bims-imicid 2025-05-04 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2025–05–04
25 papers selected by
Dylan Ryan, University of Cambridge

Harnessing Kupffer Cell Metabolic Rewiring: Rapamycin-Gliadin Nanoparticle as a Pivotal Strategy for Immune Tolerance in Celiac Disease.
Metabolic interference impairs influenza A virus replication by dampening vRNA synthesis.
Glutamine limits NLRP3 inflammasome activation and pyroptosis in macrophages by sustaining the IRG1/itaconate axis.
Peroxisomes are critical for a unique metabolic demand and survival of alveolar macrophages.
Impact of mitochondrial metabolism on T-cell dysfunction in chronic lymphocytic leukemia.
Dietary targeting of TRPM8 rewires macrophage immunometabolism reducing colitis severity.
The Evolving Role of Macrophage Metabolic Reprogramming in Obesity.
Dissecting inflammation in the immunemetabolomic era.
Itaconate: A Potential Therapeutic Strategy for Autoimmune Disease.
Investigating how dengue virus-induced metabolic changes affect the host immune response and how to develop Immunomodulatory strategies.
Targeting CTP synthetase 1 to restore interferon induction and impede nucleotide synthesis in SARS-CoV-2 infection.
LACC1 Enhances Polyamine Immunometabolism in Inflammatory Macrophages to Inhibit Atherosclerosis Progression.
Bacteria suppress immune responses in Arabidopsis by inducing methylglyoxal accumulation and promoting H2O2 scavenging.
TAMing immunity through an unexpected source.
The role of fatty acid metabolism on B cells and B cell-related autoimmune diseases.
Systems analysis unravels a common rural-urban gradient in immunological profile, function, and metabolic dependencies.
Short-term methionine deprivation inhibits TCA cycle and regulates macrophage polarization through uncharged tRNA and PDHA1 phosphorylation.
A neuroimmune pathway drives bacterial infection.
Selective requirement of glycosphingolipid synthesis for natural killer and cytotoxic T cells.
Fumarate Hydratase Restrains mtDNA Attenuates LPS-Induced Acute Lung Injury Through cGAS-STING Pathways.
Targeting 7-Dehydrocholesterol Reductase Integrates Cholesterol Metabolism and IRF3 Activation to Eliminate Infection.
Abnormal glucose and lipid metabolism promotes disrupted differentiation of T and B cell subsets in Behçet's disease.
T cell toxicity induced by tigecycline binding to the mitochondrial ribosome.
Fasting-induced ketogenesis sensitizes bacteria to antibiotic treatment.
Epstein-Barr Virus-Driven B-Cell Transformation under Germinal Center Hypoxia Requires External Unsaturated Fatty Acids.

ACS Nano. 2025 Apr 30.

Harnessing Kupffer Cell Metabolic Rewiring: Rapamycin-Gliadin Nanoparticle as a Pivotal Strategy for Immune Tolerance in Celiac Disease.

Xiaohan Jiang, Min Wang, Ruihan Zou, Min Fu, Wentao Fan, Yao Wang, Chenguang Dai, Zaman Swapnil, Wanjun Wang, Hao Wu, Kunxin Xie, Li Liu, Yan Wang, Zhining Fan, Lili Zhao.

  Celiac disease (CeD), triggered by gliadin exposure, necessitates therapeutic strategies that establish an antigen-specific immune tolerance. This study explores the therapeutic efficacy and mechanism of rapamycin-gliadin composite nanoparticles (PLN-GR) for CeD treatment. In vivo analyses demonstrated the efficient uptake of PLN-GR by antigen-presenting cells (APCs), particularly Kupffer cells and splenic dendritic cells (DCs), driving their tolerogenic phenotypic transformation. In a murine CeD model, PLN-GR administration significantly enhanced gluten tolerance and mitigated intestinal inflammation, as indicated by reduced paw edema and improved histopathological parameters. Mechanistically, PLN-GR induced macrophage metabolic reprogramming from glycolysis to oxidative phosphorylation, concomitant with elevated serum itaconate levels. This metabolic shift potentiated interorgan immunoregulatory crosstalk, expanding PD-L1+ tolerogenic splenic DCs while suppressing pathogenic Th1 cell populations. Bone marrow-derived macrophages (BMDMs) from Acod1-/- mice (deficient in itaconate synthesis) failed to induce DC tolerance upon PLN-GR treatment. However, supplementation with the itaconate derivative 4-octyl itaconate (4-OI) restored PD-L1 expression in DC2.4 cells in vitro, revealing that itaconate induces and stabilizes the tolerant DC phenotype. These findings underscore PLN-GR as a novel nanotherapeutic platform for CeD, achieving gliadin-specific tolerance through hepatic-splenic immunometabolic reprogramming and itaconate-dependent PD-L1 regulation, thereby offering a translatable strategy for autoimmune disease management.

Keywords:  gluten sensitivity; immune tolerance; immunometabolic reprogramming; immunomodulation; itaconate metabolism

DOI:  https://doi.org/10.1021/acsnano.4c18354
Npj Viruses. 2025 Mar 28. 3(1): 22

Metabolic interference impairs influenza A virus replication by dampening vRNA synthesis.

Jens Kleinehr, Chiara Robin Bojarzyn, Michael Schöfbänker, Katharina Daniel, Stephan Ludwig, Eike R Hrincius.

For replication, viruses exploit the host cell metabolism for biosynthesis of viral components. Recently, we could show that inhibition of glycolysis interfered with IAV replication by impairing the regulation of the viral polymerase as a transcriptase or replicase. Here, we investigated how IAV replication and polymerase regulation is influenced by other metabolic pathways which are directly or indirectly linked to glycolysis. Therefore, we inhibited glutaminolysis, fatty acid synthesis (FAS), oxidative phosphorylation (OXPHOS), and the pentose phosphate pathway (PPP). Inhibition of these metabolic pathways led to a significant reduction of viral titers. Furthermore, the inhibition of glutaminolysis, FAS and OXPHOS unbalanced the cellular glycolysis and respiration network leading to a prolonged phase of viral transcription while replication was strongly decreased. Our data indicate that affecting the cellular glycolysis and respiration balance impairs the dynamic regulation of the viral polymerase, resulting in reduced synthesis of viral genomic RNA and viral particles.

DOI: https://doi.org/10.1038/s44298-025-00090-4
FEBS J. 2025 Apr 28.

Glutamine limits NLRP3 inflammasome activation and pyroptosis in macrophages by sustaining the IRG1/itaconate axis.

Xiaoli Chen, Yuanfeng Zhu, Lin Xia, Sen Su, Shijun Fan, Yongling Lu, Qian Chen, Yan Wei, Qianying Huang, Xin Liu, Xi Peng.

  Aberrant activation of NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome increases the release of mature pro-inflammatory cytokines interleukin (IL)-1β and IL-18, and enhances pyroptosis; thereby necessitating tight regulation of the NLRP3 inflammasome. Dysfunctional glutamine metabolism contributes to the pathogenesis of multiple inflammatory disorders, and the precise mechanism remains to be elucidated. Here, we provide evidence that glutamine deprivation enhances NLRP3 inflammasome activation in macrophages. Indeed, the absence of exogenous glutamine specifically enhanced NLRP3 inflammasome assembly, thereby accelerating pyroptosis and promoting the maturation of IL-1β and IL-18. Inhibition of glutaminolysis exhibited a similar effect to glutamine deprivation, whereas this effect was reversed by α-ketoglutarate (α-KG), a tricarboxylic acid (TCA)-cycle intermediate that can be replenished by glutamine supply. We further observed reduced generation of endogenous itaconate by glutamine deprivation and verified that both exogenous supplementation of itaconate derivative and increased endogenous itaconate production by overexpressing immune-responsive gene 1 [IRG1; also known as aconitate decarboxylase 1 (ACOD1)] could replace glutamine to inhibit the NLRP3 inflammasome. Mechanistically, glutamine deprivation decreased the source of substrate and inhibited transcription factor EB (TFEB)-dependent transcriptional upregulation of IRG1, thereby impairing the IRG1/itaconate axis that suppresses the NLRP3 inflammasome. Furthermore, glutamine deficiency was detected in a murine sepsis model, whereas extrinsic glutamine supplementation conferred protection against intestinal inflammation and tissue damage in septic mice. Taken together, our findings provide a novel insight into the link between glutamine metabolism and NLRP3 inflammasome activation, highlighting the target of glutamine metabolism, which holds as a potential therapeutic strategy for inflammatory diseases.

Keywords:  IRG1/itaconate axis; NLRP3 inflammasome; glutamine metabolism; itaconate; pyroptosis

DOI:  https://doi.org/10.1111/febs.70119
Cell Rep. 2025 Apr 25. pii: S2211-1247(25)00394-8. [Epub ahead of print]44(5): 115623

Peroxisomes are critical for a unique metabolic demand and survival of alveolar macrophages.

Mai Matsushita, Jonathan Muri, Ivan Berest, Fengqi Li, Huan Liu, Basak Corak, Nicola Zamboni, Joerg Buescher, Alaa Othman, Mauro Corrado, Jovana Cupovic, Sabine Werner, Werner Kovacs, Manfred Kopf.

  Tissue-resident macrophages (TRMs) populate throughout various tissues, and their homeostatic metabolism is heavily influenced by these microenvironments. Peroxisomes are organelles that contribute to lipid metabolism. However, the involvement of these organelles in the bioenergetics of TRMs remains undetermined. We conducted a developmental screen of TRMs using a conditional peroxisomal biogenesis factor 5 (Pex5) knockout mouse model that lacks functional peroxisomes in all immune cell subsets. Pulmonary alveolar macrophages (AMs) appeared as the only subset of TRMs that required functional peroxisomes for their development. Pex5 deficiency resulted in reduced AM survival due to increased sensitivity to lipotoxicity, in line with an excess accumulation of ceramides. The absence of peroxisomes had a significant effect on overall mitochondrial fitness and altered their metabolic program, allowing them to engage in glycolysis in addition to oxidative phosphorylation. Our results revealed that AMs have a unique metabolic regulation, where peroxisomes play a central role in their homeostatic development and maintenance.

Keywords:  CP: Immunology; CP: Metabolism; immunometabolism; innate immunity; peroxisomes; tissue-resident macrophages

DOI:  https://doi.org/10.1016/j.celrep.2025.115623
Front Cell Dev Biol. 2025 ;13 1577081

Impact of mitochondrial metabolism on T-cell dysfunction in chronic lymphocytic leukemia.

Wael Gamal, Melanie Mediavilla-Varela, Vishaal Kunta, Eva Sahakian, Javier Pinilla-Ibarz.

  T cells play a central role in anti-tumor immunity, yet their function is often compromised within the immunosuppressive tumor microenvironment, leading to cancer progression and resistance to immunotherapies. T-cell activation and differentiation require dynamic metabolic shifts, with mitochondrial metabolism playing a crucial role in sustaining their function. Research in cancer immunometabolism has revealed key mitochondrial abnormalities in tumor-infiltrating lymphocytes, including reduced mitochondrial capacity, depolarization, structural defects, and elevated reactive oxygen species. While these mitochondrial disruptions are well-characterized in solid tumors and linked to T-cell exhaustion, their impact on T-cell immunity in lymphoproliferative disorders remains underexplored. Chronic lymphocytic leukemia (CLL), the most prevalent chronic adult leukemia, is marked by profound T-cell dysfunction that limits the success of adoptive cell therapies. Emerging studies are shedding light on the role of mitochondrial disturbances in CLL-related T-cell dysfunction, but significant knowledge gaps remain. This review explores mitochondrial metabolism in T-cell exhaustion, emphasizing recent findings in CLL. We also discuss therapeutic strategies to restore T-cell mitochondrial function and identify key research gaps.

Keywords:  CAR T cell; CLL (chronic lymphocytic leukemia); T-cell exhaustion; adoptive cell immunotherapy; cancer; metabolism; mitochondria

DOI:  https://doi.org/10.3389/fcell.2025.1577081
Cell Death Dis. 2025 Apr 25. 16(1): 343

Dietary targeting of TRPM8 rewires macrophage immunometabolism reducing colitis severity.

D Cicia, F Biscu, F A Iannotti, M Miraglia, C Ferrante, N Iaccarino, S Cadenas de Miguel, A Chiavaroli, A Schiano Moriello, P De Cicco, M F Nanì, L Zanoletti, B-J Ke, L van Baarle, K Talavera, A Randazzo, I Elia, R Capasso, G Matteoli, E Pagano, A A Izzo.

The interplay between diet, host genetics, microbiota, and immune system has a key role in the pathogenesis of inflammatory bowel disease (IBD). Although the causal pathophysiological mechanisms remain unknown, numerous dietary nutrients have been shown to regulate gut mucosal immune function, being effective in influencing innate or adaptive immunity. Here, we proved that transient receptor potential melastatin 8 (TRPM8), a non-selective cation channel, mediates LPS- evoked Ca2+ influx in macrophages leading to their activation. Additionally, we showed that TRPM8 is selectively blocked by the dietary flavonoid luteolin, which induced a pro-tolerogenic phenotype in pro-inflammatory macrophages. Accordingly, genetic deletion of Trpm8 in macrophages caused a deficit in the activation of pro-inflammatory metabolic and transcriptional reprogramming, leading to reduced production of key pro-inflammatory cytokines such as interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α. The TRPM8 anti-inflammatory effect was found to be dependent on lactate which in turn induces IL-10 gene expression. Adoptive transfer of TRPM8-deficient bone marrow in wild-type mice improved intestinal inflammation in a model of colitis. Accordingly, oral administration of luteolin protected mice against colitis through an impairment in the innate immune response. Our study reveals the potential of targeting TRPM8 through specific nutrient interventions to regulate immune function in sub-clinical scenarios or to treat inflammatory diseases, primarily driven by chronic immune responses, such as IBD.

DOI: https://doi.org/10.1038/s41419-025-07553-9
Can J Cardiol. 2025 Apr 29. pii: S0828-282X(25)00320-4. [Epub ahead of print]

The Evolving Role of Macrophage Metabolic Reprogramming in Obesity.

Dorcus Makassy, Kyra Williams, Qutuba G Karwi.

  Recent research has extensively explored the critical role of energy metabolism in shaping the inflammatory response and polarization of macrophages in obesity. This rapidly growing field emphasizes the need to understand the connection between metabolic processes that support macrophage polarization in obesity. While most published research in this area has focused on glucose and fatty acids, how the flux through other metabolic pathways (such as ketone and amino acid oxidation) in macrophages is altered in obesity is not well defined. This review summarizes the main alterations in uptake, storage, and oxidation of oxidative substrates (glucose, fatty acids, ketone bodies and amino acids) in macrophages and how these alterations are linked to macrophage polarization and contribution to augmented inflammatory markers in obesity. The review also discusses how oxidative substrates could modulate macrophage energy metabolism and inflammatory responses via feeding into other non-oxidative pathways (such as the pentose phosphate pathway, triacylglycerol synthesis/accumulation), via acting as signalling molecules, or via mediating post-translational modifications (such as O-GlcNAcylation or β-hydroxybutyrylation). The review also identifies several critical unanswered questions regarding the characteristics (functional and metabolic) of macrophages from different origins (adipose tissue, skeletal muscle, bone marrow) in obesity and how these characteristics contribute to early vs late phases of obesity. We also identified a number of new therapeutic targets that could be evaluated in future investigations. Targeting macrophage metabolism in obesity is an exciting and active area of research with significant potential to help identify new treatments to limit the detrimental effects of inflammation in obesity.

Keywords:  Obesity; energy metabolism; insulin resistance; macrophage; polarization

DOI:  https://doi.org/10.1016/j.cjca.2025.04.017
Cell Mol Life Sci. 2025 Apr 28. 82(1): 182

Dissecting inflammation in the immunemetabolomic era.

Patricia P Ogger, Peter J Murray.

  The role of immune metabolism, specific metabolites and cell-intrinsic and -extrinsic metabolic states across the time course of an inflammatory response are emerging knowledge. Targeted and untargeted metabolomic analysis is essential to understand how immune cells adapt their metabolic program throughout an immune response. In addition, metabolomic analysis can aid to identify pathophysiological patterns in inflammatory disease. Here, we discuss new metabolomic findings within the transition from inflammation to resolution, focusing on three key programs of immunity: Efferocytosis, IL-10 signaling and trained immunity. Particularly the tryptophan-derived metabolite kynurenine was identified as essential for efferocytosis and inflammation resolution as well as a potential biomarker in diverse inflammatory conditions. In summary, metabolomic analysis and integration with transcriptomic and proteomic data, high resolution imaging and spatial information is key to unravel metabolic drivers and dependencies during inflammation and progression to tissue-repair.

Keywords:  Chronic inflammatory disease; Efferocytosis; IL-10; Kynurenine; Metabolomics; Spatial resolution; Trained immunity

DOI:  https://doi.org/10.1007/s00018-025-05715-8
Scand J Immunol. 2025 May;101(5): e70026

Itaconate: A Potential Therapeutic Strategy for Autoimmune Disease.

Yifan Xie, Qi Cheng, Meng Li Xu, Jing Xue, Huaxiang Wu, Yan Du.

  Itaconate is a metabolite of the Krebs cycle, and endogenous itaconate is driven by a variety of innate signals that inhibit the production of inflammatory cytokines. The key mechanism of action of itaconate was initially found to be the competitive inhibition of succinate dehydrogenase (SDH), which inhibits the production of inflammatory factors, as well as its antioxidant effects. With increasing research, it was discovered that it modifies cysteine residues of related proteins through the Michael addition, such as modifying the Kelch-like ECH-associated protein 1 (KEAP1) protein and activating the nuclear factor erythroid 2-related factor 2 (NRF2) signalling pathway, as well as glycolytic enzymes and cellular pathway-associated factors that attenuate inflammatory responses and oxidative stress. It also acts on a variety of immune cells, affecting their function and activity, and has been increasingly shown to play a therapeutic role in a variety of inflammatory and autoimmune diseases through a combination of these mechanisms. In conclusion, there has been a great breakthrough in the research of itaconate, from the initial industrial application to the redefinition of the biological functions of itaconate. However, with the deepening of the research, we also found that there are more questions: the mechanism of action of itaconate, more functions of itaconate, clinical application of itaconate, and the use of itaconate still needs to be solved.

Keywords:  autoimmune; diseases; immune cells; itaconate; therapy

DOI:  https://doi.org/10.1111/sji.70026
Virol J. 2025 Apr 25. 22(1): 117

Investigating how dengue virus-induced metabolic changes affect the host immune response and how to develop Immunomodulatory strategies.

Fatemeh Amini Chermahini, Pooria Mohammadi Arvejeh, Francesco M Marincola, Sajjad Ahmad, Ramtin Naderian, Omid Pajand, Majid Eslami, Maliheh Hasannia, Samira Sanami.

  Dengue virus (DENV) infection imposes a significant global health burden, driven by its ability to manipulate host cellular processes to facilitate replication and evade immune defenses. This review explores the complex interplay between DENV, host immunometabolism, and signaling pathways. DENV induces metabolic reprogramming, including glycolytic upregulation, lipid droplet utilization through lipophagy, and alterations in amino acid metabolism, to fulfill its energy and biosynthetic needs. The virus also disrupts mitochondrial dynamics, leading to increased reactive oxygen species (ROS) production, which modulates immune responses but may also contribute to oxidative stress and severe pathology. Concurrently, DENV hijacks host signaling pathways, including PI3K/Akt, NF-κB, and JAK/STAT, to suppress apoptosis, evade type I interferon responses, and drive pro-inflammatory cytokine production. The interplay between these signaling and metabolic pathways highlights a dual role of host processes: enabling viral replication while activating antiviral immune responses. The review also examines potential therapeutic strategies targeting metabolic and signaling pathways to combat DENV infection, including glycolysis inhibitors, lipid metabolism modulators, and host-directed therapies. While significant progress has been made in understanding DENV-induced immunometabolism, further research is needed to elucidate the precise molecular mechanisms and translate these findings into clinical applications. This study underscores the importance of integrating metabolic and signaling insights to identify novel therapeutic targets against DENV and related flaviviruses, addressing the critical need for effective antiviral interventions.

Keywords:  DENV; Immune response; Metabolic pathway; Viral infection

DOI:  https://doi.org/10.1186/s12985-025-02745-3
mBio. 2025 Apr 29. e0064925

Targeting CTP synthetase 1 to restore interferon induction and impede nucleotide synthesis in SARS-CoV-2 infection.

Youliang Rao, Chao Qin, Bianca Espinosa, Ting-Yu Wang, Shu Feng, Ali Can Savas, Jill Henley, Lucio Comai, Chao Zhang, Pinghui Feng.

  Despite the global impact caused by the most recent SARS-CoV-2 pandemic, our knowledge of the molecular underpinnings of its highly infectious nature remains incomplete. We report here that SARS-CoV-2 exploits cellular CTP synthetase 1 (CTPS1) to promote CTP synthesis and suppress interferon (IFN) induction. In addition to catalyzing CTP synthesis, CTPS1 also deamidates interferon regulatory factor 3 (IRF3) to dampen interferon induction. Screening a SARS-CoV-2 expression library, we identified several viral proteins that interact with CTPS1. Functional analyses demonstrate that ORF8 and Nsp8 activate CTPS1 to deamidate IRF3 and negate IFN induction, whereas ORF7b and ORF8 activate CTPS1 to promote CTP synthesis. These results highlight CTPS1 as a signaling node that integrates cellular metabolism and innate immune response. Indeed, small-molecule inhibitors of CTPS1 deplete CTP and boost IFN induction in SARS-CoV-2-infected cells, thus effectively impeding SARS-CoV-2 replication and pathogenesis in mouse models. Our work uncovers an intricate mechanism by which a viral pathogen couples immune evasion to metabolic activation to fuel viral replication. Inhibition of the cellular CTPS1 offers an attractive means to develop antiviral therapy against highly mutagenic viruses.IMPORTANCEOur understanding of the underpinnings of highly infectious SARS-CoV-2 is rudimentary at best. We report here that SARS-CoV-2 activates CTPS1 to promote CTP synthesis and suppress IFN induction, thus coupling immune evasion to activated nucleotide synthesis. Inhibition of the key metabolic enzyme not only depletes the nucleotide pool but also boosts host antiviral defense, thereby impeding SARS-CoV-2 replication. Targeting cellular enzymes presents a strategy to counter the rapidly evolving SARS-CoV-2 variants.

Keywords:  CTPS1; SARS-CoV-2; antiviral pharmacology; interferon; pyrimidine metabolism

DOI:  https://doi.org/10.1128/mbio.00649-25
J Cardiovasc Transl Res. 2025 Apr 28.

LACC1 Enhances Polyamine Immunometabolism in Inflammatory Macrophages to Inhibit Atherosclerosis Progression.

Jingyong Zhang, Yuan Xu, Zonglin Han, Bingqi Liu, Maohua Wang, Lili Bao, Yuxiang He.

  To explore the function and potential mechanism of laccase domain-containing 1 (LACC1) on atherosclerosis (AS). ApoE-/- mice feed with high-fat diet (HFD) were injected with adenovirus shLACC1 (Ad-shLACC1) or Ad-shNC via tail vein. LACC1 was highly expressed in macrophages of atherosclerotic plaque in ApoE-/- mice and ox-LDL-treated Raw264.7 macrophages. LACC1 silencing enhanced AS development and facilitated inflammation in mice. Then, we found that LACC1 silencing facilitated inflammation but repressed polyamine immunometabolism in ox-LDL-treated Raw264.7 macrophages. Through rescue experiments using ornithine or ODC1 inhibitor (DFMO), we further confirmed that LACC1 promoted polyamine immunometabolism to inhibit inflammation in ox-LDL-treated Raw264.7 macrophages. In addition, the observed LACC1 function was dependent on NOS2. In conclusion, we proved that the downregulation of LACC1 promoted AS progression via inhibiting polyamine immunometabolism in inflammatory macrophages, suggesting LACC1 may be a potential therapeutic target for AS.

Keywords:  Atherosclerosis; Inflammation; Inflammatory macrophages; LACC1; Polyamine immunometabolism

DOI:  https://doi.org/10.1007/s12265-024-10585-9
Dev Cell. 2025 Apr 21. pii: S1534-5807(25)00208-4. [Epub ahead of print]

Bacteria suppress immune responses in Arabidopsis by inducing methylglyoxal accumulation and promoting H2O2 scavenging.

Ting-Ting Yuan, Yu-Rui Feng, Hua Cheng, Shuiyuan Cheng, Ying-Tang Lu.

  Various reactive small molecules, naturally produced via cellular metabolism, function in plant immunity. However, how pathogens use plant metabolites to promote their infection is poorly understood. Here, we identified that infection with a virulent bacterial strain represses glyoxalase I (GLYI) activity, leading to elevated levels of methylglyoxal (MG) in Arabidopsis. Genetic analysis of GLYIs further supports that MG promotes bacterial infection. Mechanistically, MG modifies TRIPHOSPHATE TUNNEL METALLOENZYME2 (TTM2) at Arg-351, facilitating its interaction with CATALASE2 (CAT2), resulting in higher CAT2 activity and lower hydrogen peroxide (H2O2) accumulation. Taken together, we demonstrate that the bacterial pathogen harnesses the plant metabolite MG to promote its infection by scavenging H2O2.

Keywords:  CAT2; ROS; TTM2; metabolism; methylglyoxal; plant immunity

DOI:  https://doi.org/10.1016/j.devcel.2025.04.006
Cancer Cell. 2025 Apr 22. pii: S1535-6108(25)00163-1. [Epub ahead of print]

TAMing immunity through an unexpected source.

Ian Vogel, Sagar P Bapat.

Arginine availability and metabolism critically shape tumor-immune interactions. In this issue of Cancer Cell, Zhu et al. demonstrate that breast cancer-cell-derived arginine synthesized via ASS1 fuels macrophage polyamine synthesis, reinforcing immunosuppressive tumor-associated macrophages (TAMs). Mechanistically, this occurs through TDG/p53-dependent DNA demethylation and activation of PPARG.

DOI: https://doi.org/10.1016/j.ccell.2025.04.004
Inflamm Res. 2025 Apr 29. 74(1): 75

The role of fatty acid metabolism on B cells and B cell-related autoimmune diseases.

Yanmei Gong, Ruiqi Xu, Guohui Gao, Simiao Li, Ying Liu.

  Fatty acid metabolism plays a critical role in regulating immune cell function, including B cells, which are central to humoral immunity and the pathogenesis of autoimmune diseases. Emerging evidence suggests that fatty acid metabolism influences B cell development, activation, differentiation, and antibody production, thereby impacting B cell-related autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and multiple sclerosis (MS). In this review, we discuss the mechanisms by which fatty acid metabolism modulates B cell biology, including energy provision, membrane composition, and signaling pathways. We highlight how alterations in fatty acid synthesis, oxidation, and uptake affect B cell function and contribute to autoimmune pathogenesis. Additionally, we explore the therapeutic potential of targeting fatty acid metabolism in B cells to treat autoimmune diseases. Understanding the interplay between fatty acid metabolism and B cell immunity may provide novel insights into the development of precision therapies for B cell-mediated autoimmune disorders.

Keywords:  Autoimmune diseases; B lymphocytes; Epigenetic; Fatty acids; Immunometabolism

DOI:  https://doi.org/10.1007/s00011-025-02042-3
Sci Adv. 2025 May 02. 11(18): eadu0419

Systems analysis unravels a common rural-urban gradient in immunological profile, function, and metabolic dependencies.

Mikhael D Manurung, Graham A Heieis, Marion König, Shohreh Azimi, Malick Ndao, Tom Veldhuizen, Dennis Hoving, Pytsje T Hoekstra, Yvonne C M Kruize, Linda J Wammes, Roberta Menafra, Marouba Cisse, Souleymane Mboup, Alioune Dieye, Susan Kloet, Dicky L Tahapary, Taniawati Supali, Manfred Wuhrer, Cornelis H Hokke, Bart Everts, Ahmed Mahfouz, Simon P Jochems, Maria Yazdanbakhsh, Moustapha Mbow.

Urbanization affects environmental exposures and lifestyle, shaping immune system variation and influencing disease susceptibility and vaccine responses. Here, we present systems analysis of immune profiles across the rural-urban gradient, comparing rural and urban Senegalese with urban Dutch individuals. By integrating single-cell phenotyping, metabolic profiling, and functional analysis, we reveal a trajectory of immune remodeling along the gradient. This includes enrichment of proinflammatory CD11c+ B cells associated with altered IgG Fc glycosylation, adaptive NK cells with reduced responsiveness to accessory cytokines, and CD161+CD4+T cells with enhanced cytokine production in rural settings. Metabolic perturbation studies demonstrated distinct dependencies on glycolysis, pentose phosphate pathway, and fatty acid synthesis for cellular cytokine responses across populations. We validate core rural-urban immune signatures in an independent Indonesian cohort, suggesting shared immunological adaptations to urbanization across ancestries and geographical areas. Our findings provide insights into rural-urban immune function in understudied populations.

DOI: https://doi.org/10.1126/sciadv.adu0419
J Nutr Biochem. 2025 Apr 28. pii: S0955-2863(25)00102-0. [Epub ahead of print] 109939

Short-term methionine deprivation inhibits TCA cycle and regulates macrophage polarization through uncharged tRNA and PDHA1 phosphorylation.

Xinyu Zhu, Zinan Wang, Xiaoyi Ye, Puyang Liang, Lingling Chen, Jinzhu Chen, Chenchen Li, Jing Zhu, Shixuan Zhuo, Lanzexin Yang, Lifeng Yang, Yan Chen.

   BACKGROUND: Methionine restriction diet has been extensively studied for its beneficial effects on metabolic health and aging. However, the impact of methionine deprivation on glucose metabolism per se and macrophage functions remains incompletely understood.
METHODS: In this study, we analyzed the functional roles of methionine deprivation on glucose flux and macrophage polarization. We used metabolic flux to investigate how methionine deprivation affected glucose metabolism. The functions of methionine deficiency on macrophage polarization and the underlying mechanisms were studied at both the cellular and animal levels.
RESULTS: We found that short-term methionine deprivation represses the tricarboxylic acid (TCA) cycle in mitochondria, accompanied by rapid phosphorylation of the E1 subunit of pyruvate dehydrogenase (PDH) complex, PDHA1. This phosphorylation by methionine deprivation is dependent on increased levels of uncharged tRNA but is independent of GCN2. Furthermore, methionine deprivation promotes M1-like polarization of macrophages, consistent with metabolic reprogramming. Notably, the pro-inflammatory effect of methionine deprivation on macrophages is also mediated by PDHA1 phosphorylation and increases in uncharged tRNA, but independent of GCN2.
CONCLUSION: Our study not only elucidates a direct regulatory role of methionine depletion on the TCA cycle but also reveals that such a regulation is tightly linked to the modulation of macrophage polarization.

Keywords:  Methionine restriction; TCA cycle, PDH complex, uncharged tRNA, macrophage polarization

DOI:  https://doi.org/10.1016/j.jnutbio.2025.109939
Sci Adv. 2025 May 02. 11(18): eadr2226

A neuroimmune pathway drives bacterial infection.

Nian Wang, Jiao Liu, Runliu Wu, Feng Chen, Ruoxi Zhang, Chunhua Yu, Herbert Zeh, Xianzhong Xiao, Haichao Wang, Timothy R Billiar, Ling Zeng, Jianxin Jiang, Daolin Tang, Rui Kang.

Pathogen-induced septic death presents a substantial public health challenge, with its neuroimmune mechanisms largely unexplored. Our study investigates neurotransmitter modulation of ACOD1 expression, a regulator of immunometabolism activated by bacterial lipopolysaccharide (LPS). Screening neurotransmitters identifies dopamine as a potent inhibitor of LPS-induced ACOD1 expression in innate immune cells. Mechanistically, DRD2 forms a complex with TLR4, initiating MAPK3-dependent CREB1 phosphorylation and subsequent ACOD1 transcription. Conversely, dopamine disrupts TLR4-MYD88 interaction via DRD2 without affecting the formation of the LPS-induced TLR4-MD2-CD14 complex. Enhanced ACOD1 expression induces CD274/PD-L1 production independently of itaconate, precipitating inflammation-associated immunosuppression in sepsis. Delayed administration of pramipexole, a dopamine agonist, mitigates lethality in bacterial sepsis mouse models. Conversely, the dopamine antagonist aripiprazole exacerbates sepsis mortality. Dysregulation of the dopamine-ACOD1 axis correlates with sepsis severity in patients, indicating a potential therapeutic target for modulating this neuroimmune pathway.

DOI: https://doi.org/10.1126/sciadv.adr2226
Cell. 2025 Apr 25. pii: S0092-8674(25)00409-X. [Epub ahead of print]

Selective requirement of glycosphingolipid synthesis for natural killer and cytotoxic T cells.

Tasha A Morrison, Jaelyn Vigee, Kevin A Tovar, Taylor A Talley, Adriana M Mujal, Mari Kono, Rachael Philips, Hiroyuki Nagashima, Stephen R Brooks, Hannah Dada, Isaiah Rozich, Kelly Hudspeth, Colleen M Lau, Chen Yao, Giuseppe Sciumè, Hong-Wei Sun, Juan S Bonifacino, Yuka Kanno, Michael L Dustin, Davide Randazzo, Richard L Proia, Joseph C Sun, Han-Yu Shih, John J O'Shea.

  Cell identity genes that exhibit complex regulation are marked by super-enhancer (SE) architecture. Assessment of SEs in natural killer (NK) cells identified Ugcg, encoding the enzyme responsible for glycosphingolipid (GSL) synthesis. Conditional deletion of Ugcg in early hematopoiesis abrogated NK cell generation while sparing other lineages. Pharmacological inhibition of UGCG disrupted cytotoxic granules and cytotoxicity, reduced expansion after viral infection, and promoted apoptosis. B4galt5 transcribes an enzyme downstream of UGCG and possesses SE structure. Addition of its product, lactosylceramide (LacCer), reversed apoptosis due to UGCG inhibition. By contrast, complex GSLs, such as asialo-GM1, were not required for NK cell viability and granule integrity. Ugcg and B4galt5 were upregulated in CD8+ T cells during viral infection, correlating with the acquisition of cytotoxic machinery. Antigen-specific CD8+ T cells lacking Ugcg failed to expand during infection. Our study reveals a selective and essential role of GSL metabolism in NK and CD8+ T cell biology.

Keywords:  B4galt5; CD8(+) T cells; Ugcg; cytotoxic granules; glycosphingolipids; immunometabolism; lactosylceramide; lymphocytes; natural killer cells; super-enhancers

DOI:  https://doi.org/10.1016/j.cell.2025.04.007
J Inflamm Res. 2025 ;18 5399-5413

Fumarate Hydratase Restrains mtDNA Attenuates LPS-Induced Acute Lung Injury Through cGAS-STING Pathways.

Zewen Jiang, Ruyuan He, Yujian Zhong, Bohao Liu, Ziqi He.

   Background: The metabolic reprogramming of alveolar macrophages, particularly mitochondrial energy metabolism centered on the tricarboxylic acid (TCA) cycle, plays a pivotal role in acute lung injury (ALI). Fumarate hydratase (FH), a key enzyme catalyzing fumarate-to-malate conversion in the TCA cycle, is implicated in macrophage inflammatory responses, but its specific role in ALI remains unclear.
Methods: We employed FHIN1 to assess its regulatory effects in LPS-induced ALI models. Wildtype C57BL/6 mice were randomly divided into control group, FHIN1 group, LPS group and LPS+FHIN1 group. FHIN1 and RU.521 was used to explored the interaction of FH and cGAS-STING in THP-1 cells.
Results: LPS stimulation suppressed FH expression and induced fumarate accumulation in macrophages. Pharmacological FH inhibition exacerbated LPS-triggered inflammatory cytokine release, oxidative stress and aggravated lung injury in mice. Mechanistically, FH inhibition promoted mtDNA leakage, activating the cGAS-STING pathway to amplify inflammation. Blocking cGAS with RU.521 significantly attenuated FHIN1-driven inflammatory responses and mitigated lung injury exacerbation.
Conclusion: FH critically modulates ALI progression by restraining cGAS-STING-dependent inflammation. Targeting the FH-mtDNA-cGAS axis may offer therapeutic potential for ALI management.

Keywords:  ALI; fumarate hydratase; mtDNA

DOI:  https://doi.org/10.2147/JIR.S518589
Immunity. 2025 Apr 25. pii: S1074-7613(25)00187-6. [Epub ahead of print]

Targeting 7-Dehydrocholesterol Reductase Integrates Cholesterol Metabolism and IRF3 Activation to Eliminate Infection.

Jun Xiao, Weiyun Li, Xin Zheng, Linlin Qi, Hui Wang, Chi Zhang, Xiaopeng Wan, Yuxiao Zheng, Ruiyue Zhong, Xin Zhou, Yao Lu, Zhiqi Li, Ying Qiu, Chang Liu, Fang Zhang, Yanbo Zhang, Xiaoyan Xu, Zhongzhou Yang, Hualan Chen, Qiwei Zhai, Bin Wei, Hongyan Wang.

DOI: https://doi.org/10.1016/j.immuni.2025.04.024
Immunother Adv. 2025 ;5(1): ltaf010

Abnormal glucose and lipid metabolism promotes disrupted differentiation of T and B cell subsets in Behçet's disease.

Minghao Li, Ping Li, Xin Wang, Lijie Wang, Guanmin Gao, Guosheng Jiang, Tingting Liu, Wei Lin.

   Introduction: Behçet's disease (BD) is a chronic, systemic inflammatory condition characterized by recurrent immune dysregulation.
Materials & Methods: This study conducted a comprehensive analysis of immune cell subsets, metabolic markers, and their interplay in BD patients. Using multiparametric flow cytometry, we identified elevated Th1 cells, senescent CD8+ T cells, and abnormal B cell activation as hallmarks of the chronic inflammatory state in BD.
Results: Despite immunotherapy, innate immune activation persisted, with increased mature NK cells, γδT1 cells, and conventional dendritic cells (cDCs), alongside reduced plasmacytoid dendritic cells (pDCs). Elevated glucose (GLU) and triacylglycerol (TAG) levels in BD patients correlated with increased Th1 cells, functional CD8+ T cells, and B cell activation. In vitro experiments demonstrated that GLU and TAG promote Th1 differentiation, CD8+ T cell activation, and B cell antibody production, revealing their role as drivers of immune dysregulation.
Conclusion: These findings underscore the intricate relationship between metabolic dysregulation and immune dysfunction in BD, highlighting potential diagnostic and therapeutic targets. Our study provides critical insights into BD pathogenesis, offering a foundation for optimizing disease management and monitoring immune and metabolic markers for improved patient outcomes.

Keywords:  B cells; Behçet’s disease; Th1; glucose metabolism; immune dysregulation; triglyceride metabolism

DOI:  https://doi.org/10.1093/immadv/ltaf010
Nat Commun. 2025 May 01. 16(1): 4080

T cell toxicity induced by tigecycline binding to the mitochondrial ribosome.

Qiuya Shao, Anas Khawaja, Minh Duc Nguyen, Vivek Singh, Jingdian Zhang, Yong Liu, Joel Nordin, Monika Adori, C Axel Innis, Xaquin Castro Dopico, Joanna Rorbach.

Tetracyclines are essential bacterial protein synthesis inhibitors under continual development to combat antibiotic resistance yet suffer from unwanted side effects. Mitoribosomes - responsible for generating oxidative phosphorylation (OXPHOS) subunits - share structural similarities with bacterial machinery and may suffer from cross-reactivity. Since lymphocytes rely upon OXPHOS upregulation to establish immunity, we set out to assess the impact of ribosome-targeting antibiotics on human T cells. We find tigecycline, a third-generation tetracycline, to be the most cytotoxic compound tested. In vitro, 5-10 μM tigecycline inhibits mitochondrial but not cytosolic translation, mitochondrial complex I, III and IV expression, and curtails the activation and expansion of unique T cell subsets. By cryo-EM, we find tigecycline to occupy three sites on T cell mitoribosomes. In addition to the conserved A-site found in bacteria, tigecycline also attaches to the peptidyl transferase center of the large subunit. Furthermore, a third, distinct binding site on the large subunit, aligns with helices analogous to those in bacteria, albeit lacking methylation in humans. The data provide a mechanism to explain part of the anti-inflammatory effects of these drugs and inform antibiotic design.

DOI: https://doi.org/10.1038/s41467-025-59388-9
Cell Metab. 2025 Apr 27. pii: S1550-4131(25)00216-5. [Epub ahead of print]

Fasting-induced ketogenesis sensitizes bacteria to antibiotic treatment.

Shujun Cui, Danyang Chong, Yi-Xin Wang, Huixian Tong, Minggui Wang, Guo-Ping Zhao, Liang-Dong Lyu.

  Fasting metabolism is a commonly observed motivational response to acute infections and is conceptualized as being beneficial for host survival. Here, we show that fasting potentiates antibiotic treatment for murine sepsis caused by Salmonella Typhimurium, Klebsiella pneumoniae, and Enterobacter cloacae, resulting in increased bacterial clearance and improved host immune responses and survival. This effect is mediated by fasting-induced ketogenesis and could be alternatively implemented by combination therapy with antibiotics and ketone bodies. We show that the ketone body acetoacetate is an effector that sensitizes bacteria to antibiotic treatment by increasing antibiotic lethality and outer and inner membrane permeability. Our results demonstrate that acetoacetate depletes bacterial amino acids, particularly positively charged amino acids and putrescine, leading to cell membrane malfunctions and redox-related lethality. This study reveals an unrecognized role of ketogenesis in antibiotic treatment and a potential ketone body-based treatment strategy for bacterial sepsis.

Keywords:  acetoacetate; anorexia; antibiotic treatment; antibiotics; drug susceptibility; fasting metabolism; ketogenesis; ketone body; sepsis

DOI:  https://doi.org/10.1016/j.cmet.2025.04.006
Res Sq. 2025 Apr 24. pii: rs.3.rs-6506954. [Epub ahead of print]

Epstein-Barr Virus-Driven B-Cell Transformation under Germinal Center Hypoxia Requires External Unsaturated Fatty Acids.

Larissa Havey, Haixi You, John M Asara, Yin Wang, Rui Guo.

Epstein-Barr virus (EBV) contributes to over 200,000 cancers annually, predominantly aggressive lymphomas originating from hypoxic germinal centers (< 1% O₂). However, conventional models fail to recapitulate the physiologically relevant hypoxic microenvironment which profoundly influences B-cell metabolic remodeling during transformation. Here, we establish an ex vivo model of EBV-driven B-cell transformation under 1% O₂, demonstrating robust transformation and super-enhancer activation of oncogenic regulators, including MYC. Multi-omic analyses reveal distinct metabolic adaptations to hypoxia. Unlike normoxic B-cells, which rely on fatty acid desaturases and oxidation to mitigate lipotoxicity, hypoxically transformed B-cells suppress fatty acid synthesis while upregulating glycerophospholipid metabolism and lipid droplet formation to buffer excess saturated lipids. Consequently, these cells exhibit heightened dependence on external unsaturated fatty acids to support proliferation. Our findings provide the first physiologically relevant ex vivo model of EBV-driven B-cell transformation under hypoxia, uncovering metabolic vulnerabilities that could inform targeted therapeutic strategies for EBV-associated malignancies.

DOI: https://doi.org/10.21203/rs.3.rs-6506954/v1