bims-imicid 2025-04-20 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2025–04–20
27 papers selected by
Dylan Ryan, University of Cambridge

Metabolic remodelling produces fumarate via the aspartate-argininosuccinate shunt in macrophages as an antiviral defence.
Fumarate integrates metabolism and immunity in diseases.
Analyzing Ex Vivo Metabolic Flux in Splenic and Cardiac Macrophages and Bone Marrow Monocytes.
Itaconate modulates immune responses via inhibition of peroxiredoxin 5.
Metabolic Profiling of Activated T Lymphocytes Using Single-Cell Energetic Metabolism by Profiling Translation Inhibition (SCENITH).
Influence of cell bioenergetics on host-pathogen interaction in the lung.
Reprogramming Glucose Metabolism of Macrophage for Acute Liver Failure Therapy with Itaconate Lipo-Nanodrug.
Human Cytomegalovirus Infection Reduces an Endogenous Antiviral Fatty Acid by Promoting Host Metabolism.
Methotrexate loaded extracellular vesicles attenuate periodontitis by suppressing ACSL1 and promoting anti-inflammatory macrophage.
SIRT2 suppresses aging-associated cGAS activation and protects aged mice from severe COVID-19.
Measuring Mitochondrial Function of Naïve and Effector CD8 T Cells.
Metabolic Dialogue Shapes Immune Response in the Tumor Microenvironment.
UDP-glucose Regulates Dendritic Cell Mitochondrial Respiration via a Nitric Oxide-Dependent Mechanism.
Mitochondrial metabolism sustains DNMT3A-R882-mutant clonal haematopoiesis.
CAR T cell-driven induction of iNOS in tumor-associated macrophages promotes CAR T cell resistance in B cell lymphoma.
Analysis of Metabolomic Reprogramming Induced by Infection with Kaposi's Sarcoma-Associated Herpesvirus Using Untargeted Metabolomic Profiling.
The unusual metabolism of germinal center B cells.
Elevated mitochondrial membrane potential is a therapeutic vulnerability in Dnmt3a-mutant clonal hematopoiesis.
Oxidized LDL stimulates PKM2-mediated mtROS production and phagocytosis.
Mechanical Force Triggers Macrophage Pyroptosis and Sterile Inflammation by Disrupting Cellular Energy Metabolism.
Metabolic Screening of T Lymphocytes During Activation via SEAHORSE Extracellular Flux (XF) Analysis.
The role of PKM2-mediated metabolic reprogramming in the osteogenic differentiation of BMSCs under diabetic periodontitis conditions.
Chlamydia trachomatis exploits sphingolipid metabolic pathways during infection of phagocytes.
Exploring the Role of T-Cell Metabolism in Modulating Immunotherapy Efficacy for Non-Small Cell Lung Cancer Based on Clustering.
Metabolic Reprogramming of Glycolysis, Lipids, and Amino Acids in Tumors: Impact on CD8+ T Cell Function and Targeted Therapeutic Strategies.
The role of heme in sepsis induced Kupffer cell PANoptosis and senescence.
Acute exposure to high-fat diet impairs ILC3 functions and gut homeostasis.

Nat Microbiol. 2025 Apr 18.

Metabolic remodelling produces fumarate via the aspartate-argininosuccinate shunt in macrophages as an antiviral defence.

Wenjun Xia, Youxiang Mao, Ziyan Xia, Jie Cheng, Peng Jiang.

Metabolic remodelling underpins macrophage effector functions in response to various stimuli, but the mechanisms involved are unclear. Here we report that viral-infection-induced inflammatory stimulation causes a rewiring of the urea cycle and the tricarboxylic acid cycle metabolism in macrophages to form a cyclic pathway called the aspartate-argininosuccinate (AAS) shunt. Using RNA sequencing, unbiased metabolomics and stable isotope tracing, we found that fumarate generated from the AAS shunt is driven by argininosuccinate synthase (ASS1) in the cytosol and potentiates inflammatory effects. Genetic ablation of ASS1 reduces intracellular fumarate levels and interferon-β production, and mitochondrial respiration is also suppressed. Notably, viral challenge or fumarate esters enhance interferon-β production via direct succination of the mitochondrial antiviral signalling protein and activation of the retinoic acid-inducible gene-I-like receptor signalling. In addition to the vesicular stomatitis virus, the Sendai virus and influenza A virus can also exert these effects. In addition, patients with Ebola virus disease have increased ASS1 expression and ASS1-deficient mice show suppressed macrophage interferon responses to vesicular stomatitis virus infection. These findings reveal that fumarate can be produced from the viral inflammation-induced AAS shunt and is essential for antiviral innate immunity.

DOI: https://doi.org/10.1038/s41564-025-01985-x
Trends Endocrinol Metab. 2025 Apr 16. pii: S1043-2760(25)00051-7. [Epub ahead of print]

Fumarate integrates metabolism and immunity in diseases.

Jie Cheng, Yifeng Xiao, Peng Jiang.

  Fumarate is a key metabolite produced primarily by the tricarboxylic acid (TCA) and urea cycles. In addition to having a metabolic role, its electrophilicity enables it to covalently modify cysteines; moreover, because of its α-ketoglutarate (α-KG)-like structure, it can also act as a competitive inhibitor of α-KG-dependent dioxygenases for epigenetic remodeling. Recent advances have broadened the role of fumarate as a bridge between metabolism and both innate and adaptive immunity, suggesting potentially important functions in anticancer immunity and autoimmune diseases. Here we review the connections between fumarate metabolism and immunity; we describe the mechanisms of fumarate regulation in cancer, autoimmunity, and other diseases; and we explore the clinical implications of fumarate and its esters for immunotherapy.

Keywords:  diseases; fumarate metabolism; immunity; succination

DOI:  https://doi.org/10.1016/j.tem.2025.03.008
J Vis Exp. 2025 Mar 28.

Analyzing Ex Vivo Metabolic Flux in Splenic and Cardiac Macrophages and Bone Marrow Monocytes.

Erin B Taylor, Robert W Spitz, Katherine R O'Quinn, Alan J Mouton.

Metabolic reprogramming is a hallmark of monocyte/macrophage activation and polarization between pro- and anti-inflammatory states. For example, pro-inflammatory (i.e., M1-like) monocytes/macrophages display more reliance on anaerobic glycolysis and less reliance on mitochondrial oxidative phosphorylation, whereas anti-inflammatory (M2-like) macrophages display more reliance on glucose and fatty acid oxidation in the mitochondria. Here, we describe in-depth protocols for extracting macrophages from the two major monocyte/macrophage reservoirs in the body, the spleen and bone marrow, as well as injured tissues such as the heart following myocardial infarction. Macrophages or monocytes are extracted by immunomagnetic sorting by using antibody-tagged microbeads, which easily bind to cells without compromising their phenotypes. The extracted cells are then cultured in 96-well plates, followed by extracellular flux analysis using a metabolic flux analyzer. Both glycolysis and mitochondrial oxidative phosphorylation can be measured simultaneously in small numbers of cells (as little as 2-3 × 105 cells). This method can easily be performed in 1 day and produces reliable and repeatable results. Ultimately, these methods help to enhance our understanding of metabolic changes during immune and inflammatory responses to injury and disease, which could lead to the development of novel therapeutic targets for immunometabolic pathways.

DOI: https://doi.org/10.3791/67824
Nat Metab. 2025 Apr 18.

Itaconate modulates immune responses via inhibition of peroxiredoxin 5.

Tomas Paulenda, Barbora Echalar, Lucie Potuckova, Veronika Vachova, Denis A Kleverov, Johannes Mehringer, Ekaterina Potekhina, Alex Jacoby, Devashish Sen, Chris Nelson, Rick Stegeman, Vladimir Sukhov, Danielle Kemper, Cheryl F Lichti, Nicholas J Day, Tong Zhang, Kamila Husarcikova, Monika Bambouskova, Daved H Fremont, Wei-Jun Qian, Sergej Djuranovic, Slavica Pavlovic-Djuranovic, Vsevolod V Belousov, Andrzej M Krezel, Maxim N Artyomov.

The immunoregulatory metabolite itaconate accumulates in innate immune cells upon Toll-like receptor stimulation. In response to macrophage activation by lipopolysaccharide, itaconate inhibits inflammasome activation and boosts type I interferon signalling; however, the molecular mechanism of this immunoregulation remains unclear. Here, we show that the enhancement of type I interferon secretion by itaconate depends on the inhibition of peroxiredoxin 5 and on mitochondrial reactive oxygen species. We find that itaconate non-covalently inhibits peroxiredoxin 5, leading to the modulation of mitochondrial peroxide in activating macrophages. Through genetic manipulation, we confirm that peroxiredoxin 5 modulates type I interferon secretion in macrophages. The non-electrophilic itaconate mimetic 2-methylsuccinate inhibits peroxiredoxin 5 and phenocopies immunoregulatory action of itaconate on type I interferon and inflammasome activation, providing further support for a non-covalent inhibition of peroxiredoxin 5 by itaconate. Our work provides insight into the molecular mechanism of actions and biological rationale for the predominantly immune specification of itaconate.

DOI: https://doi.org/10.1038/s42255-025-01275-0
Methods Mol Biol. 2025 ;2904 259-271

Metabolic Profiling of Activated T Lymphocytes Using Single-Cell Energetic Metabolism by Profiling Translation Inhibition (SCENITH).

Katrin Sinning, Sophia M Hochrein, Gabriela F Gubert, Martin Vaeth.

  Metabolic reprogramming is increasingly recognized as a fundamental aspect of T cell activation, influencing the differentiation, proliferation, and effector functions of lymphocytes. Measuring and screening the metabolic states of activated T cells provide insights into the dynamic interplay between cellular metabolism and immune function. In the following chapter, we provide a simple protocol based on the publication of Argüello et al. [1] to analyze the metabolic state of activated T cells at the single-cell level using standard flow cytometry.

Keywords:  FACS; Glycolysis; Metabolism; Oxidative phosphorylation; SCENITH; T cells

DOI:  https://doi.org/10.1007/978-1-0716-4414-0_18
Front Immunol. 2025 ;16 1549293

Influence of cell bioenergetics on host-pathogen interaction in the lung.

Gaurav Kumar Lohia, Sebastián A Riquelme.

  Pulmonary diseases, arising from infections caused by bacteria, fungi, and viruses, or stemming from underlying genetic factors are one of the leading causes of mortality in humans, accounting for millions of deaths every year. At the onset of pulmonary diseases, crucial roles are played by phagocytic immune cells, particularly tissue-resident macrophages, in regulating the immune response at the mucosal barrier. Recent strides have illuminated the pivotal role of host bioenergetics modulated by metabolites derived from both pathogens and hosts in influencing the pathophysiology of major organs. Their influence extends to processes such as the infiltration of immune cells, activation of macrophages, and the polarization phenomenon. Furthermore, host-derived metabolites, such as itaconate, contribute to the promotion of anti-inflammatory responses, thereby preventing immunopathology and facilitating the preservation of mucosal niches to thrive for the long-term. This review explores recent advancements in the field of immunometabolism, with a particular emphasis on the intricacies of disease progression in pulmonary infections caused by bacteria such as P. aeruginosa, M. tuberculosis and S. aureus and fungi like C. albicans.

Keywords:  ESKAPE bacteria; MACROPHAGE METABOLISM; bioenergetics; fungal infection; host-pathogen interaction; immunometabolism; itaconate; pneumonia (infectious disease)

DOI:  https://doi.org/10.3389/fimmu.2025.1549293
Adv Healthc Mater. 2025 Apr 18. e2500019

Reprogramming Glucose Metabolism of Macrophage for Acute Liver Failure Therapy with Itaconate Lipo-Nanodrug.

Chen Qiu, Wei Zhang, Yanan Zhao, Tian Han, Wende Yang, Yajing Liu, Peile Jin, Jifan Chen, Xintao Shuai, Jie Ren, Pintong Huang.

  Acute liver failure (ALF) is a life-threatening disease featuring comprehensive inflammatory response and metabolic disorders in which macrophages exert central roles. A glucose metabolism mediator of macrophages, itaconate, has demonstrated potent anti-inflammatory efficacy in various diseases, implying that itaconate could work in treating ALF. However, systemic administration of itaconate may lead to immune disorder, making targeting the delivery of itaconate to the liver lesion area highly important. Herein, a liposomal nanodrug incorporating itaconate is developed, and its potential in treating acute liver failure in an ALF murine model established by LPS/D-GalN administration is tested. The nanodrug shows preferential liver accumulation to effectively alleviate LPS/D-GalN-induced hepatic histopathological injury by decreasing oxidative stress. Moreover, it reprograms the glucose metabolism of macrophages, resulting in macrophage repolarization toward the anti-inflammatory phenotype. Furthermore, western-blot and immunohistochemical assays verifies that the nanodrug may inhibit aerobic glycolysis of macrophages in an NRF2 and STING-dependent manner. These results underline the promise of the nanodrug for ALF treatment by reprogramming glucose metabolism.

Keywords:  acute liver failure; liposome; macrophage repolarization

DOI:  https://doi.org/10.1002/adhm.202500019
bioRxiv. 2025 Mar 31. pii: 2025.03.31.646481. [Epub ahead of print]

Human Cytomegalovirus Infection Reduces an Endogenous Antiviral Fatty Acid by Promoting Host Metabolism.

Yuecheng Xi, Rebekah L Mokry, Nicholas D Armas, Ian Kline, Maxwell Wegner, John G Purdy.

Some viruses, including human cytomegalovirus (HCMV), induce the synthesis of fatty acids and lipids to ensure that the lipid environment of infected cells supports virus replication. HCMV infection broadly reprograms metabolism to ensure central carbon metabolism provides the metabolites required for anabolic synthesis of nucleotides, proteins, and lipids while also meeting the energy demands placed on the infected cells. While HCMV infection increases the levels of most very long chain fatty acids (VLCFA), we found that the levels of erucic acid (EA), a C22:1 monounsaturated VLCFA, are reduced. Treating infected cells with EA disrupted a late step in virus replication, resulting in the release of virions with reduced infectivity. Moreover, we used lipidomics to determine that EA-treated cells had elevated levels of lipids containing a combination of a C22:1 tail and a VLC polyunsaturated fatty acid tail (VLC-PUFA). We demonstrate that fatty acid elongase 5 (ELOVL5) mediated production of VLC-PUFAs is stimulated by HCMV infection. ELOVL5 aided the increase in lipids with C22:1 plus VLC-PUFA tails following EA treatment and reduced the overall level of C22:1 in HCMV-infected cells. Moreover, we found that ELOVL5 mollified EA inhibition of HCMV replication, suggesting ELOVL5 plays a critical role in reducing the level of an endogenous FA with antiviral properties. Our study provides insight into how infection may increase the synthesis of an antiviral metabolite or FA and how the virus may evade their antiviral effect by promoting their metabolism.

DOI: https://doi.org/10.1101/2025.03.31.646481
Mol Immunol. 2025 Apr 16. pii: S0161-5890(25)00102-6. [Epub ahead of print]182 83-95

Methotrexate loaded extracellular vesicles attenuate periodontitis by suppressing ACSL1 and promoting anti-inflammatory macrophage.

Zhi Liu, Jianhua Yang, Guodong Tan, Yuanyuan Shi, Dihao Tao, Wenzhe Wang, Bei Li, Fang Jin, Xiaoning He.

  Macrophages are crucial immune cells in periodontal tissues, which play key roles in both the destruction and repair of associated with periodontitis. Targeted modulation of macrophage function has emerged as a potentially effective approach to influence periodontitis progression. This study investigates the effects of methotrexate-loaded extracellular vesicles (MTX-EVs) on inflammatory macrophage polarization both in vivo and in vitro. In a murine periodontitis model, MTX-EVs inhibited alveolar bone resorption, suppressed pro-inflammatory macrophage activation, and promoted anti-inflammatory macrophages. Mechanistically, MTX-EVs reduced acyl-CoA synthetase-1 (ACSL1) expression, which was elevated during inflammation. Inhibition of ACSL1 with triacsin-C in macrophages suppressed the inflammatory phenotype through the promotion of the oxidative phosphorylation (OXPHOS). In contrast, MTX-EVs counteracted the effects of ACSL1 overexpression on macrophage polarization and metabolism. Our findings suggest that targeting ACSL1 via MTX-EVs represents a therapeutic strategy for modulating macrophage polarization and improving periodontitis treatment outcomes.

Keywords:  ACSL1; Extracellular vesicles; Macrophage; Methotrexate; Periodontitis

DOI:  https://doi.org/10.1016/j.molimm.2025.04.005
Cell Rep. 2025 Apr 11. pii: S2211-1247(25)00333-X. [Epub ahead of print]44(4): 115562

SIRT2 suppresses aging-associated cGAS activation and protects aged mice from severe COVID-19.

Marine Barthez, Biyun Xue, Jian Zheng, Yifei Wang, Zehan Song, Wei-Chieh Mu, Chih-Ling Wang, Jiayue Guo, Fanghan Yang, Yuze Ma, Xuetong Wei, Chengjin Ye, Nicholas Sims, Luis Martinez-Sobrido, Stanley Perlman, Danica Chen.

  Aging-associated vulnerability to coronavirus disease 2019 (COVID-19) remains poorly understood. Here, we show that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected aged mice lacking SIRT2, a cytosolic NAD+-dependent deacetylase, develop more severe disease and show increased mortality, while treatment with an NAD+ booster, 78c, protects aged mice from lethal infection. Mechanistically, we demonstrate that SIRT2 modulates the acetylation of cyclic GMP-AMP synthase (cGAS), an immune sensor for cytosolic DNA, and suppresses aging-associated cGAS activation and inflammation. Furthermore, we show that SARS-CoV-2 infection-induced inflammation is mediated at least in part by ORF3a, which triggers mtDNA release and cGAS activation. Collectively, our study reveals a molecular basis for aging-associated susceptibility to COVID-19 and suggests therapeutic approaches to protect aged populations from severe SARS-CoV-2 infection.

Keywords:  COVID-19; CP: Immunology; CP: Microbiology; NAD; ORF3a; SARS-CoV-2; SIRT1; SIRT2; SIRT3; SIRT6; SIRT7; aging; cGAS; inflammation; mitochondria; sirtuin

DOI:  https://doi.org/10.1016/j.celrep.2025.115562
J Vis Exp. 2025 Mar 28.

Measuring Mitochondrial Function of Naïve and Effector CD8 T Cells.

Jacqueline A Turner, Elizabeth Katsnelson, Raul M Torres.

Understanding how immunometabolism impacts the function, differentiation, and fate of lymphocytes has garnered significant interest and attention. Lymphocyte biology has been explored using bioenergetic analysis and has now become a critically import tool in the field. Thus, we sought to optimize a bioenergetic analysis assay that can be adapted with pretreatments and acute injection for receptor stimulations. Here, we evaluated CD8 T cell ex vivo metabolism using the Cell Mito Stress Test to assess rates of oxygen consumption and extracellular acidification in naïve and effector CD8 T cells. Antigen-specific effector CD8 T cells were derived via ex vivo stimulation, and naïve CD8 T cells harvested from splenocytes and isolated with magnetic bead column separation. Pretreatments are performed in microplates and we detail how to prepare sensor cartridges. We show how injection ports can loaded with drugs to indirectly measure metabolic capacities and with metabolic modulators, this protocol can be used to study specific enzyme activity. T-cell receptor stimulations can be studied in real time with acute injection and stimulation with anti-CD3/CD28 using the injection ports. Instrument analyzers are used for measurements and data collection and data visualization is done with software programs to interpret cellular metabolism. This strategy produces an extensive amount of data on immune cell biology and mitochondrial bioenergetics allowing researchers to customize the protocol in numerous ways to explore CD8 T cell metabolism.

DOI: https://doi.org/10.3791/65642
Eur J Immunol. 2025 Apr;55(4): e202451102

Metabolic Dialogue Shapes Immune Response in the Tumor Microenvironment.

Fengxia Gao, Rushil Shah, Gang Xin, Ruoning Wang.

The fate of immune cells is fundamentally linked to their metabolic program, which is also influenced by the metabolic landscape of their environment. The tumor microenvironment represents a unique system for intercellular metabolic interactions, where tumor-derived metabolites suppress effector CD8+ T cells and promote tumor-promoting macrophages, reinforcing an immune-suppressive niche. This review will discuss recent advancements in metabolism research, exploring the interplay between various metabolites and their effects on immune cells within the tumor microenvironment.

DOI: https://doi.org/10.1002/eji.202451102
J Leukoc Biol. 2025 Apr 17. pii: qiaf047. [Epub ahead of print]

UDP-glucose Regulates Dendritic Cell Mitochondrial Respiration via a Nitric Oxide-Dependent Mechanism.

Bay Vagher, Soyeon K Gullickson, Julia P Snyder, Tyler Hogan, Roxana Del Rio-Guerra, Keke C Fairfax, Eyal Amiel.

  Bone marrow-derived dendritic cell (BMDC) activation is associated with rewiring of cellular metabolism and concurrent large-scale changes in gene expression promoting a pro-inflammatory program characterized by expression of inducible nitric oxide synthase (iNOS) and the production of nitric oxide (NO). NO inhibits vital cellular activities including mitochondrial respiration. Mitochondrial respiration inhibition via NO occurs at discrete levels of activating stimulus, termed the mitochondrial respiration threshold, and regulation of this threshold is not fully understood. In this work, we characterize the role of UDP-glucose as a modulator of NO-mediated mitochondrial respiration inhibition via P2Y14 receptor signaling in stimulated BMDCs. We demonstrate BMDCs exhibit an enhanced pro-inflammatory profile in the presence of UDP-glucose, providing evidence for a new NO-regulatory axis in BMDCs. These studies highlight the importance of the growing body of literature supporting metabolites as signaling molecules in activating conditions thus allowing for better modeling of physiologically-relevant contexts for myeloid cell encounters with microbial stimuli.

Keywords:  Bone Marrow-Derived Dendritic Cells; NO; Nitric Oxide; Real-Time Extracellular Flux Analysis; Seahorse

DOI:  https://doi.org/10.1093/jleuko/qiaf047
Nature. 2025 Apr 16.

Mitochondrial metabolism sustains DNMT3A-R882-mutant clonal haematopoiesis.

Malgorzata Gozdecka, Monika Dudek, Sean Wen, Muxin Gu, Richard J Stopforth, Justyna Rak, Aristi Damaskou, Guinevere L Grice, Matthew A McLoughlin, Laura Bond, Rachael Wilson, George Giotopoulos, Vijaya Mahalingam Shanmugiah, Rula Bany Bakar, Eliza Yankova, Jonathan L Cooper, Nisha Narayan, Sarah J Horton, Ryan Asby, Dean C Pask, Annalisa Mupo, Graham Duddy, Ludovica Marando, Theodoros Georgomanolis, Paul Carter, Amirtha Priya Ramesh, William G Dunn, Clea Barcena, Paolo Gallipoli, Kosuke Yusa, Slavé Petrovski, Penny Wright, Pedro M Quiros, Christian Frezza, James A Nathan, Arthur Kaser, Siddhartha Kar, Konstantinos Tzelepis, Jonathan Mitchell, Margarete A Fabre, Brian J P Huntly, George S Vassiliou.

Somatic DNMT3A R882 codon mutations drive the most common form of clonal haematopoiesis (CH) and are associated with increased acute myeloid leukaemia (AML) risk1,2. Preventing expansion of DNMT3A-R882-mutant haematopoietic stem/progenitor cells (HSPCs) may therefore avert progression to AML. To identify DNMT3A-R882-mutant-specific vulnerabilities, we conducted a genome-wide CRISPR screen on primary mouse Dnmt3aR882H/+ HSPCs. Amongst the 640 vulnerability genes identified, many were involved in mitochondrial metabolism and metabolic flux analysis confirmed enhanced oxidative phosphorylation usage in Dnmt3aR882H/+ vs Dnmt3a+/+ (WT) HSPCs. We selected citrate/malate transporter Slc25a1 and complex I component Ndufb11, for which pharmacological inhibitors are available, for downstream studies. In vivo administration of SLC25A1 inhibitor CTPI2 and complex I inhibitors IACS-010759 and metformin, suppressed post-transplantation clonal expansion of Dnmt3aR882H/+, but not WT, LT-HSC. The effect of metformin was recapitulated using a primary human DNMT3A-R882 CH sample. Notably, analysis of 412,234 UK Biobank (UKB) participants revealed that individuals taking metformin had markedly lower prevalence of DNMT3A-R882-mutant CH, after controlling for potential confounders including glycated haemoglobin, diabetes and body mass index. Collectively, our data propose modulation of mitochondrial metabolism as a therapeutic strategy for prevention of DNMT3A-R882-mutant AML.

DOI: https://doi.org/10.1038/s41586-025-08980-6
Res Sq. 2025 Mar 31. pii: rs.3.rs-3481746. [Epub ahead of print]

CAR T cell-driven induction of iNOS in tumor-associated macrophages promotes CAR T cell resistance in B cell lymphoma.

Marco Davila, Sae Bom Lee, Yun Pyo Kang, Justin Boucher, Jay Mandula, Emiliano Roselli, Darwin Chang, Rachel Jimenez, Hiroshi Kotani, Kayla Reid, Julio Vazquez-Martinez, Nolan Beatty, Payal Goala, Rosa Sierra-Mondragon, Min Liu, John Koomen, Jonathan Nguyen, Mohammad Hussaini, Timothy Shaw, Xuefeng Wang, Rawan Faramand, Michael Jain, Frederick Locke, Paulo Rodriguez, Cooper Sailer, Shannon McSain, Showkat Hamid, Muhammad Tariq, Jianmin Wang, Julieta Abraham-Miranda.

Chimeric antigen receptor (CAR) T cell therapies have revolutionized B cell malignancy treatment, but subsets of patients with large B cell lymphoma (LBCL) experience primary resistance or relapse after CAR T cell treatment. To uncover tumor microenvironment (TME)-induced resistance mechanisms, we examined patients' intratumoral immune infiltrates and observed that elevated levels of immunoregulatory macrophages in pre-infusion tumor biopsies are correlated with poor clinical responses. CAR T cell-produced interferon-gamma (IFN-γ) promotes the expression of inducible nitric oxide synthase (iNOS, NOS2) in immunoregulatory macrophages, impairing CAR T cell function. Mechanistically, iNOS-expressing macrophages upregulated the p53 pathway, mediating apoptosis and cell cycle arrest in CAR T cells, while downregulating the MYC pathway involved in ribosome biogenesis and protein synthesis. Furthermore, CAR T cell metabolism is compromised by depletion of glycolytic intermediates and rewiring of the TCA cycle. Pharmacological inhibition of iNOS enhances the CAR T cell treatment efficacy in B cell tumor-bearing mice. Notably, elevated levels of iNOS+CD14+ monocytes were observed in leukaphereses of patients with non-durable response to CAR T cell therapy. These findings suggest that mitigating iNOS in tumor-associated macrophages (TAMs) by blocking IFN-γ secretion from CAR T cells will improve outcomes for LBCL patients.

DOI: https://doi.org/10.21203/rs.3.rs-3481746/v1
Int J Mol Sci. 2025 Mar 28. pii: 3109. [Epub ahead of print]26(7):

Analysis of Metabolomic Reprogramming Induced by Infection with Kaposi's Sarcoma-Associated Herpesvirus Using Untargeted Metabolomic Profiling.

Abdulkarim Alfaez, Michael W Christopher, Timothy J Garrett, Bernadett Papp.

  Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic double-stranded DNA virus. There are no vaccines or antiviral therapies for KSHV. Identifying the cellular metabolic pathways that KSHV manipulates can broaden the knowledge of how these pathways contribute to sustaining lytic infection, which can be targeted in future therapies to prevent viral spread. In this study, we performed an untargeted metabolomic analysis of KSHV infected telomerase-immortalized gingival keratinocytes (TIGK) cells at 4 h post-infection compared to mock-infected cells. We found that the metabolomic landscape of KSHV-infected TIGK differed from that of the mock. Specifically, a total of 804 differential metabolic features were detected in the two groups, with 741 metabolites that were significantly upregulated, and 63 that were significantly downregulated in KSHV-infected TIGK cells. The differential metabolites included ornithine, arginine, putrescine, dimethylarginine, orotate, glutamate, and glutamine, and were associated with pathways, such as the urea cycle, polyamine synthesis, dimethylarginine synthesis, and de novo pyrimidine synthesis. Overall, our untargeted metabolomics analysis revealed that KSHV infection results in marked rapid alterations in the metabolic profile of the oral epithelial cells. We envision that a subset of these rapid metabolic changes might result in altered cellular functions that can promote viral lytic replication and transmission in the oral cavity.

Keywords:  KSHV; de novo infection; metabolomics; oral epithelial cells

DOI:  https://doi.org/10.3390/ijms26073109
Trends Immunol. 2025 Apr 11. pii: S1471-4906(25)00058-4. [Epub ahead of print]

The unusual metabolism of germinal center B cells.

Caitlin J Gracie, Robert Mitchell, Julia C Johnstone, Alexander J Clarke.

  In the germinal center (GC), B cells undergo rounds of somatic hypermutation (SHM), proliferation, and positive selection to develop into high-affinity, long-lived plasma cells and memory B cells. It is well established that, upon activation, B cells significantly alter their metabolism, but until recently little was understood about their metabolism within the GC. In this review we discuss novel in vivo models in which GC B cell (GCBC) metabolism is disrupted; these have greatly increased our understanding of B cell metabolic phenotype. GCBCs are unusual in that, unlike almost all other rapidly proliferating immune cells, they use little glycolysis but prefer fatty acid oxidation (FAO) to fuel ATP synthesis, whilst preferentially utilizing glucose and amino acids as carbon and nitrogen sources for biosynthetic pathways.

Keywords:  B cell; germinal center; metabolism

DOI:  https://doi.org/10.1016/j.it.2025.02.015
Nat Commun. 2025 Apr 16. 16(1): 3306

Elevated mitochondrial membrane potential is a therapeutic vulnerability in Dnmt3a-mutant clonal hematopoiesis.

Kira A Young, Mohsen Hosseini, Jayna J Mistry, Claudia Morganti, Taylor S Mills, Xiurong Cai, Brandon T James, Griffin J Nye, Natalie R Fournier, Veronique Voisin, Ali Chegini, Aaron D Schimmer, Gary D Bader, Grace Egan, Marc R Mansour, Grant A Challen, Eric M Pietras, Kelsey H Fisher-Wellman, Keisuke Ito, Steven M Chan, Jennifer J Trowbridge.

The competitive advantage of mutant hematopoietic stem and progenitor cells (HSPCs) underlies clonal hematopoiesis (CH). Drivers of CH include aging and inflammation; however, how CH-mutant cells gain a selective advantage in these contexts is an unresolved question. Using a murine model of CH (Dnmt3aR878H/+), we discover that mutant HSPCs sustain elevated mitochondrial respiration which is associated with their resistance to aging-related changes in the bone marrow microenvironment. Mutant HSPCs have DNA hypomethylation and increased expression of oxidative phosphorylation gene signatures, increased functional oxidative phosphorylation capacity, high mitochondrial membrane potential (Δψm), and greater dependence on mitochondrial respiration compared to wild-type HSPCs. Exploiting the elevated Δψm of mutant HSPCs, long-chain alkyl-TPP molecules (MitoQ, d-TPP) selectively accumulate in the mitochondria and cause reduced mitochondrial respiration, mitochondrial-driven apoptosis and ablate the competitive advantage of HSPCs ex vivo and in vivo in aged recipient mice. Further, MitoQ targets elevated mitochondrial respiration and the selective advantage of human DNMT3A-knockdown HSPCs, supporting species conservation. These data suggest that mitochondrial activity is a targetable mechanism by which CH-mutant HSPCs gain a selective advantage over wild-type HSPCs.

DOI: https://doi.org/10.1038/s41467-025-57238-2
J Lipid Res. 2025 Apr 16. pii: S0022-2275(25)00069-0. [Epub ahead of print] 100809

Oxidized LDL stimulates PKM2-mediated mtROS production and phagocytosis.

Jue Zhang, Jackie Chang, Vaya Chen, Mirza Ahmar Beg, Wenxin Huang, Lance Vick, Yaxin Wang, Heng Zhang, Erin Yttre, Ankan Gupta, Mark Castleberry, Ziyu Zhang, Wen Dai, Jieqing Zhu, Shan Song, Moua Yang, Ashley Kaye Brown, Zhen Xu, Yan-Qing Ma, Brian C Smith, Jacek Zielonka, James G Traylor, Cyrine Ben Dhaou, A Wayne Orr, Weiguo Cui, Yiliang Chen.

  Oxidized low-density lipoprotein (oxLDL) promotes proatherogenic phenotypes in macrophages, accelerating the progression of atherosclerosis. Our previous studies demonstrated that oxLDL binds to its receptor CD36, stimulating mitochondrial reactive oxygen species (mtROS), which are critical in atherosclerosis development. However, the mechanisms underlying mtROS induction and their effects on macrophage cellular functions remain poorly understood. Macrophages rely on phagocytosis to clear pathogens, apoptotic cells, or other particles, a process critical for tissue homeostasis. Dysregulated or excessive particle ingestion, a key step in phagocytosis, can lead to lipid overloading and foam cell formation, a hallmark of atherosclerosis. In this study, we showed that macrophages pre-treated with oxLDL exhibit increased particle ingestion, a phagocytic response significantly attenuated in Cd36-null macrophages. Further investigations revealed that oxLDL-induced phagocytosis depends on mtROS, as their suppression inhibited the process. In vivo, atherosclerosis-prone Apoe-null mice on a high-fat diet exhibited increased mtROS levels and enhanced phagocytic activity in aortic foamy macrophages compared to those from chow diet-fed mice, supporting a role of mtROS in promoting lesional macrophage phagocytosis. Mechanistically, we identified a novel signaling pathway whereby oxLDL/CD36 interaction induces the translocation of the cytosolic enzyme pyruvate kinase muscle 2 (PKM2) to mitochondria. Disruption of PKM2 mitochondrial translocation using siRNA knockdown or a specific chemical inhibitor reduced mtROS production and attenuated oxLDL-induced phagocytosis. In conclusion, our findings reveal a novel oxLDL-CD36-PKM2 signaling axis that drives mtROS production and phagocytosis in atherogenic macrophages.

Keywords:  CD36; PKM2; atherosclerosis; glycolysis; macrophages; mitochondria; phagocytosis; reactive oxygen species

DOI:  https://doi.org/10.1016/j.jlr.2025.100809
Int J Mol Sci. 2025 Apr 02. pii: 3321. [Epub ahead of print]26(7):

Mechanical Force Triggers Macrophage Pyroptosis and Sterile Inflammation by Disrupting Cellular Energy Metabolism.

Hao Tan, Guoyin Yang, Ye Zhu, Xinyi He, Lan Yang, Yun Hu, Leilei Zheng.

  Mechanical force regulates tissue remodeling during orthodontic tooth movement (OTM) by inducing macrophage-mediated sterile inflammatory responses. Pyroptosis, as an inflammatory form of programmed cell death, triggers a robust inflammatory cascade by activating the inflammasome. Although recent reports have demonstrated that pyroptosis can be activated by mechanical force, it remains unclear whether and how orthodontic force induces macrophage pyroptosis and sterile inflammation. In this study, by establishing a rat OTM model and a force-loaded macrophage model, we found that force induces Caspase1-dependent pyroptosis in macrophages and activates sterile inflammation both in vivo and in vitro. Mechanistically, we uncovered that mechanical force disrupts macrophage energy metabolism, characterized by an imbalance between lactate dehydrogenase A (LDHA) and pyruvate dehydrogenase (PDH), as well as mitochondrial dysfunction. Notably, inhibiting pyruvate dehydrogenase kinase 1 (PDK1) effectively restored this metabolic balance, thereby alleviating pyroptosis and sterile inflammation in force-stimulated macrophages. Overall, this study elucidates that force induces macrophage pyroptosis and sterile inflammation, and further identifies imbalances in the LDHA/PDH ratio and mitochondrial dysfunction as pivotal mechanistic features. These insights offer novel perspectives and potential therapeutic targets for the precise and effective modulation of OTM.

Keywords:  energy metabolism; macrophage; mechanical force; orthodontic tooth movement; pyroptosis; sterile inflammation

DOI:  https://doi.org/10.3390/ijms26073321
Methods Mol Biol. 2025 ;2904 243-258

Metabolic Screening of T Lymphocytes During Activation via SEAHORSE Extracellular Flux (XF) Analysis.

Gabriela F Gubert, Sophia M Hochrein, Katrin Sinning, Martin Vaeth.

  Upon activation, T cells undergo a profound reconfiguration of their metabolic profile, transitioning from a quiescent to a metabolically active state characterized by an increase in both aerobic glycolysis and mitochondrial respiration. Seahorse extracellular flux (XF) analysis is a powerful method for measuring the changes in fundamental metabolic pathways in real-time, including aerobic glycolysis and mitochondrial respiration of live T cells. This method allows a precise determination of mitochondrial performance and lactate secretion, which is measured as oxygen consumption rate (OCR) and glycolytic proton efflux rate (ECAR), respectively. By dynamically monitoring these metabolic changes, Seahorse XF analysis provides comprehensive insights into the metabolic dynamics of (activated) T cells across diverse experimental conditions or treatments.

Keywords:  Bioenergetic profile; ECAR; Glycolysis; Metabolic remodeling; Metabolism; Mitochondrial respiration; OCR; Seahorse; T cell activation

DOI:  https://doi.org/10.1007/978-1-0716-4414-0_17
Stem Cell Res Ther. 2025 Apr 18. 16(1): 186

The role of PKM2-mediated metabolic reprogramming in the osteogenic differentiation of BMSCs under diabetic periodontitis conditions.

Yanlin Zhu, Yuhan Yang, Yuyan Lan, Zun Yang, Xiang Gao, Jie Zhou.

   BACKGROUND: Diabetes mellitus (DM) and periodontitis have a bidirectional relationship, with each being a high-risk factor for the other. Prolonged hyperglycemia exacerbates periodontal inflammation and disrupts bone homeostasis. Pyruvate kinase M2 (PKM2), a key enzyme in glycolysis, is involved in metabolic reprogramming, but its role in osteogenesis under high-glucose (HG) inflammatory conditions remains largely unknown. This study aimed to investigate the effects of HG and inflammation on bone marrow mesenchymal stem cells (BMSCs) under indirect co-culture conditions and to explore how PKM2 regulates metabolism and mitochondrial function during osteogenic differentiation in HG inflammatory environments, elucidating its role in diabetic periodontitis (DP).
METHODS: Expose BMSCs to conditioned medium (CM) collected from RAW264.7 cells stimulated with HG and/or lipopolysaccharide (LPS). BMSCs functionality was assessed using CCK8, EdU, Annexin V-PI apoptosis assay, alkaline phosphatase (ALP), and Alizarin Red S (ARS) staining. Metabolic characteristics were evaluated through Seahorse assays, lactate production, glucose uptake, and ATP measurements. Mitochondrial function was assessed via JC-1, and ROS staining, Mito-Tracker staining, and transmission electron microscopy (TEM). Gene and protein expression were analyzed by quantitative real-time PCR and western blotting. In vivo therapeutic effects of shikonin were validated via micro-CT and histological staining in a diabetic periodontitis mouse model.
RESULTS: In vitro experiments demonstrated that HG inflammatory conditions impaired the survival of BMSCs, suppressed osteogenic differentiation, and induced metabolic reprogramming. This reprogramming was characterized by enhanced glycolysis, impaired oxidative phosphorylation (OXPHOS), abnormal upregulation of PKM2 expression, and mitochondrial dysfunction accompanied by morphological alterations. Shikonin effectively reversed these adverse effects by inhibiting PKM2 tetramerization, rescuing the loss of osteogenic function in BMSCs. The therapeutic potential of shikonin was confirmed in the diabetic periodontitis mouse model.
CONCLUSION: PKM2 impairs the osteogenesis of BMSCs by affecting metabolism and mitochondrial function, suggesting it as a potential therapeutic target for diabetic periodontitis.

Keywords:  Diabetes periodontitis; Metabolic reprogramming; Mitochondrial dynamics; Osteogenic differentiation; PKM2

DOI:  https://doi.org/10.1186/s13287-025-04301-w
mBio. 2025 Apr 18. e0398124

Chlamydia trachomatis exploits sphingolipid metabolic pathways during infection of phagocytes.

Adriana Moldovan, Fabienne Wagner, Fabian Schumacher, Dominik Wigger, David Komla Kessie, Marcel Rühling, Kathrin Stelzner, Regina Tschertok, Louise Kersting, Julian Fink, Jürgen Seibel, Burkhard Kleuser, Thomas Rudel.

  Chlamydiae are obligate intracellular pathogens that utilize host cell metabolites for catabolic and anabolic processes. The bacteria replicate in epithelial cells from which they take up sphingolipids (SL) and incorporate them into the chlamydial membrane and the vacuole (termed inclusion). SL uptake is essential for Chlamydia trachomatis (Ctr) in epithelial cells; however, they can also infect phagocytes, but the consequences for the SL metabolism have not yet been investigated in these cells. We performed a quantitative sphingolipidome analysis of infected primary neutrophils, macrophages, and immortalized fallopian tube epithelial cells. Sphingosine (Sph) levels are elevated in primary M2-like macrophages and human neutrophils infected with C. trachomatis. Human neutrophils respond to the pathogen by markedly upregulating sphingosine kinase 1 (SPHK1). We show in M2-like macrophages, by RNAseq, that two counteracting pathways involving upregulation of SPHK1, but also sphingosine-1-phosphate phosphatases 1 and 2 (SGPP1 and SGPP2) and sphingosine-1-phosphate lyase (SGPL1), maintain a steady pool of S1P. Using click chemistry, we show that exogenously added sphingomyelin (SM) and ceramide (Cer) are efficiently taken up into the chlamydial inclusion and are integrated into bacterial membranes in infected M2-like macrophages. Exogenous Sph reduces chlamydial infectivity, is transported into the inclusion lumen, and integrates into chlamydial membranes, suggesting that this particular SL species could represent a host defense mechanism. Taken together, our data indicate an important role for Sph/Sph kinase vs S1P/S1P phosphatase balance in infected phagocytes and a previously unrecognized role for sphingosine in the immune defense against chlamydial infection.IMPORTANCEChlamydia trachomatis (Ctr) is the leading cause of sexually transmitted diseases worldwide. Left untreated, it can cause severe complications such as blindness, pelvic inflammatory disease, or infertility. To date, no vaccines are available, and antibiotic treatment represents the only therapeutic approach to cure the infection. Limited access to antibiotics and displaced antibiotic intake increase the risk of developing recurring infections. Immune cells which fail to clear the infection and serve as a niche for chlamydial survival and replication, favor this outcome. Our research aims to elucidate the influence of sphingolipids (SL) during chlamydial infection, especially of phagocytic cells. Identifying relevant targets offers new strategies to develop alternative treatment methods.

Keywords:  Chlamydia; macrophage; neutrophil; phagocyte; sphingolipids; sphingosine; sphingosine kinase 1; sphingosine-1-phosphate phosphatase 2

DOI:  https://doi.org/10.1128/mbio.03981-24
J Clin Lab Anal. 2025 Apr 17. e25020

Exploring the Role of T-Cell Metabolism in Modulating Immunotherapy Efficacy for Non-Small Cell Lung Cancer Based on Clustering.

Hongzhe Guo, Liangyu Zhang, Hu Tang, Peiwen Liu, Bin Hu, Yue Gong, Rui Hou, Ziheng Wu.

   BACKGROUND: Immunotherapy, especially immune checkpoint blockade (ICB) therapy, has demonstrated noteworthy advancements in the realm of non-small cell lung cancer (NSCLC). However, the efficacy of ICB therapy is limited to a small subset of patients with NSCLC, and the underlying mechanisms remain poorly understood.
STUDY DESIGN AND DISCOVERIES: In this study, we conducted a comprehensive investigation of the metabolic profiles of infiltrating T cells in NSCLC tumors and revealed the metabolic heterogeneity, which associated with the prognosis of ICB therapy, in three T-cell subtypes. After metabolic clustering, we split these metabolic clusters into two groups: Nonresponse-associated (NR) clusters that enriched with cells from nonresponders, and response-associated (R) clusters that not belonging to NR clusters. Then, we elucidated their metabolic differences and specific functions. Notably, we discovered HSPA1A was significantly downregulated in NR clusters of all three T-cell subtypes. In addition, leveraging single-cell T-cell receptor sequencing data and pseudotime series analysis, we revealed the reciprocal interconversion between R and NR metabolic clusters within the same T-cell clone. This suggests a potential metabolic reprogramming capability of T cells. Furthermore, through the analysis of intercellular communication, we identified the specific intercellular signaling in the R clusters, which might promote the activation and regulation of signal transduction pathways that affect the prognosis of ICB therapy.
CONCLUSION: In conclusion, our study offers substantial insights into the mechanisms of relationships between T-cell metabolisms and ICB therapy outcomes, shedding light on the mechanism of immunotherapy efficacy in patients with NSCLC. Such investigations will contribute to overcoming treatment resistance.

Keywords:  T cell; clustering; immune metabolism; immunotherapy; non‐small cell lung cancer

DOI:  https://doi.org/10.1002/jcla.25020
FASEB J. 2025 Apr 30. 39(8): e70520

Metabolic Reprogramming of Glycolysis, Lipids, and Amino Acids in Tumors: Impact on CD8+ T Cell Function and Targeted Therapeutic Strategies.

Panping Liang, Zedong Li, Zhengwen Chen, Zehua Chen, Tao Jin, Fengjun He, Xiaolong Chen, Hongfeng Gou, Kun Yang.

  Tumor cells undergo metabolic reprogramming to support their rapid proliferation and to adapt to the challenges of the tumor microenvironment (TME). This involves significant changes in glycolysis, lipid, and amino acid metabolism, which not only promote tumor survival but also impact CD8+ T cells within the TME. This review examines how these metabolic alterations affect CD8+ T cell function, particularly through competition for energy resources and microenvironmental changes. For instance, aerobic glycolysis in tumor cells depletes glucose and leads to lactate accumulation, both of which suppress CD8+ T cell activity. Additionally, changes in lipid metabolism affect the composition of cell membranes and disrupt signal transduction, impairing T cell function. Amino acid reprogramming, such as increased consumption of glutamine and arginine by tumor cells, further hinders the activity and proliferation of CD8+ T cells. We also explore therapeutic strategies that target these metabolic pathways in tumor cells, such as inhibitors of glycolysis and fatty acid synthesis, which may enhance the antitumor activity of CD8+ T cells. These approaches show promise in improving both T cell function and the effectiveness of immune checkpoint blockade therapies. By investigating the link between tumor metabolism and CD8+ T cell dysfunction, this review highlights mechanisms of tumor immune evasion. This understanding can guide the development of novel immunotherapies aimed at enhancing T cell function within the TME.

Keywords:  CD8+ T cell; fatty acids; glutamine; glycolysis; metabolic reprogramming

DOI:  https://doi.org/10.1096/fj.202403019R
Cell Death Dis. 2025 Apr 13. 16(1): 284

The role of heme in sepsis induced Kupffer cell PANoptosis and senescence.

Tingting Li, Joseph Adams, Peilin Zhu, Tao Zhang, Fei Tu, Amy Gravitte, Xiaojin Zhang, Li Liu, Jared Casteel, Valentin Yakubenko, David L Williams, Chuanfu Li, Xiaohui Wang.

Elevated heme levels, a consequence of hemolysis, are strongly associated with increased susceptibility to bacterial infections and adverse sepsis outcomes, particularly in older populations. However, the underlying mechanisms remain poorly understood. Using a cecal ligation and puncture (CLP) model of sepsis, we demonstrate that elevated heme levels correlate with Kupffer cell loss, increased bacterial burden, and heightened mortality. Mechanistically, we identify mitochondrial damage as a key driver of heme- and bacterial-induced Kupffer cell PANoptosis, a form of cell death integrating pyroptosis, apoptosis, and necroptosis, as well as cellular senescence. Specifically, heme activates phospholipase C gamma (PLC-γ), facilitating the translocation of cleaved gasdermin D (c-GSDMD) to mitochondria, resulting in GSDMD pore formation, mitochondrial dysfunction, and the release of mitochondrial DNA (mtDNA) during bacterial infection. This mitochondrial damage amplifies PANoptosis and triggers the cGAS-STING signaling pathway, further driving immune senescence. Notably, PLC-γ inhibition significantly reduces mitochondrial damage, cell death, and senescence caused by heme and bacterial infection. Furthermore, we show that hemopexin, a heme scavenger, effectively mitigates sepsis-induced Kupffer cell death and senescence, enhances bacterial clearance, and improves survival outcomes in both young and aged mice. These findings establish mitochondrial damage as a central mediator of heme induced Kupffer cell loss and highlight PLC-γ inhibition and hemopexin administration as promising therapeutic strategies for combating sepsis associated immune dysfunction.

DOI: https://doi.org/10.1038/s41419-025-07637-6
Immunity. 2025 Apr 09. pii: S1074-7613(25)00136-0. [Epub ahead of print]

Acute exposure to high-fat diet impairs ILC3 functions and gut homeostasis.

Le Xiong, Shanti Diwakarla, Roxanne Chatzis, Olivia Artaiz, Matthew Macowan, Shengbo Zhang, Alexandra Garnham, Pooranee K Morgan, Natalie A Mellett, Peter J Meikle, Graeme I Lancaster, Benjamin J Marsland, Stephen L Nutt, Cyril Seillet.

  Prolonged exposure to a high-fat diet (HFD) exacerbates intestinal disease pathology, yet the early events preceding the development of gut inflammation remain poorly understood. Here, we show that within 48 h, HFD impairs intestinal group 3 innate lymphoid cells (ILC3s) and their capacity to produce interleukin-22 (IL-22), critical for maintaining gut homeostasis. This loss of function was associated with rapid dysbiosis, increased gut permeability, and reduced production of antimicrobial peptides, mucus, and tight-junction proteins. While saturated fatty acids metabolized through oxidation impaired ILC3 function, unsaturated fatty acids sustained IL-22 secretion by ILC3s through the formation of lipid droplets using diacylglycerol O-acyltransferase (DGAT) enzymes. Upon inflammation, saturated fatty acids impaired IL-22 production by ILC3s and increased the susceptibility of the gut to injury. Our findings reveal the differential acute impact of saturated and unsaturated fatty acids on gut homeostasis through distinct metabolic pathways in ILC3s.

Keywords:  DGAT; IL-22; group 3 innate lymphoid cells; high-fat diet; inflammation; inflammatory bowel disease; intestinal homeostasis; lipid droplets; metabolism; saturated fatty acid

DOI:  https://doi.org/10.1016/j.immuni.2025.03.017