bims-imicid 2025-07-06 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2025–07–06
29 papers selected by
Dylan Ryan, University of Cambridge

Circadian metabolism in myeloid cells.
Live fast, die young: neutrophils streamline their metabolism to maximize inflammation.
PGI2 signaling metabolically reprograms CD4 Th2 cells and represses allergic airway inflammation.
Systemic metabolic changes in acute and chronic lymphocytic choriomeningitis virus infection.
You are what you eat: autophagy guides CD8+ T cell function through metabolism.
Weight Loss-Associated Remodeling of Adipose Tissue Immunometabolism.
Mitochondrial metabolic regulation of macrophage polarization in osteomyelitis and other orthopedic disorders: mechanisms and therapeutic opportunities.
Lessons from cross-pathogen studies: understanding the metabolic rewiring of macrophages upon infection.
Thermal proteome profiling of itaconate interactome in macrophages.
RAB4A DRIVES PROINFLAMMATORY CD4+ T CELL SIGNALING VIA CD38-DEPENDENT NAD+ METABOLISM.
Mitochondrial dysfunction enhances influenza pathogenesis by up-regulating de novo sialic acid biosynthesis.
Epigenetic and metabolic regulation of macrophage responsiveness and memory.
SMRT-depleted conventional DCs maintain inflammation despite lower glycolysis via mTOR signalling and succinate oxidation.
P-glycoprotein expression skews mitochondrial dye measurements in T cells.
GLP-1/GLP-1R axis: from metabolism (obesity and T2DM) to immunity.
Covalent Organic Frameworks-Delivered Reuterin Drives Trained Immunity in Tumor-Associated Macrophages to Enhance Melanoma Immunotherapy via Glycerophospholipid Metabolism.
Histone lactylation as a driver of metabolic reprogramming and immune evasion.
Inhibition of the Na+-glucose transporter SGLT2 reduces glucose uptake and IFNγ release from activated human CD4+ T cells.
FABP7 is increased in progressive multiple sclerosis and induces a pro-inflammatory phenotype in monocytes through a glycolytic switch.
Gamma-Glutamyl Cysteine Ligase Activity as a Proxy for Human T Cell Function and Drug-Induced Immunosuppression.
Sphingosine 1-phosphate derived from tumor-educated hepatic stellate cells combining with S1PR4 promotes tumor associated macrophages differentiation through FAO modulation.
Immunometabolism and oxidative stress: roles and therapeutic strategies in cancer and aging.
Metabolic compartmentalization via glycogenolysis-derived G1P bolsters T cell memory.
Host glutathione is required for Rickettsia parkeri cell division and intracellular survival.
Metabotropic glutamate receptor 4-mediated glutamatfergic signaling reshapes the tumor microenvironment by regulating dendritic cell maturation.
Identification of picornavirus proteins that inhibit de novo nucleotide synthesis during infection.
Arginine at the host-pathogen interface.
The swine acute diarrhea syndrome coronavirus spike protein promotes syncytial formation via upregulation of cellular cholesterol synthesis.
Viruses hijack FPN1 to disrupt iron withholding and suppress host defense.

Life Metab. 2025 Aug;4(4): loaf018

Circadian metabolism in myeloid cells.

Yingxi Xu, Chen Wang, Ping-Chih Ho.

  Circadian rhythms are fundamental regulators of physiological processes, including immune function. Recent insights uncover that not only lymphocytes but also myeloid cells possess intrinsic circadian clocks that govern their behavior and function. Emerging evidence highlights how circadian regulation of metabolism critically shapes the inflammatory and tissue-repair functions of myeloid subsets. Furthermore, mitochondrial dynamics, a key metabolic feature, are under circadian control and influence antigen presentation and effector functions. Here, we review the interplay between circadian clocks, metabolism, and myeloid immunity, discussing their therapeutic opportunities for optimizing vaccination, infection management, and immunotherapy.

Keywords:  circadian rhythms; metabolism; myeloid cell

DOI:  https://doi.org/10.1093/lifemeta/loaf018
Infect Immun. 2025 Jun 30. e0049824

Live fast, die young: neutrophils streamline their metabolism to maximize inflammation.

Bailey E Holder, Callista P Reber, Andrew J Monteith.

  Neutrophils are the most abundant leukocytes at sites of inflammation and form the front line of the innate immune response. Neutrophils have a relatively short lifespan compared to other cell types, as they have streamlined their metabolic processes to support an arsenal of antimicrobial functions to combat invading pathogens at the cost of maximizing ATP output. To elicit antimicrobial stress, neutrophils rewire their glycolytic pathways to sustain phagocytosis and the oxidative burst and modify their mitochondrial metabolism to dictate degranulation or release of neutrophil extracellular traps. While many of these effector functions are sufficient to protect the "healthy" host from infection, chronic diseases disrupting metabolic and inflammatory homeostasis render the host susceptible to more frequent and severe bacterial infections. With the growing incidence of many metabolic and autoimmune diseases, a clearer understanding of the mechanisms regulating or disrupting neutrophil antimicrobial processes is required. This review focuses on the relationship between neutrophil function and metabolism and what is known about how this impacts autoimmune and metabolic diseases and/or disorders in the case of bacterial infection.

Keywords:  bacterial infection; diabetes; glycolysis; inflammation; metabolism; mitochondria; neutrophils; obesity; pentose phosphate pathway; systemic lupus erythematosus

DOI:  https://doi.org/10.1128/iai.00498-24
J Immunol. 2025 Jun 30. pii: vkaf130. [Epub ahead of print]

PGI2 signaling metabolically reprograms CD4 Th2 cells and represses allergic airway inflammation.

Weisong Zhou, Jian Zhang, Nowrin U Chowdhury, Allison E Norlander, Shinji Toki, Masako Abney, Mark Rusznak, Katherine N Gibson-Corley, Daniel P Cook, Dawn C Newcomb, Ray Stokes Peebles.

  Prostaglandin I2 (PGI2) is a lipid mediator known to inhibit T helper 2 (Th2) immune responses and allergic inflammation, but its role in regulating Th2 cell metabolism remains underexplored. Using the Seahorse assay, we evaluated the effects of PGI2 signaling on Th2 cell glycolysis and mitochondrial respiration. Our results show that cicaprost, a stable PGI2 analog, significantly reduced basal, maximal, and spare glycolytic capacities in wild-type Th2 cells, while these effects are absent in Th2 cells lacking the PGI2 IP receptor (IP knockout [KO]). Cicaprost also impaired mitochondrial respiration and adenosine triphosphate production in wild-type Th2 cells, but not in IP KO cells, indicating that PGI2 signaling is essential for these metabolic changes. Further analysis revealed that cicaprost decreased glucose transporter 1 expression and glucose uptake and inhibited mitochondrial mass and membrane potential, suggesting that PGI2 signaling inhibits Th2 cell metabolism by reducing glucose availability and mitochondrial respiratory functions. Metabolomic profiling of cicaprost-treated Th2 cells showed dose-dependent changes, with 126 downregulated and 233 upregulated metabolites showing over 2-fold significant changes compared with vehicle-treated cells. Pathway analysis of these altered metabolites suggests a shift from catabolism to anabolism in cicaprost-treated Th2 cells. In vivo, CD4-specific conditional IP KO mice (CD4Cre+IPflox) exhibited exacerbated lung inflammation following exposure to Alternaria alternata extract, marked by increased IL-5 and IL-13 production, enhanced eosinophilia, and elevated mucus production. These findings establish a mechanistic link between PGI2-mediated immunoregulation and metabolic reprogramming, reinforcing its role as a key modulator of allergic inflammation.

Keywords:  T cells; inflammation; lung; mouse

DOI:  https://doi.org/10.1093/jimmun/vkaf130
Mol Metab. 2025 Jun 26. pii: S2212-8778(25)00101-2. [Epub ahead of print] 102194

Systemic metabolic changes in acute and chronic lymphocytic choriomeningitis virus infection.

Caroline Bartman, Shengqi Hou, Fabian Correa, Yihui Shen, Victoria da Silva-Diz, Maya Aleksandrova, Daniel Herranz, Joshua D Rabinowitz, Andrew Intlekofer.

  Viral infection of cells leads to metabolic changes, but how viral infection changes whole-body and tissue metabolism in vivo has not been comprehensively studied. In particular, it is unknown how metabolism might be differentially affected by an acute infection that the immune system can successfully clear compared to a chronic persistent infection. Here we used metabolomics and isotope tracing to identify metabolic changes in mice infected with acute or chronic forms of lymphocytic choriomeningitis virus (LCMV) for three or eight days. Both types of infection alter metabolite levels in blood and tissues, including itaconate and thymidine. However, we observed more dramatic metabolite changes in the blood and tissues of mice with persisting LCMV infection compared to those infected with the acute viral strain. Isotope tracing revealed that the contribution of both glucose and glutamine to the tricarboxylic acid (TCA) cycle increase in the spleen, liver, and kidneys of mice infected with chronic LCMV, while acute LCMV only increases the contribution of glutamine to the TCA cycle in the spleen. We found that whole-body turnover of both glutamine and thymidine increase during acute and chronic infection, whereas whole-body glucose turnover was surprisingly unchanged. Activated T cells in vitro produce thymidine and virus-specific T cells ex vivo have increased thymidine levels, nominating T lymphocytes as the source of thymidine in LCMV infection. In sum, we provide comprehensive measurements of whole-body and tissue metabolism in acute and chronic viral infection, and identify altered thymidine metabolism as a marker of viral infection.

Keywords:  Immunometabolism; Isotope tracing; Metabolomics; Tissue metabolism; Whole-body metabolism

DOI:  https://doi.org/10.1016/j.molmet.2025.102194
Immunometabolism (Cobham). 2025 Jul;7(3): e00064

You are what you eat: autophagy guides CD8+ T cell function through metabolism.

Caio Loureiro Salgado, Henrique Borges da Silva.

  The differentiation of naive CD8+ T cells into effector or memory populations requires dynamic remodeling of cellular metabolism and proteome composition. In a recent study published in Nature Immunology, Sinclair et al offer critical insights into the role of autophagy, particularly mitophagy, in regulating these processes during CD8+ T cell differentiation. Autophagy, a conserved catabolic mechanism, is traditionally associated with cellular homeostasis and survival during nutrient deprivation. In contrast, Sinclair et al reveal that, in the immune system, autophagy is not simply a survival mechanism but a fine-tuned regulator of CD8+ T cell metabolism and function, fine-tuning CD8+ T cell effector vs quiescence choices.

Keywords:  CD8+ T cells; autophagy; cytotoxic T cell; mitophagy; naive T cells

DOI:  https://doi.org/10.1097/IN9.0000000000000064
Obes Rev. 2025 Jun 30. e13975

Weight Loss-Associated Remodeling of Adipose Tissue Immunometabolism.

Paulo José Basso, Alejandro Schcolnik-Cabrera, Mengyi Zhu, Erin Strachan, Xavier Clemente-Casares, Sue Tsai.

  Obesity is a multifactorial condition characterized by excessive adiposity and systemic chronic low-grade inflammation. Recent literature reflects a growing appreciation for the complex interplay between metabolism and the immune system in the pathogenesis of obesity-related health conditions. However, this field of investigation, also known as immunometabolism, requires more in-depth study to fully understand the impact of weight loss treatments on the metabolism and function of immune cells. Despite indications that weight loss can alleviate certain metabolic dysfunctions associated with obesity, the extent to which immunometabolic parameters return to baseline posttherapy remains largely unexplored. Therefore, this review intends to re-examine critical aspects of obesity pathophysiology and highlight recent advancements in literature regarding the effects of weight loss interventions on the metabolism and function of immune cells. Addressing this field is crucial for optimizing obesity management strategies and gaining insights into long-term metabolic health outcomes.

Keywords:  adipose tissue‐infiltrating immune cells; anti‐obesity medication; exercise/caloric restriction; metabolism

DOI:  https://doi.org/10.1111/obr.13975
Front Cell Dev Biol. 2025 ;13 1604320

Mitochondrial metabolic regulation of macrophage polarization in osteomyelitis and other orthopedic disorders: mechanisms and therapeutic opportunities.

Jinglin Li, Lin Zhang, Jiaze Peng, Chuntao Zhao, Wenguang Li, Yang Yu, Xianpeng Huang, Fuyin Yang, Xuan Deng, Xuxu Yang, Tao Zhang, Jiachen Peng.

  Osteomyelitis is a complex infectious bone disease involving pathogen invasion, host immune responses, and dysregulation of the local microenvironment. As a critical component of the innate immune system, macrophages play a pivotal role in inflammatory responses and tissue repair. Their polarization states (M1/M2) directly influence disease progression, while mitochondrial metabolism, as the central hub of cellular energy metabolism, has recently been shown to play a key role in macrophage polarization and functional regulation. However, how mitochondrial metabolism regulates macrophage polarization to affect the pathological mechanisms of osteomyelitis, and how to develop novel therapeutic strategies based on this mechanism, remain critical scientific questions to be addressed. This review systematically summarizes the molecular mechanisms by which mitochondrial metabolism regulates macrophage polarization and its role in osteomyelitis, with a focus on the impact of mitochondrial dynamics (fission/fusion), metabolic reprogramming, and reactive oxygen species (ROS) generation on macrophage polarization. Additionally, potential therapeutic strategies targeting mitochondrial metabolism are analyzed. For the first time, this review integrates the interplay between mitochondrial metabolism and macrophage polarization in osteomyelitis, revealing how mitochondrial dysfunction exacerbates inflammation and bone destruction through metabolic reprogramming. Based on these findings, we propose novel therapeutic strategies targeting mitochondrial metabolism, offering new perspectives and directions for understanding the pathogenesis and clinical treatment of osteomyelitis.

Keywords:  bone repair; inflammation; macrophage polarization; mitochondrial dynamics; mitochondrial metabolism; osteomyelitis

DOI:  https://doi.org/10.3389/fcell.2025.1604320
Front Cell Infect Microbiol. 2025 ;15 1584777

Lessons from cross-pathogen studies: understanding the metabolic rewiring of macrophages upon infection.

Marisol Perez-Toledo, Alba Llibre.

  Bacterial infections remain a significant cause of morbidity and mortality globally. Compounding the issue is the rise of antimicrobial-resistant strains, which limit treatment options. Macrophages play key roles in the immunity and pathogenicity of intracellular infections, such as those caused by Mycobacterium tuberculosis and Salmonella. Recent advancements have enabled us to better understand how the host orchestrates immune responses to fight these infections and, specifically how the infected cell rewires its metabolism to face this challenge. The engagement of the host cell in specific metabolic pathways impacts cell function and behaviour, and ultimately, infection outcomes. In this perspective, we summarise key findings regarding the metabolic adaptations in macrophages induced by Mycobacterium tuberculosis and Salmonella infections. We also explore how cross-pathogen studies can deepen our insights into infection biology to improve therapeutic design.

Keywords:  Mycobacterium tuberculosis; Salmonella typhimurium; host-direct therapies; macrophage; metabolism rewiring

DOI:  https://doi.org/10.3389/fcimb.2025.1584777
Chem Sci. 2025 Jul 02.

Thermal proteome profiling of itaconate interactome in macrophages.

Yunzhu Meng, Tiantian Wei, Chenlin Zhang, Anqi Yu, Yuan Liu, Junyu Xiao, Chu Wang.

Itaconate (ITA) is an upregulated immunometabolite in macrophages during pathogen infection. It is known to influence oxidation stress, cellular metabolism, programmed cell death and many other biological processes to regulate the immune response via interaction with proteins. Previous studies capture covalently ITA-modified proteins by activity-based proteome profiling with bioorthogonal chemical probes; however, how itaconate interacts non-covalently with other proteins at the proteome level remains unexplored. Here we applied thermal proteome profiling (TPP) to globally identify a large number of ITA-interacting proteins in macrophage proteomes. Among these targets, we verified mitochondrial branched-chain aminotransferase (BCAT2) as a novel non-covalent binding target of itaconate via biochemical and structural experiments. The binding of itaconate could inhibit transamination activity of BCAT and regulate the metabolism of branched-chain amino acids (BCAAs) in lipopolysaccharide (LPS)-activated inflammatory macrophages. This study offers a valuable resource that helps decipher novel and comprehensive functions of ITA in macrophages during the immune response and other related biological processes.

DOI: https://doi.org/10.1039/d5sc02378e
Res Sq. 2025 Jun 12. pii: rs.3.rs-6787101. [Epub ahead of print]

RAB4A DRIVES PROINFLAMMATORY CD4+ T CELL SIGNALING VIA CD38-DEPENDENT NAD+ METABOLISM.

Joy S Park, Daniel Krakko, Jessica Nolan, Brandon Wyman, Mahsa Sadeghzadeh, Andras Perl.

  Rab4A, a small GTPase overexpressed in T cells of patients with systemic lupus erythematosus (SLE), has been shown to activate mechanistic target of rapamycin (mTOR) signaling, which promotes proinflammatory T cell development and predisposes to nephritis in SLE. In this study, we demonstrate that Rab4A facilitates the endocytic recycling and surface expression of CD38, which, in turn, triggers NAD+ depletion, activates mTOR complex 1, and suppresses interleukin-2 (IL-2) production in CD4+ T cells. Rab4A-driven CD38-mediated NAD+ depletion elicits the accumulation of nicotinamide and ADP-ribose and secondary depletion of cyclic ADP-ribose. Surprisingly, rapamycin further enhanced CD38 expression and reduced IL-2 secretion, suggesting that IL-2 depletion is mTOR-independent. Alternatively, Rab4A-driven upregulation of CD38 promoted STAT3 expression and its acetylation, as well as FOXO1 expression, which underlies IL-2 depletion in CD4+ T cells. These findings reveal a novel Rab4A-driven CD38 signaling axis that links receptor trafficking to proinflammatory metabolic pathways, providing new targets for treatment in SLE.

Keywords:  CD38; CD4+ T cells; IL-2; NAD+; Rab4A; autoimmunity; endosome traffic; mTOR; metabolism; systemic lupus erythematosus

DOI:  https://doi.org/10.21203/rs.3.rs-6787101/v1
Sci Adv. 2025 Jul 04. 11(27): eadu3739

Mitochondrial dysfunction enhances influenza pathogenesis by up-regulating de novo sialic acid biosynthesis.

Amanda L Fuchs, Bharati Singh, Jillian W Jetmore, Emily B Warren, Payal Banerjee, Jose L Marin Franco, Michael A Eckhaus, Tatiana N Tarasenko, Madeleine R Assaad, Ivan Kosik, Jonathan Yewdell, Peter J McGuire.

Mitochondrial dysfunction can trigger metabolic adaptations that resemble those induced by influenza A virus (IAV) infection. Here, we show that oxidative phosphorylation (OXPHOS) impairment, modeled by Ndufs4 deficiency, reprograms lung epithelial metabolism to promote IAV pathogenesis. In both Ndufs4 knockout (KO) mice and lung epithelial cells, OXPHOS deficiency increased glycolytic flux, diverting carbons into hexosamine and de novo sialic acid (SIA) biosynthesis pathways. This led to elevated sialylation and enhanced viral attachment. In Ndufs4 KO models, adenosine monophosphate-activated protein kinase signaling was insufficient to blunt this increased metabolic flux. IAV infection further exacerbated this metabolic vulnerability, amplifying SIA and viral burden. Pharmacologic rerouting of glucose carbons with dichloroacetate reduced sialylation, viral replication, and inflammatory responses in Ndufs4 KO models. These findings reveal that mitochondrial dysfunction enhances IAV susceptibility by disrupting energy sensing and fueling viral receptor biosynthesis, highlighting the importance of epithelial metabolism in viral pathogenesis and suggesting metabolic modulation as a potential therapeutic.

DOI: https://doi.org/10.1126/sciadv.adu3739
J Immunol. 2025 Jul 01. pii: vkaf135. [Epub ahead of print]

Epigenetic and metabolic regulation of macrophage responsiveness and memory.

Maria G Daskalaki, Ioanna Lapi, Avery Ellen Hurst, Ahmed Al-Qahtani, Eleni Vergadi, Christos Tsatsanis.

  Macrophages, the central mediators of innate immune responses, can adapt and build nonspecific memory, also known as innate immune memory or trained immunity. Training of macrophages occurs through epigenetic changes and metabolic rewiring, which fuels macrophage responsiveness. In addition to training in response to infectious insults, macrophage responsiveness can be modulated by pathogenic de-regulation of hormones, cytokines, or adipokines, which similarly induce epigenetic changes in inflammatory genes. Sex specific differences in macrophage responsiveness to TLR ligands have been described, with sex hormones playing a crucial role in shaping the epigenetic landscape and regulating inflammatory responses. Chronic metabolic disorders, such as obesity and type 2 diabetes, also affect macrophage responsiveness. In particular, insulin resistance impairs Akt signaling in macrophages in an Akt isoform-specific manner, altering their metabolism, their responsiveness to inflammatory insults and their capacity to eliminate pathogens. These functional impairments are underpinned by changes in the epigenetic landscape of macrophages. Given the short half-life of macrophages in the periphery, these long-lasting alterations in their responsiveness originate in the bone marrow at the level of hematopoietic stem and progenitor cells. Recent studies have demonstrated that exposure to TLR ligands induces immunological memory driven by changes in hematopoietic stem and progenitor cells. These changes include epigenetic alterations in histones and DNA. Herein we discuss recent evidence on the epigenetic and metabolic regulation of macrophage memory, highlight sex hormone-driven changes, describe changes driven by metabolic factors and obesity, and explore the therapeutic potential of targeting epigenetic regulators for the treatment of inflammatory diseases.

Keywords:  Akt; epigenetics; gender; innate immunity; macrophages; memory; metabolism; obesity; sex; trained immunity

DOI:  https://doi.org/10.1093/jimmun/vkaf135
npj metabolic health and disease... 2024 Dec 04. 2(1): 35

SMRT-depleted conventional DCs maintain inflammation despite lower glycolysis via mTOR signalling and succinate oxidation.

Kaushik Sen, Rashmirekha Pati, Gyan Prakash Mishra, Subhasish Prusty, Sourya Prakash Nayak, Archana Tripathy, Shweta Chaudhary, Atimukta Jha, Arunita Patra, Priti Meena, Shaktiprasad Mishra, Ranjan Kumar Nanda, Alok Kumar Mantri, Bhawna Gupta, Sunil K Raghav.

Inflammatory diseases implicate a synchronised immune-metabolic rewiring to maintain homeostasis. The regulatory mechanisms governing the transcriptional control of immune-centric metabolic adjustments in dendritic cells (DCs) remains elusive. Recently we reported that Ncor2 (SMRT) loss of function in DCs potentiates strong inflammation. We found that SMRT depletion in DCs triggers a metabolic shift resulting in sustained and strong inflammation despite reduced glycolysis. This is in contrast to the widely accepted notion that glycolytic pathway activation is essential for inducing inflammation. Downregulation of mTOR emerged as a pivotal factor in attenuating the glycolytic rate. Significant metabolic alterations led to rewiring of the TCA-cycle by triggering anaplerotic glutamine catabolism and promoting succinate oxidation, thereby sustaining the inflammatory potential. Simultaneous treatment with succinate transport inhibitor DEBM and mTOR inducer Mhy1485 remarkably suppressed inflammation ex vivo and in vivo. Our findings also depicted an inverse correlation between SMRT levels with human autoimmune diseases.

DOI: https://doi.org/10.1038/s44324-024-00034-1
Front Immunol. 2025 ;16 1560104

P-glycoprotein expression skews mitochondrial dye measurements in T cells.

Sophia P M Sok, Jianan Cheng, Klaudia Strucinska, Narcis I Popescu, Lihua Wu, Qiuqing Ke, William B Kiosses, David Stanford, Willard M Freeman, Satoshi Matsuzaki, Tommy L Lewis, Meng Zhao.

  Assays to monitor metabolic parameters of immune cells at a single cell level provide efficient means to study immunometabolism. We show here that staining intensity of mitochondria targeting probes in T cells is dramatically influenced by P-glycoprotein/P-gp expression, a xenobiotic efflux pump that extrudes these fluorescent dyes. Discrepancies between MitoTracker Green FM/MTG signals and multiple dye-independent measurements are seen in CD4 T and CD8 T cell subsets and are corrected by P-gp inhibition (PSC833) during MTG staining. We further investigate invariant Natural Killer T (iNKT) cells, which express the highest level of P-glycoprotein among T cells. Using mtDNA abundance, mitochondrial volume, respiration and proteomics, we establish that iNKT cells have higher mitochondrial content and activity than CD4 T cells, opposite to what MTG signals reveal. A similar phenomenon is also seen in human PBMCs, and with TMRE, a dye indicator of mitochondrial membrane potential. Collectively, these data argue that P-glycoprotein expression is a significant confounding factor when analyzing T cells using mitochondrial specific dyes. Complementary methods are necessary to reliably assess mitochondrial features in T cells.

Keywords:  P-glycolprotein; T cells; TMRE; mitochondria; mitotracker; oxidative phosphorilation

DOI:  https://doi.org/10.3389/fimmu.2025.1560104
Open Biol. 2025 Jan;15(7): 240303

GLP-1/GLP-1R axis: from metabolism (obesity and T2DM) to immunity.

Vijay Kumar.

  The discovery of glucagon-like peptide-1 (GLP-1) has revolutionized metabolism research in the context of obesity and type 2 diabetes mellitus (T2DM). For example, worldwide, more than 537 million adults are affected with T2DM, and more than 30.3 million people in the USA alone are suffering from T2DM. Obesity is one independent risk factor for T2DM; therefore, targeting obesity may lower the T2DM development risk. Hence, pharmaceutical companies have developed different GLP-1R agonists (GLP-1RAs) to target obesity and T2DM, which comprised multibillion-dollar businesses. However, metabolism and immune response are well-correlated processes that affect each other. For example, recent advances in metabolic processes governing the immune response have led to the evolution of immunometabolism, which can be divided into cellular, tissue and systemic immunometabolism. The current open-question article is intended to explore the impact of the GLP-1/GLP-1R axis on the immune response governed by the functioning of various immune cells and their interaction with the nervous system and microbiota axis that further depends on the gender and circadian clock of the host. Along with food/sugar ingestion, several other factors controlling the GLP-1 secretion and its immunomodulatory functions have been discussed to highlight the importance of the GLP-1/GLP-1R axis in immunoregulation. Therefore, understanding the GLP-1/GLP-1R axis/interaction at the immunological level will help to understand the adverse events associated with GLP-1RAs and their use as an immunomodulatory agent in acute and chronic inflammatory conditions depending on the gender and metabolic status of the host.

Keywords:  GLP-1/GLP-1R axis; L cells; hypothalamus; immunity; intraepithelial lymphocytes; macrophages

DOI:  https://doi.org/10.1098/rsob.240303
Adv Sci (Weinh). 2025 Jun 30. e04784

Covalent Organic Frameworks-Delivered Reuterin Drives Trained Immunity in Tumor-Associated Macrophages to Enhance Melanoma Immunotherapy via Glycerophospholipid Metabolism.

Jian-Gang Zhang, Xiao-Mei Zhang, Xi Wu, Cheng-Kai Zhou, Zhen-Zhen Liu, Xue-Yue Luo, Liang Zhang, Wei Chen, Yong-Jun Yang.

  The gut microbiota is increasingly recognized as a promising therapeutic target in cancer treatment. However, the specific mechanisms by which gut bacteria and their metabolites exert therapeutic effects in melanoma remain poorly understood. In this study, it is unexpectedly demonstrated that prophylactic supplementation with Limosilactobacillus reuteri exhibits significant tumor-suppressive properties, primarily mediated by its secreted metabolite, reuterin. This metabolite induces trained immunity through macrophage metabolic reprogramming, thereby enhancing antitumor immune responses. Mechanistically, this process involves stabilizing HIF-1α via the AHR-ROS signaling pathway, enhancing glycerophospholipid metabolism, and elevating arachidonic acid levels, thereby amplifying the trained immunity response. Similar to reuterin, arachidonic acid also induces trained immunity and facilitates macrophage-mediated tumor cell killing. To enhance its therapeutic efficacy, reuterin is encapsulated in covalent organic frameworks (COFs). COF-Reuterin demonstrates superior effects in tumor-associated macrophages (TAMs), remodulating intratumor bacteria and directly facilitating tumor cell killing. Notably, COF-Reuterin demonstrates superior therapeutic efficacy compared to cisplatin. Furthermore, COF-Reuterin reprogrammed TAMs from an M2 to an M1 phenotype, increasing CD8+ T cell infiltration and decreasing myeloid-derived suppressor cells (MDSCs), reshaping the immunosuppressive tumor microenvironment. These findings highlight the potential of probiotics and their metabolites in the metabolic reprogramming of TAMs, offering a promising cancer therapeutic approach.

Keywords:  Limosilactobacillus reuteri; intratumor bacteria; melanoma; reuterin; trained immunity; tumor‐associated macrophages

DOI:  https://doi.org/10.1002/advs.202504784
Med Rev (2021). 2025 Jun;5(3): 256-259

Histone lactylation as a driver of metabolic reprogramming and immune evasion.

Qiaoting Cai, Wei Deng, Yutian Zou, Zhe-Sheng Chen, Hailin Tang.

  Lactate is the end product of glycolysis, and extensive research has shown that lactate participates in various pathophysiological processes. Along with associated hydrogen ions, lactate typically functions as an immunosuppressive negative factor and plays a crucial role in tumor metabolic reprogramming. The recently discovered lactylation is a novel epigenetic modification that, similar to other epigenetic modifications, modifies histones to alter chromatin spatial configuration, thereby affecting DNA accessibility and regulating gene expression. More importantly, the degree of lactylation is closely related to local lactate concentrations, establishing a link between epigenetics and metabolic reprogramming. During cellular metabolism, lactate accumulation promotes histone lysine lactylation in cancer cells and immune cells such as macrophages and T cells, playing an essential role in tumor immune evasion and resistance to immunotherapy. This paper details the role of lactylation modifications in cancer immune evasion and resistance to immunotherapy, providing novel therapeutic directions and targets for cancer treatment.

Keywords:  cancer; histone lactylation; immune escape; immunotherapy resistance

DOI:  https://doi.org/10.1515/mr-2024-0091
Front Immunol. 2025 ;16 1576216

Inhibition of the Na+-glucose transporter SGLT2 reduces glucose uptake and IFNγ release from activated human CD4+ T cells.

Zhe Jin, Hayma Hammoud, Amol K Bhandage, Stasini Koreli, Azazul Islam Chowdhury, Peter Bergsten, Bryndis Birnir.

  Glucose uptake in activated CD4+ T cells is essential for increased metabolic needs, synthesis of biomolecules and proliferation. Although, facilitated glucose transport is the predominant route for glucose entry at the time of activation, here we demonstrate role for the sodium-dependent glucose transporter SGLT2. By 72 h after activation, SGLT2 is expressed and functional in the human CD4+ T cells. SGLT2 inhibitors, phlorizin and empagliflozin decreased glucose uptake into the human CD4+ T cells compared to untreated cells. Phlorizin (25 μmol/L) reduced glycolysis at 5.6 mmol/L glucose and IFNγ levels at both 5.6 mmol/L and 16.7 mmol/L glucose. In contrast, empagliflozin (0.5 μmol/L) only decreased IFNγ levels in 16.7 mmol/L glucose. GABA enhanced phlorizin inhibition at both 5.6 mmol/L and 16.7 mmol/L glucose in the presence of insulin. Insulin strengthens GABAA receptors signaling in CD4+ T cells. The results are consistent with expression of SGLT2 after activation of human CD4+ T cells, that facilitates concentrating glucose uptake into the cells, enabling enhanced release of inflammatory molecules like IFNγ. Importantly, inhibition of SGLT2 decreases IFNγ release.

Keywords:  GLUT1; IFNγ; SGLT2; T cells; empagliflozin; glucose uptake; immunomodulation; phlorizin

DOI:  https://doi.org/10.3389/fimmu.2025.1576216
Nat Commun. 2025 Jul 01. 16(1): 6049

FABP7 is increased in progressive multiple sclerosis and induces a pro-inflammatory phenotype in monocytes through a glycolytic switch.

Rohit Patel, Devin King, Brenna LaBarre, Hrishikesh Lokhande, Danielle Caefer, Johnna F Varghese, Keturah Warner, Marc A Bouffard, Shrishti Saxena, Alena Zhirova, Rohit Bakshi, Tanuja Chitnis.

Multiple sclerosis (MS) involves dysregulation of innate immune cells including monocytes, especially in progressive MS. Fatty acid binding proteins (FABP) are essential for fatty acid transport and metabolism in multiple cell types. FABP7, a brain-FABP, maintains metabolic function in astrocytes and neural stem cells, but the effect of FABP7 on monocytes is unknown. Here we find elevated levels of FABP7 in the serum and cerebrospinal fluid of patients with secondary progressive MS. Elevated serum FABP7 levels positively correlate with higher disability scores, brain lesion volumes, and lower brain volumes. FABP7 levels are increased in astrocytes from MS postmortem brain lesion. Mechanistically, in vitro treatment of FABP7 induces CD16, CD80 and IL-1β expression in monocytes via increased glycolysis. FABP7-induced gene expression reflects enhanced inflammation, chemotaxis and glucose metabolism in monocytes. In conclusion, we find that FABP7 induces pro-inflammatory profiles in monocytes, correlates with disability and represents a potential biomarker and therapeutic target for progressive MS.

DOI: https://doi.org/10.1038/s41467-025-60747-9
Adv Sci (Weinh). 2025 Jun 30. e01179

Gamma-Glutamyl Cysteine Ligase Activity as a Proxy for Human T Cell Function and Drug-Induced Immunosuppression.

Francisco Fueyo-González, Carmen Salto-Giron, Mehek Ningoo, Laura Espinar-Barranco, Rafael Salto, Jose Manuel Paredes, Rosario Herranz, Angel Orte, Miguel Fribourg, Juan A González-Vera.

  T cell effector functions are critical for immune defense, but their dysregulation can cause diseases like immune exhaustion in cancer and loss of tolerance in autoimmunity. Curtailing these functions is essential in therapies such as chimeric antigen receptor T-cell (CAR-T) therapies or organ transplantation to avoid hyperactivation and rejection. A major challenge in the field is the precise, live measurement of T cell function at the single-cell level, limiting the prediction of immune responses, the development of effective immunotherapies, and optimization of immunosuppressive regimens. Gamma-Glutamyl Cysteine Ligase (GCL), the rate-limiting enzyme in glutathione (GSH) synthesis, is essential for T cell function in mice, but its role in human T cells is underexplored. GLed, a novel reversible lanthanide-based GSH sensor is introduced that enables real-time, quantitative measurements of GCL activity at single-cell resolution. The GLed approach distinguishes GSH contributions from GCL and GSR, linking GCL activity directly to human T cell effector functions. Additionally, this reveals previously unknown modulation of GCL activity by immunosuppressive drugs, underscoring GCL as a critical player in T cell function and a potential therapeutic target in immune-related diseases.

Keywords:  T cells; glutamate‐cysteine ligase; glutathione; immunosuppression; lanthanide sensor

DOI:  https://doi.org/10.1002/advs.202501179
Sci Rep. 2025 Jul 01. 15(1): 20507

Sphingosine 1-phosphate derived from tumor-educated hepatic stellate cells combining with S1PR4 promotes tumor associated macrophages differentiation through FAO modulation.

Rui Feng, Zilin Cui, Long Yang, Zirong Liu.

The tumor immune microenvironment (TIME) is significance to the occurrence and development of tumors. Macrophages, making great contributes to TIME, develop into tumor-associated macrophages (TAM) under the influence of the tumor microenvironment (TME), resulting in altered metabolic pathways. Sphingosine 1-phosphate (S1P) is involved in immune regulation as a lipid metabolite. The role of S1P in the differentiation and metabolic regulation of tumor-associated macrophages is unknown. Meanwhile, the source of S1P in TME is not very clear. Our research found that hepatic stellate cells co-cultured with tumor cells could prompt macrophages to the M2 phenotype of TAM differentiation. It was further discovered that S1P activated peroxisome proliferator-activated receptor α (PPARα) by binding to S1P receptor 4 (S1PR4) of macrophages, upregulating lipid metabolism and inducing the TAM differentiation. Ultimately, tumor cells activated nuclear factor erythroid 2-related factor 2 (Nrf2) in hepatic stellate cells (HSCs), enhancing sphingosine kinase 1 (SphK1) expression and elevating S1P production and secretion. This study has demonstrated a possible interaction pathway among tumor cells, HSCs and macrophages. It has revealed that tumor cells activate the Nrf2/SphK1 pathway in HSCs to secrete S1P, which subsequently bound S1PR4, triggered PPARα activation, and drove macrophage polarization toward pro-tumor M2-type TAMs.

DOI: https://doi.org/10.1038/s41598-025-02588-6
NPJ Aging. 2025 Jul 01. 11(1): 59

Immunometabolism and oxidative stress: roles and therapeutic strategies in cancer and aging.

Nan-Jie Zhou, Wei-Qian Bao, Cui-Fen Zhang, Meng-Lin Jiang, Tu-Liang Liang, Gang-Yuan Ma, Liang Liu, Hu-Dan Pan, Run-Ze Li.

Immunometabolism, encompassing metabolic processes within the immune system, plays a pivotal role in modulating the development, activity, and function of immune cells. Oxidative stress, resulting from an imbalance between pro-oxidants and antioxidants, is a critical factor in the pathogenesis of various diseases, including cancer and aging. This review synthesizes current knowledge on the interplay between immunometabolism and oxidative stress, highlighting their mechanisms in cancer progression and the aging process. We discuss how metabolic reprogramming in our body can influence immune cell function and promoting ageing and cancer development. Additionally, we examine the impact of aging on immune metabolism, leading to a decline in immune function and a predisposition to chronic diseases. The review also explores the potential of traditional Chinese medicine in targeting oxidative stress to delay aging and combat cancer, underscoring the need for further research to elucidate the molecular mechanisms underlying these effects. Our findings suggest that interventions targeting immunometabolism and oxidative stress could offer novel therapeutic avenues for cancer and aging-related diseases.

DOI: https://doi.org/10.1038/s41514-025-00250-z
Mol Cell. 2025 Jul 03. pii: S1097-2765(25)00462-9. [Epub ahead of print]85(13): 2455-2457

Metabolic compartmentalization via glycogenolysis-derived G1P bolsters T cell memory.

Hao Shi, Hongbo Chi.

In this issue of Molecular Cell, Zhou et al.1 show that glycogenolysis-derived glucose-1-phosphate enhances glucose-6-phosphate dehydrogenase oligomerization and activity, promoting the formation of a liquid-liquid phase separation compartment containing glycogen. This channels glycogenolysis-derived glucose-6-phosphate into the pentose phosphate pathway, supporting CD8+ memory T cell fitness and antitumor effects.

DOI: https://doi.org/10.1016/j.molcel.2025.05.023
Nat Commun. 2025 Jul 01. 16(1): 5547

Host glutathione is required for Rickettsia parkeri cell division and intracellular survival.

Han Sun, Anh Phuong Luu, Meggie Danielson, Thomas P Burke.

Intracellular bacteria rely on eukaryotic metabolites for their fitness and pathogenesis. Yet, the mechanisms of how host metabolites promote bacterial physiology and immune evasion are often unclear. Here, we employed obligate cytosolic Rickettsia parkeri, which parasitizes over fifty host metabolites, to investigate bacterial utilization of host glutathione (GSH). We observed that GSH depletion impaired R. parkeri intracellular survival. Super-resolution microscopy revealed that GSH depletion caused bacterial chaining in the host cytosol, prohibiting proper actin-based motility and cell-to-cell spread. GSH was especially critical for bacterial survival in primary macrophages, where it enabled R. parkeri to evade ubiquitylation and antibacterial autophagy. Cell division and survival defects were restored by supplementing N-acetylcysteine, suggesting that GSH serves as a cysteine source for R. parkeri. Together, these data suggest that Rickettsia requires GSH as a nutrient source to promote cell division, actin-based motility, evasion of antibacterial autophagy, and intracellular survival. This knowledge contributes to the expanding paradigm that GSH plays diverse roles in the pathogenesis of intracellular bacteria and represents a potential target for host-acting therapeutics.

DOI: https://doi.org/10.1038/s41467-025-60509-7
Nat Commun. 2025 Jul 01. 16(1): 5874

Metabotropic glutamate receptor 4-mediated glutamatfergic signaling reshapes the tumor microenvironment by regulating dendritic cell maturation.

Xiaoman Ju, Eva Maria Putz, Yaqi Liu, Dongchen Yuan, Guowei Sun, Stephane Koda, Zhuo Fu, Simin Shao, Chunrong Tong, Biping Deng, Jing Hu, Juming Yan.

Metabotropic glutamate receptor 4 (mGluR4, encoded by Grm4), is a neurotransmitter receptor, known to play roles in tumor progression and immune modulation through the nervous system. Here we show that mGluR4 may regulate immune responses in the tumor microenvironment (TME) also via non-neuronal mechanisms. We observe that dendritic cells (DC) from mGluR4-deficient mice display enhanced migration, maturation and antigen-presentation capacity, which promote T cell and NK cell responses against tumor cells. Tumor growth and metastases are suppressed in Grm4-/- mice in different preclinical tumor models, including orthotopic liver cancer, subcutaneous melanoma, colorectal tumors, and fibrosarcoma. We show that the tumor suppressive effect of Grm4-deficiency requires host immunity, in particular CD8+ T cells, NK cells, and IFNγ, but independent of the nervous system. Single-cell RNA-sequencing and ex vivo assays show changes in the composition and functional state of the immune TME. Mechanistically, mGluR4 suppresses the adenyl cyclase/PKA signaling pathway, leading to metabolic reprogramming of DCs. Importantly, adoptive transfer of DCs pretreated with the AC agonist forskolin therapeutically suppressed tumor growth in an orthotopic liver cancer model. Our study thus demonstrates that mGluR4 is a checkpoint for DC maturation and that mGluR4 may serve as an immunotherapeutic target.

DOI: https://doi.org/10.1038/s41467-025-60922-y
PLoS Pathog. 2025 Jul 03. 21(7): e1013293

Identification of picornavirus proteins that inhibit de novo nucleotide synthesis during infection.

Lonneke V Nouwen, Esther A Zaal, Inge Buitendijk, Marleen Zwaagstra, Chiara Aloise, Arno L W van Vliet, Jelle G Schipper, Alain van Mil, Celia R Berkers, Frank J M van Kuppeveld.

Viruses, including picornaviruses, modulate cellular metabolism to generate sufficient building blocks for virus replication and dissemination. Previously, we showed that two picornaviruses, coxsackievirus B3 (CVB3) and EMCV, remodel nucleotide metabolism during infection. Here, we investigated whether this modulation is attributable to specific viral proteins. For this, we studied the modulation of metabolism by several recombinant CVB3 and EMCV viruses in HeLa cells. Using isotope tracing metabolomics with three distinct labels, 13C6-glucose or 13C5/15N2-glutamine, we reveal that the 2A protease of CVB3 and the Leader protein of EMCV inhibit de novo nucleotide synthesis. Furthermore, we show that nucleotide metabolism is also reprogrammed by CVB3 and EMCV in human induced pluripotent stem cell-derived cardiomyocytes. Our insights are important to increase understanding of picornavirus-host interactions and may lead to novel therapeutic strategies.

DOI: https://doi.org/10.1371/journal.ppat.1013293
Infect Immun. 2025 Jul 03. e0061224

Arginine at the host-pathogen interface.

Brooke E Ryan, Laura A Mike.

  Nutrient availability shapes the course of infection. Arginine, a conditionally essential amino acid, plays a crucial role in both host immune defense and pathogen metabolism. As a precursor for nitric oxide production, arginine supports immune functions in multiple immune cell types to control infections. However, it also serves as a signal for pathogens that promotes bacterial survival and growth. A plethora of recent studies have shown that arginine functions not only as a metabolic substrate but also as a key environmental cue that can alter cyclic diguanylate levels. Arginine availability regulates multiple bacterial processes in both Gram-positive and Gram-negative species including toxin production, biofilm formation, Type III secretion system, swarming, persistence, and immune evasion. In this way, arginine levels can shape how pathogens behave within the host environment. This review examines how fluctuations in arginine levels across different host niches influence microbial pathogenesis and highlights the complex interplay between arginine availability and bacterial behavior. Understanding the role of arginine in host-pathogen interactions may provide new therapeutic strategies to combat infections by targeting bacterial responses to this crucial nutrient.

Keywords:  AhrC; ArgR; arginine; biofilm; gene regulation; metabolic regulation; secretion systems; swarming; toxins

DOI:  https://doi.org/10.1128/iai.00612-24
mBio. 2025 Jun 30. e0097625

The swine acute diarrhea syndrome coronavirus spike protein promotes syncytial formation via upregulation of cellular cholesterol synthesis.

Dakai Liu, Miaomiao Zeng, Jiyu Zhang, Liaoyuan Zhang, Hongyan Shi, Xin Zhang, Jialin Zhang, Jianfei Chen, Zhaoyang Ji, Xiuwen Li, Gengting Gu, Tingshuai Feng, Da Shi, Dongbo Sun, Li Feng.

  Swine acute diarrhea syndrome coronavirus (SADS-CoV) is a novel coronavirus that causes acute diarrhea, vomiting, and high mortality in suckling piglets. Research has demonstrated that certain viruses enhance their replication by modulating intracellular cholesterol metabolism. However, the impact of SADS-CoV infection on cellular cholesterol synthesis remains unclear. Here, we found that SADS-CoV Spike (S) protein promoted syncytium formation by positively regulating cholesterol synthesis. Specifically, the virus upregulated the rate-limiting enzyme 3-hydroxy-3-methyl-glutaryl-CoA reductase through the inhibition of AMP-activated protein kinase (AMPK) activity. This inhibition was mediated by the activation of AKT-dependent phosphorylation of AMPKα at Ser485. Further investigation revealed that SADS-CoV S protein activated the PI3K/AKT pathway to promote cholesterol synthesis, a process that required the membrane protein integrin β1 (ITGB1). Importantly, we discovered that cholesterol facilitated cell-to-cell fusion mediated by the viral S protein, which enhanced syncytium formation. In summary, our findings demonstrate that the SADS-CoV S protein enhances cellular cholesterol accumulation by activating the PI3K/AKT/AMPK pathway through ITGB1, and that cholesterol facilitates syncytium formation mediated by the viral S protein. These insights contribute to a better understanding of SADS-CoV infection mechanisms and may inform future therapeutic strategies.
IMPORTANCE: Cholesterol, a vital component of cellular membranes, is crucial for maintaining cell structure and function. It also acts as an essential host factor for the entry, replication, and propagation of various viruses. In this study, we show that the Spike protein of swine acute diarrhea syndrome coronavirus (SADS-CoV) promotes syncytial formation by upregulating cellular cholesterol synthesis. The viral Spike protein activates the PI3K/AKT signaling pathway, leading to increased cholesterol production through the inhibition of AMP-activated protein kinase (AMPK). This upregulation of cholesterol facilitates cell-to-cell fusion, a process that enhances viral spread and pathogenesis. Moreover, we demonstrate that integrin β1 (ITGB1) acts as a critical host factor that links the viral Spike protein to the activation of the PI3K/AKT pathway. ITGB1 interacts with the S protein, playing a pivotal role in viral replication and cholesterol synthesis regulation. Our findings highlight the critical role of cholesterol in SADS-CoV infection and provide a deeper understanding of the molecular mechanisms behind viral replication. This research opens up potential therapeutic strategies targeting cholesterol metabolism to mitigate the effects of SADS-CoV and similar viral infections.

Keywords:  cholesterol; spike protein; swine acute diarrhea syndrome coronavirus; syncytia

DOI:  https://doi.org/10.1128/mbio.00976-25
Nat Commun. 2025 Jul 01. 16(1): 5912

Viruses hijack FPN1 to disrupt iron withholding and suppress host defense.

Li Tong, Jie Wang, Yunjin Ma, Chunying Wang, Yue Fu, Qi Li, Chengjiang Gao, Hui Song, Ying Qin, Chunyuan Zhao, Wei Zhao.

Viruses rely on intracellular materials, including iron, to complete their life cycles and iron withholding may limit viral infections. However, the mechanisms through which viruses disrupt host iron homeostasis and the impact of intracellular iron on the host's antiviral defense aren't well studied. Here we show that viral infections facilitate the polyubiquitination and degradation of ferroportin (FPN1, the only cellular iron exporter) by upregulating the host E3 ubiquitin ligase DTX3L, leading to an elevation in cellular iron levels. Excessive ferrous iron suppresses type I IFN responses and autophagy by promoting TBK1 hydroxylation and STING carbonylation in macrophages. FPN1 deficiency suppresses host antiviral defense and facilitates viral replication in vitro and in vivo, while DTX3L deficiency has the opposite effect. These results reveal that viruses hijack host FPN1 to disrupt iron withholding and achieve immune escape, and suggest that iron homeostasis maintained by FPN1 is required for the optimal activation of TBK1- and STING-dependent antiviral responses.

DOI: https://doi.org/10.1038/s41467-025-60031-w