonia. The innate immune response, especially the response of macrophages, plays a crucial role in the host's defense against bacterial infections. Glycolysis is implicated in the modulation of immune functions in macrophages. Here, we provide evidence supporting the role of GPR35 in decreasing glycolysis and reducing the secretion of IL-1β in macrophages by inhibiting the transcription of HK2 during K. pneumoniae-induced pneumonia. Mice with GPR35 knock-out exhibit higher mortality and increased lung bacterial burdens. Mechanistically, GPR35 activation by kynurenic acid inhibits caspase-1 cleavage and reduces IL-1β secretion in macrophages by specifically suppressing activation of the NLRP3 inflammasome. These findings underscore the role of GPR35 in regulating inflammation during K. pneumoniae-induced pneumonia and suggest that GPR35 is a potential therapeutic target for clinical treatment.

Keywords:  GPR35; Glycolysis; IL-1β; Klebsiella pneumoniae; Kynurenic acid; Macrophage

DOI:  https://doi.org/10.1016/j.intimp.2025.114416
Arch Biochem Biophys. 2025 Mar 14. pii: S0003-9861(25)00097-9. [Epub ahead of print]768 110384

Impact of oxidized phosphatidylcholine supplementation on the lipidome of RAW264.7 macrophages.

Matilde Santos, Tatiana Maurício, Rosário Domingues, Pedro Domingues.

  Oxidized phospholipids (OxPLs) have emerged as critical damage-associated molecular patterns (DAMPs) and modulators of numerous biological processes, including inflammation, playing a significant role in health and disease. Despite their recognized influence on macrophage polarization, the precise mechanisms by which distinct OxPL species shape macrophage behavior remains poorly understood. The present study investigates the impact of two oxidized phosphatidylcholines (OxPC): omega 3 1-stearoyl-2-docosahexaenoyl-sn-glycero-3-phosphatidylcholine (OxPC22:6), and omega 6 1-stearoyl-2-linoleoyl-sn-glycero-3-phosphatidylcholine (OxPC18:2), on the lipidomic profile of RAW264.7 macrophages, through an LC-MS lipidomic analysis. Our findings demonstrate that the OxPCs under study modulate macrophage lipidome differently, highlighting the significance of the sn-2 acyl chain composition for their biological function. When administered alone, neither of the OxPCs induced a pro-inflammatory phenotype in macrophages. OxPC22:6 appears to induce a preparatory pro-inflammatory state in macrophages, improving their subsequent inflammatory responses, while OxPC18:2 seems to induce a resting state on macrophages. Under LPS stimulation, both OxPCs were found to selectively attenuate certain LPS-driven lipidomic changes (PC.O, PC.P, PI.P, PE.P) while amplifying others (DG, Cer, LPC, PE.O, PI.O, TG, PC, PI) and introducing unique alterations to the macrophage lipidome (SM, PE, LPE). Core lipidomic changes, crucial for macrophages' LPS response, were identified, with sustained elevation of TG, DG, Cer, PC, LPC, and PI.O and reduction of PE.O, PI, and CAR. These observations suggest that, in the presence of LPS, mainly OxPC22:6 amplifies the pro-inflammatory lipidomic signature of macrophages. Further research is needed to clarify whether the observed lipidomic adaptations improve, impair, or inhibit macrophages' inflammatory capacities and response.

Keywords:  Immune response; Lipidome remodeling; Lipidomics; Macrophage polarization; Oxidized phospholipids; Pro-inflammatory phenotype

DOI:  https://doi.org/10.1016/j.abb.2025.110384
Proc Natl Acad Sci U S A. 2025 Mar 25. 122(12): e2425309122

ACOD1-mediated lysosomal membrane permeabilization contributes to Mycobacterium tuberculosis-induced macrophage death.

Ziwei Yang, Li Zhang, Samantha Ottavi, Jacob B Geri, Andrew Perkowski, Xiuju Jiang, Daniel Pfau, Ruslana Bryk, Jeffrey Aubé, Matthew Zimmerman, Véronique Dartois, Carl Nathan.

  Mycobacterium tuberculosis (Mtb) primarily infects macrophages. In vitro without antibiotics, wild-type Mtb hastens death of the macrophages, but the processes leading to rapid cell death are not well understood. Our earlier work indicated that the death of Mtb-infected mouse macrophages in vitro is markedly exacerbated by induction of interferon-β (IFN-β) [L. Zhang et al., J. Exp. Med. 18, e20200887 (2021)]. Here, we identified a key downstream response to IFN-β in the context of Mtb infection as the massive induction of cis-aconitate decarboxylase (ACOD1), not only in its canonical subcellular localization in mitochondria but also in the cytosol, where it bound to the lysosome-stabilizing protein HSP70. ACOD1's product, itaconate, protected Mtb-infected macrophages. However, the contrasting and predominant effect of high-level ACOD1 expression was to act in a noncatalytic manner to promote HSP70's degradation, leading to lysosomal membrane permeabilization (LMP). Mtb-induced macrophage death was markedly diminished by inhibitors of cysteine proteases, consistent with lysosome-mediated cell death. Neither ACOD1 inhibitors nor cysteine protease inhibitors are suitable for potential host-directed therapy (HDT) of tuberculosis. Instead, this work directs attention to how ACOD1 acts nonenzymatically to promote the degradation of HSP70.

Keywords:  ACOD1; IRG1; lysosomes; macrophages; tuberculosis

DOI:  https://doi.org/10.1073/pnas.2425309122
Nat Metab. 2025 Mar 14.

Human gut microbial aromatic amino acid and related metabolites prevent obesity through intestinal immune control.

Zengliang Jiang, Liuqing He, Diyin Li, Laibao Zhuo, Lingjun Chen, Rui-Qi Shi, Jianhua Luo, Yuhui Feng, Yuhui Liang, Danyang Li, Xiao Congmei, Yuanqing Fu, Yu-Ming Chen, Ju-Sheng Zheng, Liang Tao.

Obesity affects millions of people in the world. The gut microbiome influences body fat accumulation, but the mechanisms remain to be investigated. Here, we show an association between microbial aromatic amino acid metabolites in serum and body fat accumulation in a large Chinese longitudinal cohort. We next identify that 4-hydroxyphenylacetic acid (4HPAA) and its analogues effectively protect male mice from high-fat-diet-induced obesity. These metabolites act on intestinal mucosa to regulate the immune response and control lipid uptake, which protects against obesity. We further demonstrate that T cells and B cells are not vital for 4HPAA-mediated obesity prevention, and innate lymphoid cells have antagonistic roles. Together, these findings reveal specific microbial metabolites as pivotal molecules to prohibit obesity through immune control, establishing mechanisms of host modulation by gut microbial metabolites.

DOI: https://doi.org/10.1038/s42255-025-01246-5
bioRxiv. 2025 Mar 06. pii: 2025.03.06.641752. [Epub ahead of print]

Human cytomegalovirus promotes de novo PC synthesis during early virus replication.

Ian Kline, Rebekah L Mokry, Yuecheng Xi, Magí Passols Manzano, Sidnie Layesa, Nowroz Sohrab Ali, Melissa A Moy, Felicia D Goodrum, John G Purdy.

Human cytomegalovirus (HCMV) infection reprograms metabolism, including lipid synthesis. While several metabolite-related pathways have been demonstrated to have altered activity in infected cells, the alteration of lipid-related pathways by HCMV has not been examined beyond fatty acid synthesis and elongation. In this study, we addressed this lack of understanding by focusing on phosphatidylcholine (PC), a class of lipids we previously showed is increased by HCMV infection in human foreskin fibroblasts. Here, we found that HCMV infection increases the abundance of PCs in several different fibroblasts and, similarly, in endothelial and epithelial cells. Additionally, HCMV elevates PC levels regardless of the level of confluency, type of growth medium, and presence of serum. Next, we investigated if HCMV alters the activity in the three PC synthesis pathways. We demonstrate that HCMV infection promotes the activity in the de novo PC synthesis pathway using a 13 C-choline isotopic tracer and liquid chromatography high resolution tandem mass spectrometry (LC-MS/MS). Infection did not alter the activity in the other two pathways. Moreover, we examined the kinetics of PC remodeling by HCMV and found that the de novo synthesis pathway is promoted and the PC lipidome shifts 24 hours post infection. That led us to examining if the early stages of replication are sufficient to alter PC levels. After inhibiting late virus replication, we found that HCMV alters the PC lipidome independent of late gene expression. Overall, this work suggests that an immediate-early or early viral protein promotes the reprogramming of host lipid metabolism to ensure the synthesis of a lipidome necessary to support HCMV replication.
IMPORTANCE: Human cytomegalovirus (HCMV) is a common herpesvirus that establishes a lifelong and persistent infection in its human host (1). HCMV infection in most people does not cause overt disease (1). However, in immunocompromised individuals, severe CMV-associated disease can lead to permanent disabilities and even death (1, 2). Additionally, congenital CMV is the leading infectious cause of birth defects (3, 4). Viruses have evolved to hijack host metabolic pathways to facilitate their replication cycle. In this study, we determine that HCMV promotes the activity in the de novo pathway of phosphatidylcholine (PC) synthesis. We demonstrate that the activity in the other PC synthesis pathways, the PEMT and Lands cycle, is unaltered by HCMV infection. Moreover, we found that HCMV infection alters metabolic activity to increase the PC lipidome before 48 hpi. Additionally, we demonstrate that changes in PC lipids during virus replication is independent of late gene expression. Together, our findings demonstrate that infection promotes the de novo PC pathway to increase PC lipids during the early stages of virus replication.

DOI: https://doi.org/10.1101/2025.03.06.641752
Gut Microbes Rep. 2025 ;2(1): 1-16

Functional regulation of cytotoxic T cells by gut microbial metabolites.

Chang H Kim.

  Metabolites from gut microbes have a wide range of functions within the host body. One important function of these metabolites is to either positively or negatively control CD8+ cytotoxic T lymphocytes (CTLs), which can kill cancer and virus-infected cells. In healthy conditions, gut microbes produce a mixture of metabolites that promote CTL activity but also suppress excessive inflammatory responses. However, gut microbial dysbiosis occurs in patients with cancer, and this leads to changes in the production of gut microbial metabolites that can suppress CTL activity, promote inflammatory responses, and/or aid cancer growth. Decreased levels of CTL-promoting metabolites such as short-chain fatty acids, indole metabolites and polyamines but increased levels of CTL-suppressing metabolites, such as certain bile acids along with oncogenic metabolites, have been observed in patients with cancer. This review summarizes the altered production of major microbial metabolites in patients with cancer and discusses the impact of these changes on anti-cancer CTL responses.

Keywords:  CD8 T cells; Cancer; Cytotoxic lymphocytes; Dendritic cells; Dietary fiber; Dysbiosis; Exhaustion; Microbial metabolites; Postbiotics; Prebiotics

DOI:  https://doi.org/10.1080/29933935.2025.2454002
PLoS Pathog. 2025 Mar 17. 21(3): e1012978

Leishmania major Dihydrolipoyl dehydrogenase (DLD) is a key metabolic enzyme that drives parasite proliferation, pathology and host immune response.

Somtochukwu S Onwah, Zhirong Mou, Gaurav Gupta, Patience Obi, Nnamdi Ikeogu, Ping Jia, Wen-Wei Zhang, Saeid Ghavami, Ayesha Saleem, Jude Uzonna.

Identifying antigens that elicit protective immunity is pivotal for developing effective vaccines and therapeutics against cutaneous leishmaniasis. Dihydrolipoyl dehydrogenase (DLD), a mitochondrial enzyme involved in oxidizing lipoamides to facilitate electron transfer for energy production and metabolism, plays a critical role in virulence of fungi and bacteria. However, its function in Leishmania virulence and pathogenesis remains unexplored. Using a CRISPR-Cas9-based approach, we generated DLD-deficient Leishmania (L.) major parasites and a complementary add-back strain by episomally reintroducing DLD gene into the knockout parasites. Loss of DLD significantly impaired parasite proliferation in axenic cultures and infected macrophages compared to wild-type (WT) and add-back control parasites. These defects were linked to reduced ROS production, impaired mitochondrial permeability, an enhanced oxygen consumption rate, and alterations in mitochondrial ultrastructure. In murine models, DLD-deficient parasites failed to cause observable lesions and exhibited significantly reduced parasite burdens compared to WT and add-back control strains. Notably, mice infected with DLD-deficient parasites displayed blunted immune responses compared to their WT controls. Importantly, vaccination with DLD-deficient parasites conferred robust protection against virulent L. major challenge, characterized by a strong IFN-γ-mediated immune response. These findings establish DLD as an essential metabolic enzyme for L. major intracellular survival and pathogenesis. Targeting DLD not only impairs parasite viability but also holds promise as a novel strategy for vaccine development to combat cutaneous leishmaniasis.

DOI: https://doi.org/10.1371/journal.ppat.1012978
Cell Rep Med. 2025 Mar 11. pii: S2666-3791(25)00101-6. [Epub ahead of print] 102028

Microbiota-produced immune regulatory bile acid metabolites control central nervous system autoimmunity.

Martina Antonini Cencicchio, Federico Montini, Vittoria Palmieri, Luca Massimino, Marta Lo Conte, Annamaria Finardi, Alessandra Mandelli, Francesco Asnicar, Radmila Pavlovic, Denise Drago, Federica Ungaro, Annapaola Andolfo, Nicola Segata, Vittorio Martinelli, Roberto Furlan, Marika Falcone.

  The commensal gut microbiota has a role in the pathogenesis of extra-intestinal autoimmune diseases such as multiple sclerosis (MS) with unknown mechanisms. Deoxycholic acid (DCA) and lithocholic acid (LCA) are secondary bile acid metabolites (BAMs) produced from primary bile acids by gut microbiota that play key immune regulatory functions by promoting FOXP3+ regulatory T (Treg) cell differentiation at the expense of Th17 cells. Here, we show that bacteria releasing enzymes responsible for secondary BAMs production are under-represented in the gut of MS patients, resulting in significantly reduced intestinal concentration of DCA and immune dysregulation with increased percentage of Th17 cells. We validated our human findings in a preclinical model of MS by showing that DCA/LCA administration prevents experimental autoimmune encephalomyelitis (EAE) by dampening Th17 cell differentiation and the effector phenotype of myelin-reactive T cells. Our data highlight the key role of immune regulatory BAMs for the prevention of central nervous system (CNS) autoimmunity.

Keywords:  FoxP3+ Treg cells; T helper 17 cells; bile acid metabolites; metabolomics; microbiome; multiple sclerosis

DOI:  https://doi.org/10.1016/j.xcrm.2025.102028
J Immunol. 2025 Mar 19. pii: vkae064. [Epub ahead of print]

IL-7Rα signaling in regulatory T cells of adipose tissue is essential for systemic glucose homeostasis.

Shizue Tani-Ichi, Shinya Abe, Hitoshi Miyachi, Satsuki Kitano, Akihiro Shimba, Aki Ejima, Takahiro Hara, Guangwei Cui, Tomonobu Kado, Shohei Hori, Kazuyuki Tobe, Koichi Ikuta.

  Regulatory T cells (Tregs) mediate tissue homeostasis and repair. The function of the interleukin-7 receptor α (IL-7Rα) in nonlymphoid tissue Tregs is still unknown, although low expression of IL-7Rα is a widely accepted marker for Tregs. Here, we show that IL-33R (ST2)-expressing Tregs in the visceral adipose tissue (VAT) express the IL-7Rα at high levels. Treg-specific IL-7Rα-deficient mice exhibited reduced adipose ST2+ Tregs and impaired glucose tolerance, whereas IL-7Rα was dispensable for Tregs in lymphoid tissues. Mice deficient in thymic stromal lymphopoietin (TSLP), an additional ligand for IL-7Rα, displayed a modest decrease in adipose ST2+ Tregs and a reduced accumulation of adipose eosinophils, accompanied by slightly impaired glucose tolerance. In the VAT, mesothelial cells expressed IL-7, whereas adipose stem cells and folate receptor β-expressing tissue-resident macrophages expressed TSLP. Thus, this study indicates the significance of IL-7Rα signaling in the maintenance of VAT Tregs and glucose homeostasis, revealing a novel role for IL-7 and TSLP in immunometabolism.

Keywords:  IL-7; TSLP; adipose tissue; eosinophils; regulatory T cells

DOI:  https://doi.org/10.1093/jimmun/vkae064
Alzheimers Dement. 2025 Mar;21(3): e70060

Metabolic stress and age drive inflammation and cognitive decline in mice and humans.

Sarah E Elzinga, Kai Guo, Ali Turfah, Rosemary E Henn, Ian F Webber-Davis, John M Hayes, Crystal M Pacut, Samuel J Teener, Andrew D Carter, Diana M Rigan, Adam M Allouch, Dae-Gyu Jang, Rachel Parent, Emily Glass, Geoffrey G Murphy, Stephen I Lentz, Kevin S Chen, Lili Zhao, Junguk Hur, Eva L Feldman.

   INTRODUCTION: Metabolic stressors (obesity, metabolic syndrome, prediabetes, and type 2 diabetes [T2D]) increase the risk of cognitive impairment (CI), including Alzheimer's disease (AD). Immune system dysregulation and inflammation, particularly microglial mediated, may underlie this risk, but mechanisms remain unclear.
METHODS: Using a high-fat diet-fed (HFD) model, we assessed longitudinal metabolism and cognition, and terminal inflammation and brain spatial transcriptomics. Additionally, we performed hippocampal spatial transcriptomics and single-cell RNA sequencing of post mortem tissue from AD and T2D human subjects versus controls.
RESULTS: HFD induced progressive metabolic and CI with terminal inflammatory changes, and dysmetabolic, neurodegenerative, and inflammatory gene expression profiles, particularly in microglia. AD and T2D human subjects had similar gene expression changes, including in secreted phosphoprotein 1 (SPP1), a pro-inflammatory gene associated with AD.
DISCUSSION: These data show that metabolic stressors cause early and progressive CI, with inflammatory changes that promote disease. They also indicate a role for microglia, particularly microglial SPP1, in CI.
HIGHLIGHTS: Metabolic stress causes persistent metabolic and cognitive impairments in mice. Murine and human brain spatial transcriptomics align and indicate a pro-inflammatory milieu. Transcriptomic data indicate a role for microglial-mediated inflammatory mechanisms. Secreted phosphoprotein 1 emerged as a potential target of interest in metabolically driven cognitive impairment.

Keywords:  cognitive impairment; hippocampus; human; inflammation; microglia; mouse; obesity; prediabetes; type 2 diabetes

DOI:  https://doi.org/10.1002/alz.70060
ACS Chem Neurosci. 2025 Mar 17.

Exploring Human Brain Metabolism via Genome-Scale Metabolic Modeling with Highlights on Multiple Sclerosis.

Mustafa Sertbas, Kutlu O Ulgen.

  Cerebral dysfunctions give rise to a wide range of neurological diseases due to the structural and functional complexity of the human brain stemming from the interactive cellular metabolism of its specific cells, including neurons and glial cells. In parallel with advances in isolation and measurement technologies, genome-scale metabolic models (GEMs) have become a powerful tool in the studies of systems biology to provide critical insights into the understanding of sophisticated eukaryotic systems. In this study, brain cell-specific GEMs were reconstructed for neurons, astrocytes, microglia, oligodendrocytes, and oligodendrocyte precursor cells by integrating single-cell RNA-seq data and global Human1 via a task-driven integrative network inference for tissues (tINIT) algorithm. Then, intercellular reactions among neurons, astrocytes, microglia, and oligodendrocytes were added to generate a combined brain model, iHumanBrain2690. This brain network was used in the prediction of metabolic alterations in glucose, ketone bodies, oxygen change, and reporter metabolites. Glucose supplementation increased the subsystems' activities in glycolysis, and ketone bodies elevated those in the TCA cycle and oxidative phosphorylation. Reporter metabolite analysis identified L-carnitine and arachidonate as the top reporter metabolites in gray and white matter microglia in multiple sclerosis (MS), respectively. Carbamoyl-phosphate was found to be the top reporter metabolite in primary progressive MS. Taken together, single and integrated iHumanBrain2690 metabolic networks help us elucidate complex metabolism in brain physiology and homeostasis in health and disease.

Keywords:  brain metabolism; flux balance analysis; genome-scale metabolic modeling; multiple sclerosis; reporter metabolites

DOI:  https://doi.org/10.1021/acschemneuro.5c00006
Sci Adv. 2025 Mar 21. 11(12): eadr1378

Bcl-xL overexpression in T cells preserves muscle mitochondrial structure and function and prevents frailty in old mice.

Cristina Mas-Bargues, Aurora Román-Domínguez, Jorge Sanz-Ros, Nekane Romero-García, Javier Huete-Acevedo, Mar Dromant, Ana María Cuervo, Consuelo Borrás, José Viña.

Our previous transcriptomic analysis revealed an up-regulation of the antiapoptotic protein B cell lymphoma-extra large (Bcl-xL) in centenarians relative to octogenarians or younger cohorts. In this study, we used Bcl-xL-overexpressing mice to assess its impact on successful aging. Our findings indicate that Bcl-xL overexpression modifies T cell subsets and improves their metabolism, apoptosis resistance, macroautophagy, and cytokine production during aging. This more resilient immune system reduces inflammation and preserves mitochondrial integrity and function in muscle tissue, thereby retarding the onset of frailty. These results underscore the important contribution of Bcl-xL to healthy aging, a phenomenon that is conserved across mammalian species.

DOI: https://doi.org/10.1126/sciadv.adr1378
Cell Rep. 2025 Mar 18. pii: S2211-1247(25)00212-8. [Epub ahead of print]44(4): 115441

Lactylation orchestrates ubiquitin-independent degradation of cGAS and promotes tumor growth.

Keqiang Rao, Xinchao Zhang, Yi Luo, Qiang Xia, Yuting Jin, Jing He.

  Lactate extensively associates with metabolic reprogramming, signal transduction, and immune modulation. Nevertheless, the regulatory role of lactate in immune sensing of cytosolic DNA remains uncertain. Here, we report that lactate serves as an initiator to facilitate proteasomal degradation of cyclic GMP-AMP synthase (cGAS) independent of ubiquitin, thus repressing the production of interferon and contributing to tumor growth. Mechanistically, lactylation of K21 stimulates cGAS translocation from the nucleus to the proteasome for degradation, which is compromised by phosphorylation of PSMA4 S188 via disrupting its association with cGAS. Concurrently, lactylation of K415 rewires PIK3CB activity and impairs ULK1-driven phosphorylation of PSMA4 S188. Physiologically, lactylation of cGAS sustains tumor growth. Expression of cGAS correlates with the antitumor effect of the LDHA inhibitor FX11. Finally, the lactate-cGAS axis indicates a prognostic outcome of lung adenocarcinoma. Collectively, these findings not only put forth a mechanism of cGAS degradation but also unravel the clinical relevance of cGAS lactylation.

Keywords:  CP: Cancer; PIK3CB; PSMA4; ULK1; cGAS; innate immune system; lactylation; tumor growth; ubiquitin-independent degradation

DOI:  https://doi.org/10.1016/j.celrep.2025.115441
PLoS Pathog. 2025 Mar 17. 21(3): e1012979

Myeloid-derived suppressor cell inhibits T-cell-based defense against Klebsiella pneumoniae infection via IDO1 production.

Qi Xu, Xiaoxuan Liu, Heng Heng, Han Wang, Kaichao Chen, Edward Wai-Chi Chan, Guan Yang, Sheng Chen.

Klebsiella pneumoniae (Kp) is responsible for a wide range of infections, including pneumonia, sepsis, and urinary tract infections. However, the treatment options are limited due to the continuous evolution of drug-resistant and hypervirulent variants. It is crucial to investigate the mechanisms behind the high mortality rate of hypervirulent Kp (hvKp) strains to develop new strategies for preventing hvKp from evading the host's defenses and improving treatment effectiveness for these fatal infections. In this study, we used a hvKp-induced mouse bacteremia model and performed single-cell RNA sequencing to investigate the effects of hvKp infection. Our findings demonstrated that hvKp infection led to a decrease in lymphocytes (lymphopenia), attributed to impaired proliferation and apoptosis. The infiltration of myeloid-derived suppressor cells (MDSCs) in the infected lungs was confirmed to suppress T cell proliferation, leading to lymphopenia. We further identified that hvKp promotes tryptophan metabolism in infected lungs, enhancing the immunosuppressive activity of MDSCs by inducing the production of the enzyme IDO1. Our ex vivo inhibition experiment revealed that L-kynurenine, a product of tryptophan metabolism, inhibits T-cell proliferation and induces T-cell apoptosis, further suppressing T-cell mediated responses against bacteria. Importantly, when we knocked out the Ido1 gene or inhibited IDO1 expression using a specific inhibitor 1-MT in mice, we observed a significant enhancement in T-cell mediated responses against hvKp. These findings highlight the crucial role of MDSCs in hvKp-induced bacteremia and suggest a promising immunotherapeutic approach by inhibiting IDO1 production to combat infectious diseases.

DOI: https://doi.org/10.1371/journal.ppat.1012979
Cell Rep. 2025 Mar 17. pii: S2211-1247(25)00182-2. [Epub ahead of print]44(3): 115411

Multi-platform omics analysis of Nipah virus infection reveals viral glycoprotein modulation of mitochondria.

Gunner P Johnston, Fikret Aydemir, Haewon Byun, Emmie de Wit, Kristie L Oxford, Jennifer E Kyle, Jason E McDermott, Brooke L Deatherage Kaiser, Cameron P Casey, Karl K Weitz, Heather M Olson, Kelly G Stratton, Natalie C Heller, Viraj Upadhye, I Abrrey Monreal, J Lizbeth Reyes Zamora, Lei Wu, D H Goodall, David W Buchholz, Joeva J Barrow, Katrina M Waters, Ruth N Collins, Heinz Feldmann, Joshua N Adkins, Hector C Aguilar.

  The recent global pandemic illustrates the importance of understanding the host cellular infection processes of emerging zoonotic viruses. Nipah virus (NiV) is a deadly zoonotic biosafety level 4 encephalitic and respiratory paramyxovirus. Our knowledge of the molecular cell biology of NiV infection is extremely limited. This study identified changes in cellular components during NiV infection of human cells using a multi-platform, high-throughput transcriptomics, proteomics, lipidomics, and metabolomics approach. Remarkably, validation via multi-disciplinary approaches implicated viral glycoproteins in enriching mitochondria-associated proteins despite an overall decrease in protein translation. Our approach also allowed the mapping of significant fluctuations in the metabolism of glucose, lipids, and several amino acids, suggesting periodic changes in glycolysis and a transition to fatty acid oxidation and glutamine anaplerosis to support mitochondrial ATP synthesis. Notably, these analyses provide an atlas of cellular changes during NiV infections, which is helpful in designing therapeutics against the rapidly growing Henipavirus genus and related viral infections.

Keywords:  CP: Microbiology; Nipah virus; host; infection; lipidomics; metabolism; metabolomics; omics; paramyxovirus; proteomics; transcriptomics

DOI:  https://doi.org/10.1016/j.celrep.2025.115411