bims-imicid 2025-05-18 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2025–05–18
twenty papers selected by
Dylan Ryan, University of Cambridge

Itaconate Has Limited Protective Effects in Experimental Malaria Models.
Metabolic reprogramming of interleukin-17-producing γδ T cells promotes ACC1-mediated de novo lipogenesis under psoriatic conditions.
Dietary lipid overload creates a suppressive environment that impedes the antiviral functions of NK cells.
Adipocyte-expressed SIRT3 manipulates carnitine pool to orchestrate metabolic reprogramming and polarization of macrophages.
Adipocyte metabolic state regulates glial phagocytic function.
Mitochondrial metabolism is rapidly re-activated in mature neutrophils to support stimulation-induced response.
Functional Regulation of Macrophages by Ces1d-Mediated Lipid Signaling in Immunometabolism.
TIGIT deficiency promotes autoreactive CD4+ T-cell responses through a metabolic‒epigenetic mechanism in autoimmune myositis.
Mesenchymal stem cell-mediated mitochondrial transfer regulates the fate of B lymphocytes.
Hypercapnia Increases Influenza A Virus Infection of Bronchial Epithelial Cells by Augmenting Cellular Cholesterol via mTOR and Akt.
Mitoquinol improves phagocytosis and glycolysis in ethanol-exposed macrophages via HIF-1α-PFKP axis.
IRE1α promotes phagosomal calcium flux to enhance macrophage fungicidal activity.
Mitochondria regulate MR1 protein expression and produce self-metabolites that activate MR1-restricted T cells.
Lactate facilitates pancreatic repair following acute pancreatitis by promoting reparative macrophage polarization.
ATP functions as a pathogen-associated molecular pattern to activate the E3 ubiquitin ligase RNF213.
Inhibition of ENT1 relieves intracellular adenosine-mediated T cell suppression in cancer.
Pre-existing epigenetic state and differential NF-κB activation shape type 2 immune cell responses.
Circulating inflammatory markers linked to dysregulated postprandial metabolism in postmenopausal women.
Fever-range temperature alters continual efferocytosis mediated by mouse pro-inflammatory macrophages.
NRF1 coordinates mitochondrial adaptations to dampen intracellular ROS and inflammatory responses during ischemia reperfusion.

Eur J Immunol. 2025 May;55(5): e202451595

Itaconate Has Limited Protective Effects in Experimental Malaria Models.

Fran Prenen, Emilie Pollenus, Hanne Meers, Sofie Knoops, Rebecca Sadler, Margot Deckers, Evanna L Mills, Philippe E Van den Steen.

  In severe malaria, dysregulated metabolism and excessive inflammatory responses contribute to fatal outcomes. Therapeutic strategies that address both metabolic and inflammatory balances are thus required. Itaconate, a metabolite produced by aconitate decarboxylase 1 (ACOD1), is a potent inhibitor of both inflammation and glycolysis with protective effects in various inflammatory diseases. Although elevated itaconate levels have been observed in Plasmodium-infected individuals, its role in malaria is still poorly understood, making further investigation essential for assessing its therapeutic potential. We investigated the role of itaconate in both severe and mild malaria using Plasmodium berghei NK65 (PbNK65) and Plasmodium chabaudi AS (PcAS) models, respectively. Using 13C-tracer metabolomics, we detected increased itaconate levels in various organs during infection and identified inflammatory monocytes as the source of this production. Nevertheless, ACOD1 knockout mice displayed no significant changes in phenotype after PbNK65 infection, and treatment of PbNK65-infected mice with 4-octyl itaconate did not affect disease severity either. However, in the PcAS model, ACOD1 deficiency worsened the disease, as indicated by increased weight loss, higher clinical scores, and elevated parasitemia. Therefore, in contrast to the findings in recent literature, our study shows that itaconate does not contribute to susceptibility, but rather provides limited protection to malaria.

Keywords:  immunometabolism; inflammation; itaconate; malaria; monocyte

DOI:  https://doi.org/10.1002/eji.202451595
Nat Metab. 2025 May 13.

Metabolic reprogramming of interleukin-17-producing γδ T cells promotes ACC1-mediated de novo lipogenesis under psoriatic conditions.

Yu-San Kao, Mario Lauterbach, Aleksandra Lopez Krol, Ute Distler, Gloria Janet Godoy, Matthias Klein, Rafael Jose Argüello, Fatima Boukhallouk, Sara Vallejo Fuente, Kathrin Luise Braband, Assel Nurbekova, Monica Romero, Panagiota Mamareli, Luana Silva, Luis Eduardo Alves Damasceno, Francesca Rampoldi, Luciana Berod, Lydia Lynch, Karsten Hiller, Tim Sparwasser.

Metabolic reprogramming determines γδ T cell fate during thymic development; however, the metabolic requirements of interleukin (IL)-17A-producing γδ T cells (γδT17 cells) under psoriatic conditions are unclear. Combining high-throughput techniques, including RNA sequencing, SCENITH, proteomics and stable isotope tracing, we demonstrated that psoriatic inflammation caused γδT17 cells to switch toward aerobic glycolysis. Under psoriatic conditions, γδT17 cells upregulated ATP-citrate synthase to convert citrate to acetyl-CoA, linking carbohydrate metabolism and fatty acid synthesis (FAS). Accordingly, we used a pharmacological inhibitor, Soraphen A, which blocks acetyl-CoA carboxylase (ACC), to impair FAS in γδT17 cells, reducing their intracellular lipid stores and ability to produce IL-17A under psoriatic conditions in vitro. We pinpointed the pathogenic role of ACC1 in γδT17 cells in vivo by genetic ablation, ameliorating inflammation in a psoriatic mouse model. Furthermore, ACC inhibition limited human IL-17A-producing γδT17 cells. Targeting ACC1 to attenuate pathogenic γδT17 cell function has important implications for psoriasis management.

DOI: https://doi.org/10.1038/s42255-025-01276-z
iScience. 2025 May 16. 28(5): 112396

Dietary lipid overload creates a suppressive environment that impedes the antiviral functions of NK cells.

Simone Schimmer, Leonie Kerkmann, Nele Kahlert, Shahd Al Jubeh, Tanja Werner, Carrie Corkish, Hannah Prendeville, David K Finlay, Kathrin Sutter, Ulf Dittmer, Elisabeth Littwitz-Salomon.

  Natural killer (NK) cells are innate immune cells able to recognize and eliminate virus-infected cells. NK cell activity strongly correlates with a metabolic reprogramming and breakdown of fatty acids by β-oxidation during virus infections. However, there is limited knowledge regarding the impact of obesity on antiviral NK cell functions. Here, employing the Friend retrovirus mouse model, we show that the cytotoxicity and cytokine production of NK cells was impaired in obesity, leading to higher viral loads. NK cells suppression in obesity was mediated by activated Tregs. Furthermore, obese mice that were switched back to a regular diet showed complete recovery of the NK cell activity. Interestingly, feeding mice with a high-fat diet (HFD) for just ten days caused NK cell dysfunction and increased retroviral burden. This study is the first to link the detrimental impact of an obesity-induced immunosuppressive microenvironment with NK cell dysfunction during an acute retroviral infection.

Keywords:  Friend retrovirus; Interleukin-10; Natural killer cells; obesity; regulatory T cells; suppressive microenvironment

DOI:  https://doi.org/10.1016/j.isci.2025.112396
Cell Death Dis. 2025 May 15. 16(1): 381

Adipocyte-expressed SIRT3 manipulates carnitine pool to orchestrate metabolic reprogramming and polarization of macrophages.

Jiali Chen, Fei Zhou, Lei Zhang, Ruohan Lou, Cangman Zhang, Jianbo Wan, Xiaojun Ma, Ligen Lin.

Obesity is accompanied with accumulation and pro-inflammatory polarization of macrophages in adipose tissue (AT), leading to systematical inflammation and insulin resistance. Impaired lipid metabolism and endocrine function in adipocytes is recognized as a culprit in the onset of adipose tissue inflammation. Lipid levels can be managed via inhibiting both synthesis and transport or via increasing fatty acid oxidation (FAO). The deacetylase Sirtuin 3 (SIRT3) participates in inflammatory responses via regulating mitochondrial function and FAO. Herein, an AT-specific SIRT3 overexpression mice model (AT-SIRT3OE) was generated using adeno-associated virus transduction. AT-specific SIRT3 overexpression did not alter body weight or adiposity in either regular chow diet or high-fat diet (HFD) fed mice. AT-SIRT3OE mice exhibited improved insulin sensitivity in HFD-fed mice, through alleviating infiltration of macrophage and pro-inflammatory macrophage polarization in the epididymal AT. The metabolomics analysis indicated that SIRT3 overexpressed adipocytes accumulated more L-carnitine (LC) and less long-chain acylarnitines in the medium. Furthermore, SIRT3 directly deacetylates and activates carnitine palmitoyltransferase 2 (CPT2), an obligate step in mitochondrial long-chain FAO, to enhance the LC turnover pool in adipocytes, which in turn promoted lipid metabolism and anti-inflammatory polarization in macrophages. Collectively, our study provided new evidence that adipocyte-expressed SIRT3 alleviates inflammatory crosstalk between adipocytes and macrophages through manipulating LC pool. Activating SIRT3 in adipocytes could be a potential strategy to alleviate obesity-related metabolic diseases.

DOI: https://doi.org/10.1038/s41419-025-07699-6
Cell Rep. 2025 May 14. pii: S2211-1247(25)00475-9. [Epub ahead of print]44(5): 115704

Adipocyte metabolic state regulates glial phagocytic function.

Mroj Alassaf, Aditi Madan, Sunidhi Ranganathan, Shannon Marschall, Jordan J Wong, Zachary H Goldberg, Ava E Brent, Akhila Rajan.

  Excess dietary sugar profoundly impacts organismal metabolism and health, yet it remains unclear how metabolic adaptations in adipose tissue influence other organs, including the brain. Here, we show that a high-sugar diet (HSD) in Drosophila reduces adipocyte glycolysis and mitochondrial pyruvate uptake, shifting metabolism toward fatty acid oxidation and ketogenesis. These metabolic changes trigger mitochondrial oxidation and elevate antioxidant responses. Adipocyte-specific manipulations of glycolysis, lipid metabolism, or mitochondrial dynamics non-autonomously modulate Draper expression in brain ensheathing glia, key cells responsible for neuronal debris clearance. Adipocyte-derived ApoB-containing lipoproteins maintain basal Draper levels in glia via LpR1, critical for effective glial phagocytic activity. Accordingly, reducing ApoB or LpR1 impairs glial clearance of degenerating neuronal debris after injury. Collectively, our findings demonstrate that dietary sugar-induced shifts in adipocyte metabolism substantially influence brain health by modulating glial phagocytosis, identifying adipocyte-derived ApoB lipoproteins as essential systemic mediators linking metabolic state with neuroprotective functions.

Keywords:  ApoB; CP: Metabolism; CP: Neuroscience; Drosophila; OxPhos; adipokine; glycolysis; high-sugar diet; injury-response; ketogenesis; lipid metabolism; mitochondria; neurodegeneration; pyronic sensor

DOI:  https://doi.org/10.1016/j.celrep.2025.115704
Front Immunol. 2025 ;16 1572927

Mitochondrial metabolism is rapidly re-activated in mature neutrophils to support stimulation-induced response.

Jorgo Lika, James A Votava, Rupsa Datta, Carlos A Mellado Fritz, Aleksandr M Kralovec, Frances M Smith, Anna Huttenlocher, Melissa C Skala, Jing Fan.

   Introduction: Neutrophils are highly abundant innate immune cells that are constantly produced from myeloid progenitors in the bone marrow. Differentiated neutrophils can perform an arsenal of effector functions critical for host defense. This study aims to quantitatively understand neutrophil mitochondrial metabolism throughout differentiation and activation, and to elucidate the impact of mitochondrial metabolism on neutrophil functions.
Methods: To study metabolic remodeling throughout neutrophil differentiation, murine ER-Hoxb8 myeloid progenitor-derived neutrophils and human induced pluripotent stem cell-derived neutrophils were assessed as models. To study the metabolic remodeling upon neutrophil activation, differentiated ER-Hoxb8 neutrophils and primary human neutrophils were activated with various stimuli, including ionomycin, monosodium urate crystals, and phorbol 12-myristate 13-acetate. Characterization of cellular metabolism by isotopic tracing, extracellular flux analysis, metabolomics, and fluorescence-lifetime imaging microscopy revealed dynamic changes in mitochondrial metabolism.
Results: As neutrophils mature, mitochondrial metabolism decreases drastically, energy production is offloaded from oxidative phosphorylation, and glucose oxidation through the TCA cycle is substantially reduced. Nonetheless, mature neutrophils retain the capacity for mitochondrial metabolism. Upon stimulation with certain stimuli, TCA cycle is rapidly activated. Mitochondrial pyruvate carrier inhibitors reduce this re-activation of the TCA cycle and inhibit the release of neutrophil extracellular traps. Treatment with these inhibitors also impacts neutrophil redox status, migration, and apoptosis without significantly changing overall bioenergetics.
Conclusions: Together, these results demonstrate that mitochondrial metabolism is dynamically remodeled and plays a significant role in neutrophils. Furthermore, these findings point to the therapeutic potential of mitochondrial pyruvate carrier inhibitors in a range of conditions where dysregulated neutrophil response drives inflammation and contributes to pathology.

Keywords:  TCA cycle; metabolism; mitochondria; neutrophil; neutrophil extracellular traps

DOI:  https://doi.org/10.3389/fimmu.2025.1572927
Mol Metab. 2025 May 09. pii: S2212-8778(25)00073-0. [Epub ahead of print] 102166

Functional Regulation of Macrophages by Ces1d-Mediated Lipid Signaling in Immunometabolism.

Long J Shao, Fathima Elizondo, Feng Gao, Rabie Habib, Xin Li, Katherine Pham, Jazmin Ysaguirre, Maryam Elizondo, Shirindokht Shirazi, Kristin L Eckel-Mahan, Sean Hartig, Huaizhu Wu, Kai Sun.

OBJECTIVE: Macrophage accumulation in metabolically active tissues during obesity is common in both animals and humans, but the lipid signaling mechanisms that trigger macrophage inflammation remain unclear. This study investigates the role of Ces1d, an unconventional lipase, in regulating macrophage inflammation under nutritional stress.
METHODS: A myeloid-specific Ces1d knockout (LysM-Cre-Ces1d floxed/floxed, KO) mouse model was used for the studies. For in vitro tests, bone marrow-derived macrophages (BMDMs) from control (Ces1d floxed/floxed, WT) and KO mice were assessed for migration, polarization, and activation. For in vivo experiments, WT and KO mice were induced to obesity via a high-fat diet (HFD) and subjected to metabolic characterization. Adipose tissue, liver, and serum samples were analyzed histologically and biochemically. Endogenous macrophages and T cells from adipose tissue were isolated and analyzed for functional interactions by flow cytometry.
RESULTS: Ces1d expression changes during the differentiation of monocytes into macrophages in both mice and humans. Loss of Ces1d causes larger lipid droplets, with increased accumulation of triacylglycerol (TAG) and diacylglycerol (DAG), and impaired lipid signaling in KO macrophages. Lipid dysregulation in macrophages triggers pro-inflammatory activation, enhancing migration, activation, and polarization toward an M1-like phenotype. The pro-inflammatory macrophages further promote CD3+CD8+ T cell accumulation in obese adipose tissue, which contributes to worsened metabolic disorders, including more severe fatty liver, increased local inflammation in adipose tissue, and impaired systemic glucose tolerance in KO mice on a high-fat diet.
CONCLUSION: This study demonstrates Ces1d is a crucial factor in maintaining lipid homeostasis in macrophages. Loss of Ces1d leads to metabolic dysregulation in macrophages and other immune cells during obesity.

DOI: https://doi.org/10.1016/j.molmet.2025.102166
Nat Commun. 2025 May 15. 16(1): 4502

TIGIT deficiency promotes autoreactive CD4+ T-cell responses through a metabolic‒epigenetic mechanism in autoimmune myositis.

Yimei Lai, Shuang Wang, Tingting Ren, Jia Shi, Yichao Qian, Shuyi Wang, Mianjing Zhou, Ryu Watanabe, Mengyuan Li, Xinyuan Ruan, Xin Wang, Lili Zhuang, Zunfu Ke, Niansheng Yang, Yuefang Huang, Hui Zhang.

Polymyositis (PM) is a systemic autoimmune disease characterized by muscular inflammatory infiltrates and degeneration. T-cell immunoreceptor with Ig and ITIM domains (TIGIT) contributes to immune tolerance by inhibiting T cell-mediated autoimmunity. Here, we show that a reduced expression of TIGIT in CD4+ T cells from patients with PM promotes these cells' differentiation into Th1 and Th17 cells, which could be rescued by TIGIT overexpression. Knockout of TIGIT enhances muscle inflammation in a mouse model of experimental autoimmune myositis. Mechanistically, we find that TIGIT deficiency enhances CD28-mediated PI3K/AKT/mTOR co-stimulatory pathway, which promotes glucose oxidation, citrate production, and increased cytosolic acetyl-CoA levels, ultimately inducing epigenetic reprogramming via histone acetylation. Importantly, pharmacological inhibition of histone acetylation suppresses the differentiation of Th1 and Th17 cells, alleviating muscle inflammation. Thus, our findings reveal a mechanism by which TIGIT directly affects the differentiation of Th1 and Th17 T cells through metabolic‒epigenetic reprogramming, with important implications for treating systemic autoimmune diseases.

DOI: https://doi.org/10.1038/s41467-025-59786-z
Eur J Clin Invest. 2025 May 15. e70073

Mesenchymal stem cell-mediated mitochondrial transfer regulates the fate of B lymphocytes.

Veronika Somova, Natalie Jaborova, Bianka Porubska, Daniel Vasek, Natalie Fikarova, Martin Prevorovsky, Zuzana Nahacka, Jiri Neuzil, Magdalena Krulova.

   BACKGROUND: Mitochondrial transfer is becoming recognized as an important immunomodulatory mechanism used by mesenchymal stem cells (MSCs) to influence immune cells. While effects on T cells and macrophages have been documented, the influence on B cells remains unexplored. This study investigates the modulation of B lymphocyte fate by MSC-mediated mitochondrial transfer.
METHODS: MSCs labelled with MitoTracker dyes or derived from mito::mKate2 transgenic mice were co-cultured with splenocytes. Flow cytometry assessed mitochondrial transfer, reactive oxygen species (ROS) levels, apoptosis and mitophagy. Glucose uptake was measured using the 2-NBDG assay. RNA sequencing analysed gene expression changes in CD19+ mitochondria recipients and nonrecipients. Pathway analysis identified affected processes. In an LPS-induced inflammation model, mito::mKate2 MSCs were administered, and B cells from different organs were analysed for mitochondrial uptake and phenotypic changes. MSC-derived mitochondria were also isolated to confirm uptake by FACS-sorted CD19+ cells.
RESULTS: MSCs transferred mitochondria to CD19+ cells, though less than to other immune cells. Transfer correlated with ROS levels and mitophagy induction. Mitochondria were preferentially acquired by activated B cells, as indicated by increased CD69 expression and glycolytic activity. Bidirectional transfer occurred, with immune cells exchanging dysfunctional mitochondria for functional ones. CD19+ recipients exhibited increased viability, proliferation and altered gene expression, with upregulated cell division genes and downregulated antigen presentation genes. In vivo, mitochondrial acquisition reduced B cell activation and inflammatory cytokine production. Pre-sorted B cells also acquired isolated mitochondria, exhibiting a similar anti-inflammatory phenotype.
CONCLUSIONS: These findings highlight mitochondrial trafficking as a key MSC-immune cell interaction mechanism with immunomodulatory therapeutic potential.

Keywords:  B cell; immunoregulation; mesenchymal stem cell; metabolism; mitochondria

DOI:  https://doi.org/10.1111/eci.70073
Int J Mol Sci. 2025 Apr 26. pii: 4133. [Epub ahead of print]26(9):

Hypercapnia Increases Influenza A Virus Infection of Bronchial Epithelial Cells by Augmenting Cellular Cholesterol via mTOR and Akt.

Fei Chen, Aiko Matsuda, Peter H S Sporn, S Marina Casalino-Matsuda.

  Hypercapnia, the elevation of CO2 in blood and tissue, is a risk factor for mortality in patients with severe lung disease and pulmonary infections. We previously showed that hypercapnia increases viral replication and mortality in mice infected with influenza A virus (IAV). Elevated CO2 also augmented cholesterol content and pseudo-SARS-CoV-2 entry in bronchial epithelial cells. Interestingly, cellular cholesterol facilitates IAV uptake, replication, assembly, and egress from cells. Here, we report that hypercapnia increases viral protein expression in airway epithelium of mice infected with IAV. Elevated CO2 also enhanced IAV adhesion and internalization, viral protein expression, and viral replication in bronchial epithelial cells. Hypercapnia increased the expression and activation of the transcription factor sterol-regulatory element binding protein 2 (SREBP2), resulting in elevated expression of cholesterol synthesis enzymes, decreased expression of a cholesterol efflux transporter, and augmented cellular cholesterol. Moreover, reducing cellular cholesterol with an SREBP2 inhibitor or statins blocked hypercapnia-induced increases in viral adhesion and internalization, viral protein expression, and IAV replication. Inhibitors of mTOR and Akt also blocked the effect of hypercapnia on viral growth. Our findings suggest that targeting cholesterol synthesis and/or mTOR/Akt signaling may hold promise for reducing susceptibility to influenza infection in patients with advanced lung disease and hypercapnia.

Keywords:  Akt; cholesterol; hypercapnia; influenza A virus; mTOR

DOI:  https://doi.org/10.3390/ijms26094133
J Immunol. 2025 May 12. pii: vkaf078. [Epub ahead of print]

Mitoquinol improves phagocytosis and glycolysis in ethanol-exposed macrophages via HIF-1α-PFKP axis.

Bishnu D Pant, Akash Ahuja, Sanjoy Roychowdhury, Deepmala Shrestha, Emily Cross, Yuxin Wang, Christian Dwyer, Alexandra Paxitzis, Margaret Jeng, Sudhir Dudekonda, Rachel Scheraga, Vidula Vachharajani.

  Alcohol use disorder increases sepsis mortality. Acute ethanol exposure impairs pathogen clearance in the macrophages via dampened glycolysis and phagocytosis, exaggerates oxidative stress, and regulates the function of the hypoxia-regulating factor 1α (HIF-1α), a master regulator of glycolysis. Decreased expression of the platelet isoform of phosphofructokinase (PFKP), a key glycolytic enzyme, in ethanol-exposed macrophages, is reported. However, transcriptional regulation of PFKP with ethanol exposure is unclear. We hypothesized that acute ethanol exposure-induced oxidative stress dampens macrophage phagocytosis and glycolysis via the HIF-1α-PFKP axis. In ethanol-exposed mouse bone marrow-derived macrophages with lipopolysaccharide stimulation, we studied (i) reactive oxygen species (ROS), phagocytosis, glycolysis, PFKP, and HIF-1α expressions ± ethanol exposure; (ii) the role of HIF-1α in transcriptionally controlling PFKP messenger RNA by chromatin immunoprecipitation-quantitative polymerase chain reaction technique; and (iii) the effect of mitoquinol (MitoQ), a mitochondria-specific antioxidant, on HIF-1α function, glycolysis, phagocytosis, and pathogen clearance in ethanol-exposed macrophages. Last, we examined the effect of MitoQ on 7-d survival in alcohol vs. vehicle-drinking mice with cecal slurry-induced sepsis. In ethanol-exposed and lipopolysaccharide-stimulated macrophages, we found that (i) excessive total and mitochondrial ROS production and dampened phagocytosis, glycolysis, and PFKP expression; (ii) dysfunctional HIF-1α downregulates PFKP transcription; (iii) MitoQ restrains ROS production, restores HIF-1α function, and improves glycolysis and phagocytosis via preserved PFKP messenger RNA and protein expression; and (iv) MitoQ treatment improves survival and pathogen clearance in ethanol with sepsis mice. In conclusion, we found that the HIF-1α-PFKP axis regulates glycolysis and phagocytosis in ethanol-exposed macrophages and is a potential therapeutic target in ethanol with sepsis.

Keywords:  alcohol; macrophages; oxidative stress; phagocytosis; sepsis

DOI:  https://doi.org/10.1093/jimmun/vkaf078
Cell Rep. 2025 May 09. pii: S2211-1247(25)00465-6. [Epub ahead of print]44(5): 115694

IRE1α promotes phagosomal calcium flux to enhance macrophage fungicidal activity.

Michael J McFadden, Mack B Reynolds, Britton C Michmerhuizen, Einar B Ólafsson, Sofia M Marshall, Faith Anderson Davis, Tracey L Schultz, Takao Iwawaki, Jonathan Z Sexton, Mary X D O'Riordan, Teresa R O'Meara.

  The mammalian endoplasmic reticulum (ER) stress sensor inositol-requiring enzyme 1α (IRE1α) is essential for cellular homeostasis and plays key roles in infection responses, including innate immunity and microbicidal activity. While IRE1α functions through the IRE1α-XBP1S axis are known, its XBP1S-independent roles are less well understood, and its functions during fungal infection are still emerging. We demonstrate that Candida albicans activates macrophage IRE1α via C-type lectin receptor signaling independent of protein misfolding, suggesting non-canonical activation. IRE1α enhances macrophage fungicidal activity by promoting phagosome maturation, which is crucial for containing C. albicans hyphae. IRE1α facilitates early phagosomal calcium flux post-phagocytosis, which is required for phagolysosomal fusion. In macrophages lacking the IRE1α endoribonuclease domain, defective calcium flux correlates with fewer ER-early endosome contact sites, suggesting a homeostatic role for IRE1α-promoting membrane contact sites. Overall, our findings illustrate non-canonical IRE1α activation during infection and a function for IRE1α in supporting organelle contact sites to safeguard against rapidly growing microbes.

Keywords:  CP: Immunology; CP: Microbiology; Candida albicans; IRE1α; calcium; fungal infection; innate immunity; phagosome

DOI:  https://doi.org/10.1016/j.celrep.2025.115694
Proc Natl Acad Sci U S A. 2025 May 20. 122(20): e2418525122

Mitochondria regulate MR1 protein expression and produce self-metabolites that activate MR1-restricted T cells.

Gennaro Prota, Giuliano Berloffa, Wael Awad, Alessandro Vacchini, Andrew Chancellor, Verena Schaefer, Daniel Constantin, Dene R Littler, Rodrigo Colombo, Vladimir Nosi, Lucia Mori, Jamie Rossjohn, Gennaro De Libero.

  Mitochondria coordinate several metabolic pathways, producing metabolites that influence the immune response in various ways. It remains unclear whether mitochondria impact antigen presentation by the MHC-class-I-related antigen-presenting molecule, MR1, which presents small molecules to MR1-restricted T-lymphocytes. Here, we demonstrate that mitochondrial complex III and the enzyme dihydroorotate dehydrogenase are essential for the cell-surface expression of MR1 and for generating uridine- and thymidine-related compounds that bind to MR1 and are produced upon oxidation by reactive oxygen species. One mitochondria-derived immunogenic formylated metabolite we identified is 5-formyl-deoxyuridine (5-FdU). Structural studies indicate that 5-FdU binds in the A'-antigen-binding pocket of MR1, positioning the deoxyribose toward the surface of MR1 for TCR interaction. 5-FdU stimulates specific T cells and detects circulating T cells when loaded onto MR1-tetramers. 5-FdU-reactive cells resemble adaptive T cells and express the phenotypes of naïve, memory, and effector cells, indicating prior in vivo stimulation. These findings suggest that mitochondria may play a role in MR1-mediated immune surveillance.

Keywords:  MR1; T cells; antigen presentation; formylated metabolite; mitochondria

DOI:  https://doi.org/10.1073/pnas.2418525122
Cell Mol Gastroenterol Hepatol. 2025 May 09. pii: S2352-345X(25)00076-1. [Epub ahead of print] 101535

Lactate facilitates pancreatic repair following acute pancreatitis by promoting reparative macrophage polarization.

Jing Jiang, Ruiyan Wang, Pengli Song, Qi Peng, Xuerui Jin, Bin Li, Jianbo Ni, Jie Shen, Jingpiao Bao, Zengkai Wu, Xiaolu Ge, Xingpeng Wang, Guoyong Hu.

   BACKGROUND & AIMS: During acute pancreatitis (AP), glycolysis is enhanced. The upregulation of glycolysis increases the level of metabolite lactate. Lactate has been shown to facilitate tissue repair across various pathological conditions. However, its role in the recovery following AP remains unclear. This study aims to explore the role of lactate in the regenerative processes following AP and to elucidate its underlying molecular mechanisms.
METHODS: The caerulein-induced recovery AP model was established using wild type and 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 3 (Pfkfb3) heterozygous mice. Pancreatic repair was evaluated histologically, while lactate levels and inflammatory markers were measured serologically. Macrophages were isolated from pancreatic tissue using fluorescence-activated cell sorting for mRNA sequencing to identify phenotypes. In ex vivo, macrophages were indirectly co-cultured with inflammatory acinar, and the effect of lactate on macrophage phenotype were investigated through immunoprecipitation, fluorescence analysis, and western blotting.
RESULTS: We first found that exogenous lactate administration promoted pancreatic repair, while Pfkfb3 deficiency lowered lactate levels and ultimately delayed pancreatic repair. Mechanistically, lactate altered macrophage phenotype during recovery after AP, by reducing the proportion of pro-inflammatory macrophages and increasing the percentage of reparative macrophages. In the indirectly co-cultured macrophage, lactate increased lactylation levels and enhanced repair gene expression. Treatment with AZD3965, a chemical inhibitor of lactate transportation, blocked the effects on lactylation and gene expression. Besides, lactate repressed the JAK2-STAT1 pathway via GPR132 receptor, thereby suppressing the expression of pro-inflammatory genes.
CONCLUSIONS: Lactate facilitates pancreatic repair by promoting reparative macrophage polarization, achieved through promoting lactylation and inhibiting JAK2-STAT1 signaling. This phenotypic shift alleviates inflammation and facilitates tissue recovery, highlighting a potential therapeutic approach for AP.

Keywords:  lactate; lactylation; macrophage; pancreatic repair

DOI:  https://doi.org/10.1016/j.jcmgh.2025.101535
Nat Commun. 2025 May 13. 16(1): 4414

ATP functions as a pathogen-associated molecular pattern to activate the E3 ubiquitin ligase RNF213.

Juraj Ahel, Arda Balci, Victoria Faas, Daniel B Grabarczyk, Roosa Harmo, Daniel R Squair, Jiazhen Zhang, Elisabeth Roitinger, Frederic Lamoliatte, Sunil Mathur, Luiza Deszcz, Lillie E Bell, Anita Lehner, Thomas L Williams, Hanna Sowar, Anton Meinhart, Nicola T Wood, Tim Clausen, Satpal Virdee, Adam J Fletcher.

The giant E3 ubiquitin ligase RNF213 is a conserved component of mammalian cell-autonomous immunity, limiting the replication of bacteria, viruses and parasites. To understand how RNF213 reacts to these unrelated pathogens, we employ chemical and structural biology to find that ATP binding to its ATPases Associated with diverse cellular Activities (AAA) core activates its E3 function. We develop methodology for proteome-wide E3 activity profiling inside living cells, revealing that RNF213 undergoes a reversible switch in E3 activity in response to cellular ATP abundance. Interferon stimulation of macrophages raises intracellular ATP levels and primes RNF213 E3 activity, while glycolysis inhibition depletes ATP and downregulates E3 activity. These data imply that ATP bears hallmarks of a danger/pathogen associated molecular pattern, coordinating cell-autonomous defence. Furthermore, quantitative labelling of RNF213 with E3-activity probes enabled us to identify the catalytic cysteine required for substrate ubiquitination and obtain a cryo-EM structure of the RNF213-E2-ubiquitin conjugation enzyme transfer intermediate, illuminating an unannotated E2 docking site. Together, our data demonstrate that RNF213 represents a new class of ATP-dependent E3 enzyme, employing distinct catalytic and regulatory mechanisms adapted to its specialised role in the broad defence against intracellular pathogens.

DOI: https://doi.org/10.1038/s41467-025-59444-4
Nat Immunol. 2025 May 12.

Inhibition of ENT1 relieves intracellular adenosine-mediated T cell suppression in cancer.

Theodore J Sanders, Christopher S Nabel, Margreet Brouwer, Annelise L Hermant, Lucas Chaible, Jean-Philippe Deglasse, Nicolas Rosewick, Angélique Pabois, Wilfried Cathou, Aurore Smets, Michael Deligny, João Marchante, Quentin Dubray, Marie-Claire Letellier, Chiara Martinoli, Reece Marillier, Olivier De Henau, Yvonne McGrath, Matthew G Vander Heiden, Erica Houthuys.

The benefit of immune checkpoint blockade for cancer therapy is limited to subsets of patients because of factors including the accumulation of immunosuppressive metabolites, such as adenosine, within tumors. Pharmacological inhibition of adenosine generation and signaling is an active area of clinical investigation, but only limited clinical benefit has been reported. Here, we show that adenosine suppresses anti-cancer T cell responses following uptake into activated T cells by equilibrative nucleoside transporter 1 (ENT1) and inhibition of de novo pyrimidine nucleotide synthesis. We identify EOS301984 as a potent ENT1 antagonist that restores pyrimidine levels in activated T cells in adenosine-rich environments, resulting in enhanced tumor cell killing by memory T cells and increased ex vivo expansion of functional human tumor-infiltrating lymphocytes. A combination of EOS301984 with anti-PD-1 led to synergistic control of tumor growth in a humanized mouse model of triple-negative breast cancer. ENT1 inhibition, therefore, augments anti-cancer immune responses through the restoration of pyrimidine nucleotide synthesis in T cells suppressed by adenosine.

DOI: https://doi.org/10.1038/s41590-025-02153-3
Immunity. 2025 May 09. pii: S1074-7613(25)00179-7. [Epub ahead of print]

Pre-existing epigenetic state and differential NF-κB activation shape type 2 immune cell responses.

Vincent Guichard, Felipe Batista Leão, Jingyao Zhao, Yingyu Zhang, Takamasa Ito, Simon Shirley, Thomas S Postler, Ruxiao Tian, Yuefeng Huang, Sankar Ghosh.

  CD4+ T helper 2 (Th2) cells and group 2 innate lymphoid cells (ILC2s) drive type 2 immune responses via similar effector molecules that are primarily induced by different signals-interleukin (IL)-33 in ILC2s and TCR engagement in Th2 cells. Here, we examined the transcriptional regulation of type 2 immunity, focusing on the NF-κB pathway, which is differentially activated by TCR engagement or cytokine signaling. Conditional deletion of the NF-κB subunits c-Rel and p65 limited the expression of key type 2 genes, including Il13 and Il5, in ILC2s but not in Th2 cells. Genome-wide analysis revealed that the regulatory regions of such genes exist in an open chromatin state in ILC2s, allowing NF-κB binding upon IL-33 stimulation. These regions are less accessible in unstimulated Th2 cells, where NFAT plays a dominant role. Accordingly, p65 deletion impaired ILC2 activation and function during airway inflammation and helminth infection. Thus, innate and adaptive lymphocytes leverage distinct epigenetic landscapes and transcriptional regulators to control shared effector genes.

Keywords:  ILC2; Il-13; Il-33; Il-4; Il-5; NF-κB; Th2; c-rel; p65; type 2 cytokines

DOI:  https://doi.org/10.1016/j.immuni.2025.04.016
J Nutr Biochem. 2025 May 09. pii: S0955-2863(25)00121-4. [Epub ahead of print] 109958

Circulating inflammatory markers linked to dysregulated postprandial metabolism in postmenopausal women.

Carlos M Donado-Pestana, Amanda D Vasconcelos, Vinicius B Mantovam, Gustavo C de Lima, Larissa Rodrigues, Hermes V Barbeiro, Ricardo Fock, Heraldo P de Souza, Bernadette D G de M Franco, Jarlei Fiamoncini.

  Menopause induces physiological alterations predisposing women to the development of chronic diseases. The evaluation of postprandial responses allows for a comprehensive assessment of metabolism and biomarkers that may predispose to chronic disease risk. By applying a dietary challenge consisting of the ingestion of a liquid, energy-dense mixed meal, followed by blood sampling over a 6-hour period, we conducted a cross-sectional study to investigate the postprandial metabolism in postmenopausal women (PM) aged 50-70 years and women of reproductive age (RA) aged 20 and 40 years. PM body weight was only 10% higher than RA, but the first displayed twice as much (more than 20%) intrabdominal adipose tissue. PM also displayed elevated fasting and postprandial glycemia (∼20%) and lipidemia compared to RA. Differences were also observed in the postprandial levels of lactate. Both groups displayed a similar increase in white blood cell count during the challenge, despite large differences in peripheral blood mononuclear cells (PBMC) gene expression in both fasting and postprandial states, suggesting a pro-inflammatory state and HIF-α and glycolytic pathway activation in PM. Plasma levels of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-alpha (TNF-α) were increased in PM (37 and 52%, respectively). Postprandial plasma levels of incretins presented different kinetics to each group. Our findings reveal that PM display a pro-inflammatory signature and markers of metabolic deterioration after a 12-hour fasting and in the postprandial period when compared to RA.

Keywords:  aging; immunometabolism; insulin resistance; menopause

DOI:  https://doi.org/10.1016/j.jnutbio.2025.109958
J Leukoc Biol. 2025 May 14. pii: qiaf061. [Epub ahead of print]

Fever-range temperature alters continual efferocytosis mediated by mouse pro-inflammatory macrophages.

Mathieu Vetter, Melissa Maraux, Francis Bonnefoy, Ludivine Dal Zuffo, Baptiste Lamarthée, Gwenaël Rolin, Audrey Wetzel, Sylvain Perruche, Paul Peixoto, Philippe Saas.

  Fever, a cardinal sign of inflammation, has been shown to modulate macrophage functions. Here, we investigate whether fever affects macrophage efferocytosis. This process is essential for the resolution of inflammation and the return to homeostasis with the reprogramming of macrophages towards a pro-resolving phenotype. Using primary mouse bone marrow-derived macrophages stimulated with lipopolysaccharide and interferon-γ (i.e., pro-inflammatory macrophages), we first validated that exposure to febrile temperature (39.5°C) induced a heat shock protein response. Then, we observed that febrile temperature decreased the capacity of pro-inflammatory macrophages to uptake apoptotic cells. This reduced efferocytic capacity of macrophages exposed to febrile temperature resulted from a decreased capacity to interact with apoptotic cells and to internalize these dying cells. Exposure to febrile temperature reduced the cell motility of macrophages in response to apoptotic cells, as assessed by IncuCyte® live-cell imaging. RNA sequencing analysis of pro-inflammatory macrophages exposed to febrile temperature identified an upregulation of the Adam17 gene. As this gene encodes a protease that sheds the efferocytic receptor Mer, we determined cell surface expression of Mer and quantified soluble Mer in the culture supernatants of pro-inflammatory macrophages exposed to febrile temperature. While febrile hyperthermia induced the Mer cleavage from the cell surface of pro-inflammatory macrophages, ADAM17 inhibition during exposure to febrile temperature did not restore the efferocytic capacity of pro-inflammatory macrophages. Thus, reduction of Mer expression induced by hyperthermia did not represent the main mechanism explaining reduced efferocytosis. Nevertheless, our work suggests that fever, by decreasing efferocytic capacity of macrophages, maintains their pro-inflammatory state.

Keywords:  Efferocytosis; apoptotic cells; fever; inflammation; macrophage

DOI:  https://doi.org/10.1093/jleuko/qiaf061
Cell Death Discov. 2025 May 15. 11(1): 236

NRF1 coordinates mitochondrial adaptations to dampen intracellular ROS and inflammatory responses during ischemia reperfusion.

Jiakun Li, Jiawei Yan, Guowei Tu, Wenjiao Jiang, Yue Qiu, Ying Su, Changhong Miao, Zhe Luo, Tiffany Horng.

Ischemia reperfusion injury (IRI) is commonly seen in surgical procedures involving cardiopulmonary bypass and post-shock reperfusion. Sudden restoration of blood flow after a period of ischemia triggers a rapid accumulation of reactive oxygen species (ROS) and oxidative stress that promote pathological injury. Macrophage-derived inflammatory responses are also thought to contribute to such injury, but how ROS influences tissue macrophages and their elaboration of inflammatory cytokines in IRI remains poorly understood. In this study, we showed that macrophages mobilize mitochondrial adaptations during reoxygenation, including mitochondrial fission and ubiquitin proteasome system (UPS) flux. Furthermore, the transcription factor Nuclear Factor Erythroid 2 Like 1 (NRF1) is rapidly induced during reoxygenation in response to rising levels of ROS. Induction of NRF1 upregulates ubiquitin proteasome system (UPS) and mitophagy pathways to mediate mitochondrial fusion/fission dynamics and dampen ROS production, allowing for alleviation of oxidative stress and the inflammatory response. Conversely, the absence of myeloid NRF1 leads to increased ROS, driving enhanced inflammation and kidney injury in a mouse model of IRI. We thus identify macrophage NRF1 as a master regulator of mitochondrial homeostasis, antioxidant defense, and inflammatory responses in IRI.

DOI: https://doi.org/10.1038/s41420-025-02461-5