bims-imicid 2025-03-09 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2025–03–09
38 papers selected by
Dylan Ryan, University of Cambridge

Decreased Complex I Activity in Blood lymphocytes Correlates with Idiopathic Pulmonary Fibrosis Severity.
Macrophage peroxisomes guide alveolar regeneration and limit SARS-CoV-2 tissue sequelae.
Asparagine deprivation enhances T cell antitumour response in patients via ROS-mediated metabolic and signal adaptations.
Disruption of tryptophan metabolism by high-fat diet-triggered maternal immune activation promotes social behavioral deficits in male mice.
Pathogen-derived glyoxylate inhibits Tet2 DNA dioxygenase to facilitate bacterial persister formation.
SIRT3 deficiency reduces PFKFB3-driven T-cell glycolysis and promotes arthritic inflammation.
The immunometabolic topography of tuberculosis granulomas governs cellular organization and bacterial control.
NAD+ modulation of intestinal macrophages renders anti-inflammatory functionality and ameliorates gut inflammation.
Mitochondria sense bacterial lactate and drive release of neutrophil extracellular traps.
Macrophage-Derived Itaconate Suppresses Dendritic Cell Function to Promote Acquired Resistance to Anti-PD-1 Immunotherapy.
Immunometabolite L-2-HG promotes epigenetic modification of exhausted T cells and improves anti-tumor immunity.
Trained immunity causes myeloid cell hypercoagulability.
Impact of zinc on immunometabolism and its putative role on respiratory diseases.
Citrulline regulates macrophage metabolism and inflammation to counter aging in mice.
Oxidative phosphorylation is a key feature of neonatal monocyte immunometabolism promoting myeloid differentiation after birth.
24-Nor-ursodeoxycholic acid improves intestinal inflammation by targeting TH17 pathogenicity and transdifferentiation.
Neonatal fungi promote lifelong metabolic health through macrophage-dependent β cell development.
Lactate accumulation from HIF-1α-mediated PMN-MDSC glycolysis restricts brain injury after acute hypoxia in neonates.
Bile acid receptor FXR promotes intestinal epithelial ferroptosis and subsequent ILC3 dysfunction in neonatal necrotizing enterocolitis.
Microneedles Loaded with Nitric-Oxide Driven Nanomotors Improve Force-Induced Efferocytosis Impairment and Sterile Inflammation by Revitalizing Macrophage Energy Metabolism.
ACSS2 drives senescence-associated secretory phenotype by limiting purine biosynthesis through PAICS acetylation.
Interleukins-27 Aggravates Liver Injury by Impairing the Antimicrobial Response of Macrophages via the Promotion of Mitochondrial Dysfunction in the Context of Sepsis.
Synergistic metabolic modulation of fibroblast-like synoviocytes via targeted dual prodrug nanoparticles to mitigate rheumatoid arthritis.
Epstein-Barr virus infection exacerbates ulcerative colitis by driving macrophage pyroptosis via the upregulation of glycolysis.
Metabolic Reprogramming in Primary Microglial Cell and Extracellular Vesicle Triggered by Aβ Exposure.
iMetAct: An integrated systematic inference of metabolic activity for dissecting tumor metabolic preference and tumor-immune microenvironment.
Matrix Viscoelasticity Orchestrates Osteogenesis via Mechanotransduction Mediated Metabolic Switch in Macrophages.
Dietary oxidized lipids in redox biology: Oxidized olive oil disrupts lipid metabolism and induces intestinal and hepatic inflammation in C57BL/6J mice.
The polyamine-regulating enzyme SSAT1 impairs tissue regulatory T cell function in chronic cutaneous inflammation.
Metabolic crosstalk between the mitochondrion and the nucleus is essential for Toxoplasma gondii infection.
Isocyanic acid-mediated NLRP3 carbamoylation reduces NLRP3-NEK7 interaction and limits inflammasome activation.
Intracellular accumulation of free cholesterol in macrophages triggers a PARP1 response to DNA damage and PARP1 impairs lipopolysaccharide-induced inflammatory response.
Metabolic engineering to facilitate anti-tumor immunity.
Immunometabolism of tumor-associated macrophages: A therapeutic perspective.
Targeting the PDK/PDH axis modulates neutrophil and smooth muscle cell pathological responses and prevents abdominal aortic aneurysm formation.
Sodium butyrate alleviates colitis by inhibiting mitochondrial ROS mediated macrophage pyroptosis.
Discovery of A Novel Regulator, 3β-Sulfate-5-Cholestenoic Acid, of Lipid Metabolism and Inflammation.
Acute hypoxia modulate macrophage phenotype accompanied with transcriptome re-programming and metabolic re-modeling.

Biochem Genet. 2025 Mar 04.

Decreased Complex I Activity in Blood lymphocytes Correlates with Idiopathic Pulmonary Fibrosis Severity.

Emily Zifa, Sotirios Sinis, Anna-Maria Psarra, Andreas Mouikis, Aglaia Pozantzi, Konstantina Rossi, Foteini Malli, Ilias Dimeas, Paraskevi Kirgou, Konstantinos Gourgoulianis, Ourania S Kotsiou, Zoe Daniil.

  Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease linked to aging. Mitochondrial dysfunction in circulating T cells, often caused by disruption of mitochondrial DNA (mtDNA), may play a role in age-related conditions like IPF. In our previous study, we found high mtDNA mutational loads in blood lymphocytes from IPF patients, especially in regions critical for mtDNA expression. Since Complex I of the electron transport chain, partly encoded by mtDNA, is essential for energy production, we conducted a preliminary study on its activity. We found significantly reduced Complex I activity (p < 0.001) in lymphocytes from 40 IPF patients compared to 40 controls, which was positively correlated with lung function decline, specifically in functional vital capacity and diffusing capacity for carbon monoxide. These findings indicate that T cell mitochondrial dysfunction is associated with disease progression in IPF. Future work will explore the mechanisms linking T cell mitochondrial disruption with fibrosis, potentially uncovering new therapeutic targets.

Keywords:  Complex I Activity; Fibrosis; Idiopathic Pulmonary Fibrosis (IPF); Mitochondrial Dysfunction; T Cell Immunometabolism

DOI:  https://doi.org/10.1007/s10528-025-11071-w
Science. 2025 Mar 07. 387(6738): eadq2509

Macrophage peroxisomes guide alveolar regeneration and limit SARS-CoV-2 tissue sequelae.

Xiaoqin Wei, Wei Qian, Harish Narasimhan, Ting Chan, Xue Liu, Mohd Arish, Samuel Young, Chaofan Li, In Su Cheon, Qing Yu, Gislane Almeida-Santos, Xiao-Yu Zhao, Eric V Yeatts, Olivia J Spear, Megan Yi, Tanyalak Parimon, Yinshan Fang, Young S Hahn, Timothy N J Bullock, Lindsay A Somerville, Mark H Kaplan, Anne I Sperling, Yun Michael Shim, Robert Vassallo, Peter Chen, Sarah E Ewald, Anja C Roden, Jianwen Que, Dianhua Jiang, Jie Sun.

Peroxisomes are vital but often overlooked metabolic organelles. We found that excessive interferon signaling remodeled macrophage peroxisomes. This loss of peroxisomes impaired inflammation resolution and lung repair during severe respiratory viral infections. Peroxisomes were found to modulate lipid metabolism and mitochondrial health in a macrophage type-specific manner and enhanced alveolar macrophage-mediated tissue repair and alveolar regeneration after viral infection. Peroxisomes also prevented excessive macrophage inflammasome activation and IL-1β release, limiting accumulation of KRT8high dysplastic epithelial progenitors following viral injury. Pharmacologically enhancing peroxisome biogenesis mitigated both acute symptoms and post-acute sequelae of COVID-19 (PASC) in animal models. Thus, macrophage peroxisome dysfunction contributes to chronic lung pathology and fibrosis after severe acute respiratory syndrome coronavirus 2 infection.

DOI: https://doi.org/10.1126/science.adq2509
Nat Metab. 2025 Mar 05.

Asparagine deprivation enhances T cell antitumour response in patients via ROS-mediated metabolic and signal adaptations.

Hsuan-Chia Chang, Chung-Ying Tsai, Cheng-Lung Hsu, Tzong-Shyuan Tai, Mei-Ling Cheng, Yu-Ming Chuang, Hsiang-Yu Tang, Kun-Ju Lin, Jia-Jin Chen, Szu-Han Chang, Yi-Ching Ko, Yu-Wen Chi, Hsuan Liu, Bertrand Chin-Ming Tan, Chia-Rui Shen, Chih-Wei Yang, Ping-Chih Ho, Huang-Yu Yang.

Preclinical studies have shown that asparagine deprivation enhances T cell antitumour responses. Here we apply compassionate use of L-asparaginase, usually employed to treat blood malignancies, on patients with recurrent metastatic nasopharyngeal carcinoma. The use of L-asparaginase notably enhances immune-checkpoint blockade therapy in patients by strengthening CD8+T cell fitness. Our study shows that this combination is a promising avenue for clinical application and provides further mechanistic insight into how asparagine restriction rewires T cell metabolism.

DOI: https://doi.org/10.1038/s42255-025-01245-6
Nat Commun. 2025 Mar 02. 16(1): 2105

Disruption of tryptophan metabolism by high-fat diet-triggered maternal immune activation promotes social behavioral deficits in male mice.

Penghao Sun, Mengli Wang, Xuejun Chai, Yong-Xin Liu, Luqi Li, Wei Zheng, Shulin Chen, Xiaoyan Zhu, Shanting Zhao.

Diet-related maternal obesity has been implicated in neurodevelopmental disorders in progeny. Although the precise mechanisms and effective interventions remain uncertain, our research elucidates some of these complexities. We established that a prenatal high-fat diet triggered maternal immune activation (MIA), marked by elevated serum lipopolysaccharide levels and inflammatory-cytokine overproduction, which dysregulated the maternal tryptophan metabolism promoting the accumulation of neurotoxic kynurenine metabolites in the embryonic brain. Interventions aimed at mitigating MIA or blocking the kynurenine pathway effectively rescued the male mice social performance. Furthermore, excessive kynurenine metabolites initiated oxidative stress response causing neuronal migration deficits in the fetal neocortex, an effect that was mitigated by administering the glutathione synthesis precursor N-Acetylcysteine, underscoring the central role of maternal immune-metabolic homeostasis in male mice behavioral outcomes. Collectively, our study accentuated the profound influence of maternal diet-induced immuno-metabolic dysregulation on fetal brain development and provided the preventive strategies for addressing neurodevelopmental disorders.

DOI: https://doi.org/10.1038/s41467-025-57414-4
Cell Metab. 2025 Feb 26. pii: S1550-4131(25)00020-8. [Epub ahead of print]

Pathogen-derived glyoxylate inhibits Tet2 DNA dioxygenase to facilitate bacterial persister formation.

Zhou-Li Cheng, Shuyuan Zhang, Zhenning Wang, Aixia Song, Chao Gao, Jun-Bin Song, Pu Wang, Lei Zhang, Yue Zhou, Wenyan Shan, Chen Zhang, Jinye Zhang, Yiping Sun, Yanhui Xu, Fei Lan, Ming Zhong, Liang-Dong Lyu, Guanghua Huang, Fei Xavier Chen, Gang Li, Zixin Wang, Faying Chen, Jianhuang Xue, Jiejun Shi, Yujun Liu, Zihao Lin, Duojiao Wu, Jim Na, Lei-Lei Chen, Kun-Liang Guan, Yue Xiong, Dan Ye.

  Pathogenic bacterial persistence enables survival during antibiotic treatment, leading to treatment failure and recurrent infections, yet its underlying mechanisms remain unclear. Here, we reveal that glyoxylate, a metabolite originally evolved for alternative carbon utilization, functions as a signaling molecule to reprogram the host transcriptome and promote persister formation. Glyoxylate inhibits the DNA dioxygenase TET2, suppressing pro-inflammatory gene expression and attenuating host immune defense. Notably, stimulating TET2 activity with vitamin C or blocking glyoxylate production by Salmonella reduces bacterial antibiotic resistance and improves infection treatment outcomes. Beyond its metabolic role, glyoxylate emerges as a regulator of host-pathogen interactions, while TET2 plays a critical role in preventing bacterial persistence. Our findings suggest that targeting glyoxylate production or enhancing TET2 activity offers promising therapeutic strategies to combat bacterial persistence and enhance the efficacy of antibiotic treatments.

Keywords:  Tet2 DNA dioxygenase; glyoxylate; pathogenic bacterial; persister formation

DOI:  https://doi.org/10.1016/j.cmet.2025.01.019
Sci China Life Sci. 2025 Feb 27.

SIRT3 deficiency reduces PFKFB3-driven T-cell glycolysis and promotes arthritic inflammation.

Ting-Ting Wang, Taotao Han, Xinyue Xiao, Dan Guo, Xin Sun, Yudong Liu, Lidan Zhao, Haojie Xu, Rong Li, Lingjuan Jiang, Bo Zhang, Beidi Chen, Shengru Wang, Han Wang, Xiaoxi Wang, Miao Zhang, Sumei Zhang, Jian Wang, Jiahua Qu, Hou-Zao Chen, De-Pei Liu, Xuan Zhang, Min Wang.

  Cell metabolism is an indispensable biochemical process that provides the basic energy and materials necessary for normal cell function. Accumulating evidence implicates abnormal metabolism of T cells as playing a critical role in the pathogenesis of rheumatoid arthritis (RA). The deacetylase SIRT3 has been shown to directly regulate energy metabolism in nonimmune cells. However, the role of SIRT3 in T cells and whether it participates in RA process remain unclear. In this study, we demonstrated that T-cell glycolysis was inhibited after SIRT3 deficiency. Compared to wild-type mice, SIRT3 knockout mice exhibited more severe arthritis, cartilage erosion, and inflammation after immunization with antigen-induced arthritis (AIA). It is interesting to note that SIRT3 deficiency reduced the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), a regulatory and rate-limiting enzyme in glycolysis. Overexpression of PFKFB3 was shown to restore the impaired ATP production caused by SIRT3 deficiency in T cells, and protects T cells from apoptosis. In summary, SIRT3 plays an important role in the regulation of T-cell metabolism in the pathogenesis of RA. SIRT3 deficiency decreases glycolysis, reduces ATP production, induces apoptosis in CD4+ T cells, and further promotes AIA in mice.

Keywords:  SIRT3; T cells; metabolism; rheumatoid arthritis

DOI:  https://doi.org/10.1007/s11427-024-2823-2
bioRxiv. 2025 Feb 23. pii: 2025.02.18.638923. [Epub ahead of print]

The immunometabolic topography of tuberculosis granulomas governs cellular organization and bacterial control.

Erin F McCaffrey, Alea C Delmastro, Isobel Fitzhugh, Jolene S Ranek, Sarah Douglas, Joshua M Peters, Christine Camacho Fullaway, Marc Bosse, Candace C Liu, Craig Gillen, Noah F Greenwald, Sarah Anzick, Craig Martens, Seth Winfree, Yunhao Bai, Cameron Sowers, Mako Goldston, Alex Kong, Potchara Boonrat, Carolyn L Bigbee, Roopa Venugopalan, Pauline Maiello, Edwin Klein, Mark A Rodgers, Charles A Scanga, Philana Ling Lin, Denise Kirschner, Sarah Fortune, Bryan D Bryson, J Russell Butler, Joshua T Mattila, JoAnne L Flynn, Michael Angelo.

Despite being heavily infiltrated by immune cells, tuberculosis (TB) granulomas often subvert the host response to Mycobacterium tuberculosis (Mtb) infection and support bacterial persistence. We previously discovered that human TB granulomas are enriched for immunosuppressive factors typically associated with tumor-immune evasion, raising the intriguing possibility that they promote tolerance to infection. In this study, our goal was to identify the prime drivers for establishing this tolerogenic niche and to determine if the magnitude of this response correlates with bacterial persistence. To do this, we conducted a multimodal spatial analysis of 52 granulomas from 16 non-human primates (NHP) who were infected with low dose Mtb for 9-12 weeks. Notably, each granuloma's bacterial burden was individually quantified allowing us to directly ask how granuloma spatial structure and function relate to infection control. We found that a universal feature of TB granulomas was partitioning of the myeloid core into two distinct metabolic environments, one of which is hypoxic. This hypoxic environment associated with pathologic immune cell states, dysfunctional cellular organization of the granuloma, and a near-complete blockade of lymphocyte infiltration that would be required for a successful host response. The extent of these hypoxia-associated features correlated with worsened bacterial burden. We conclude that hypoxia governs immune cell state and organization within granulomas and is a potent driver of subverted immunity during TB.

DOI: https://doi.org/10.1101/2025.02.18.638923
Biomed Pharmacother. 2025 Feb 28. pii: S0753-3322(25)00132-5. [Epub ahead of print]185 117938

NAD+ modulation of intestinal macrophages renders anti-inflammatory functionality and ameliorates gut inflammation.

Young-In Kim, Inseok Ko, Eun-Je Yi, Jusik Kim, Yong Rae Hong, Wheeseong Lee, Sun-Young Chang.

  Macrophages can maintain gut immune homeostasis by driving clearance of infection, but also can prevent chronic inflammation and induce tissue repair. Reduced nicotinamide adenine dinucleotide (NAD+) levels in macrophages have been reported to be associated with the onset of severe colitis. Given that dysregulation of gut macrophages plays a significant role in inflammatory bowel disease (IBD), they represent a potential target for novel therapies. Here we show an IBD therapeutic candidate LMT503, a substrate that modulates NADH quinone oxidoreductase (NQO1), which induces anti-inflammatory macrophage polarization by NAD+ enhancement. To determine the anti-inflammatory effect of LMT503, a dextran sulfate sodium (DSS)-induced colitis mouse model was used in this study. Treatment of bone marrow-derived macrophages (BMDMs) with LMT503 increased IL-10 and Arg1 levels but decreased levels of TNF-α, iNOS, and IL-6. LMT503 also increased levels of SIRT1, SIRT3, and SIRT6, suggesting that macrophages were driven to an anti-inflammatory character. In a murine DSS-induced colitis model, oral treatment with LMT503 ameliorated colonic inflammation and decreased infiltrating monocytes and neutrophils. Although NAD+ enhancement did not alter CX3CR1intCD206- or CX3CR1hiCD206+ colon macrophage population, it decreased levels of TNF-α and iNOS and increased IL-10 level, with colonic macrophages showing an anti-inflammatory character shift. Depletion of CX3CR1 expressing gut resident macrophages abrogated the immune regulatory effect of LMT503 in the colon. These data suggest that LMT503 is a therapeutic candidate that can target macrophages to drive polarization with an immunosuppressive character and ameliorate IBD.

Keywords:  Colon; Gut macrophage; Inflammatory bowel disease; Macrophage polarization; NAD(+) modulation

DOI:  https://doi.org/10.1016/j.biopha.2025.117938
Cell Host Microbe. 2025 Feb 20. pii: S1931-3128(25)00051-4. [Epub ahead of print]

Mitochondria sense bacterial lactate and drive release of neutrophil extracellular traps.

Ashley D Wise, Eden G TenBarge, Jessica D C Mendonça, Ellie C Mennen, Sarah R McDaniel, Callista P Reber, Bailey E Holder, Madison L Bunch, Eva Belevska, Madalyn G Marshall, Nicole M Vaccaro, Christian R Blakely, Dinesh H Wellawa, Jennifer Ferris, Jessica R Sheldon, Jeffry D Bieber, Jeremiah G Johnson, Lindsey R Burcham, Andrew J Monteith.

  Neutrophils induce oxidative stress, creating a harsh phagosomal environment. However, Staphylococcus aureus can survive these conditions, requiring neutrophils to deploy mechanisms that sense bacterial persistence. We find that staphylococcal lactate is a metabolic danger signal that triggers neutrophil extracellular trap release (NETosis). Neutrophils coordinate mitochondria in proximity to S. aureus-containing phagosomes, allowing transfer of staphylococcal lactate to mitochondria where it is rapidly converted into pyruvate and causes mitochondrial reactive oxygen species, a precursor to NETosis. Similar results were observed in response to phylogenetically distinct bacteria, implicating lactate accumulation as a broad signal triggering NETosis. Furthermore, patients with systemic lupus erythematosus (SLE) are more susceptible to bacterial infections. We find that SLE neutrophils cannot sense bacterial lactate impairing their capacity to undergo NETosis upon S. aureus infection but initiate aberrant NETosis triggered by apoptotic debris. Thus, neutrophils adapt mitochondria as sensory organelles that detect bacterial metabolic activity and dictate downstream antibacterial processes.

Keywords:  NETosis; Staphylococcus aureus; lactate; lactate dehydrogenase; mitochondria; neutrophil extracellular traps; neutrophils; phagosome; reverse electron trasport; systemic lupus erythematosus

DOI:  https://doi.org/10.1016/j.chom.2025.02.003
Cancer Res. 2025 Mar 04.

Macrophage-Derived Itaconate Suppresses Dendritic Cell Function to Promote Acquired Resistance to Anti-PD-1 Immunotherapy.

Xiao Yang, Yue Deng, Ying Ye, Jingshu Meng, Mengyao Su, Wenwen Wei, You Qin, Haibo Zhang, Yu Tian, Suke Deng, Zhiyun Liao, Zhiyuan Zhou, Jie Li, Yan Hu, Bin Zhang, Yajie Sun, Lu Wen, Zhanjie Zhang, Fang Huang, Chao Wan, Kunyu Yang.

Adaptive resistance to immunotherapy remains a significant challenge in cancer treatment. The reshaping of the tumor immune microenvironment in response to therapeutic pressures is a crucial factor contributing to this resistance. Here, by comprehensive metabolic profiling of tumor tissues, we identified elevated itaconate in response to anti-PD-1 therapy as an adaptive resistance mechanism that promoted immune escape and tumor progression. CD8+ T-cell-derived interferon (IFN)-γ induced a significant upregulation of cis-aconitate decarboxylase 1 (ACOD1) in macrophages via the JAK-STAT1 pathway, thereby rewiring the Krebs cycle toward itaconate production. In murine models, macrophage-specific deletion of Acod1 increased the anti-tumor efficacy of anti-PD-1 therapy and improved survival. Additionally, itaconate and its derivative, 4-octyl itaconate (4-OI), suppressed the tumor antigen presentation and cross-priming ability of dendritic cells (DCs), resulting in the impairment of antigen-specific T-cell anti-tumor responses. In summary, these findings identify an IFN-γ-dependent immunometabolic mechanism of anti-PD-1 resistance, providing a promising strategy for combination therapy.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-2982
JCI Insight. 2025 Mar 04. pii: e174600. [Epub ahead of print]

Immunometabolite L-2-HG promotes epigenetic modification of exhausted T cells and improves anti-tumor immunity.

Yanying Yang, Xiaoyan Li, Fangming Liu, Mingyue Ma, Ying Yang, Chengchao Ruan, Yan Lu, Xiaoyang Li, Xiangdong Wang, Yinghong Shi, Zheng Zhang, Hua Wang, Zhouli Cheng, Duojiao Wu.

  This study aimed to explore the potential correlation between the metabolic intermediate L-2-hydroxyglutarate (L-2-HG) and T cell exhaustion, as well as the underlying mechanisms involved. In this study, we investigated the presence of exhausted T cells (Tex) in patients under certain conditions: HIV infection, chronic leukemia, and hepatocellular carcinoma. To gain insights into the epigenetic signatures and transcriptome alterations in Tex, we employed a combination of RNA-seq and ATAC-seq analyses. To evaluate the impact of L-2-HG on mitochondrial function, differentiation, and anti-tumor capacity of Tex, we utilized in vitro cell culture experiments and animal tumor models. We observed mitochondrial depolarization and metabolic dysfunction in Tex, accompanied by a significant reduction in the metabolic intermediate L-2-HG level. Moreover, altered epigenetic characteristics was observed in Tex, including a substantial increase in H3K27me3 abundance. Culturing Tex with L-2-HG demonstrated improved mitochondrial metabolism, reduced H3K27me3 abundance, and enhanced memory T cell differentiation. In the mouse melanoma tumor model, L-2-HG-treated CD8+T cells for adoptive therapy led to significantly reduced tumor volume and significantly enhanced effector function of T cells. The study revealed L-2-HG acted as an immune metabolite through epigenetic modifications of Tex.

Keywords:  Cancer immunotherapy; Immunology; Metabolism; T cells

DOI:  https://doi.org/10.1172/jci.insight.174600
Sci Adv. 2025 Mar 07. 11(10): eads0105

Trained immunity causes myeloid cell hypercoagulability.

Aisling M Rehill, Seán McCluskey, Anna E Ledwith, Tristram A J Ryan, Betül Ünlü, Gemma Leon, Hugo Charles-Messance, Edmund H Gilbert, Paula Klavina, Emily A Day, Judith Coppinger, Jamie M O'Sullivan, Corrina McMahon, James S O'Donnell, Annie M Curtis, Luke A J O'Neill, Frederick J Sheedy, Roger J S Preston.

The pathogenic basis for increased thrombotic risk in individuals with inflammatory diseases is poorly understood. Myeloid cell "trained immunity" describes persistent innate immune cell memory arising from prior exposure to an inflammatory stimulus, leading to an enhanced immune response to subsequent unrelated stimuli. We identify enhanced myeloid cell prothrombotic activity as a maladaptive consequence of trained immunity. Lipopolysaccharide (LPS) stimulation of macrophages trained previously with β-glucan or heme exhibited significantly enhanced procoagulant activity compared to macrophages stimulated with LPS alone, which was mediated by enhanced acid sphingomyelinase-mediated tissue factor decryption. Furthermore, splenic monocytes isolated from β-glucan-trained mice revealed enhanced procoagulant activity up to 4 weeks after β-glucan administration compared to monocytes from control mice over the same time period. Moreover, hematopoietic progenitor cells and bone marrow interstitial fluid from β-glucan-trained mice had enhanced procoagulant activity compared to control mice. Trained immunity and associated metabolic perturbations may therefore represent an opportunity for targeted intervention in immunothrombotic disease development.

DOI: https://doi.org/10.1126/sciadv.ads0105
Immunometabolism (Cobham). 2025 Jan;7(1): e00057

Impact of zinc on immunometabolism and its putative role on respiratory diseases.

Jonathan H Yao, Edwin F Ortega, Alexander Panda.

  Zinc is the second most abundant trace mineral in the human body and plays a critical role in immune cell function and metabolism. Zinc deficiency impairs immune cell function and is associated with increased susceptibility to respiratory diseases, including pneumonia, influenza, and COVID-19. Zinc homeostasis, maintained by numerous zinc transporters and metal-binding proteins (ie, metallothionein), is essential for coordinating immune cell signaling, gene expression, and enzymatic activities in response to respiratory infections. This article highlights the emerging role of zinc in various aspects of immune function, particularly through its influence on cellular metabolism. Given the significant global burden of respiratory diseases, there is a need to identify effective nutritional interventions that could be readily leveraged to prevent and/or mitigate respiratory disease risk, particularly in older adults who are prone to zinc deficiency. However, the immunometabolic mechanisms underlying zinc's protective effects remain poorly characterized. Future research should focus on elucidating how micronutrients, such as zinc, can support changes in immune cell metabolism in response to infections. Such efforts will help determine how zinc metabolism and zinc intervention strategies may best be leveraged to prevent or mitigate respiratory disease.

Keywords:  Zinc; immunity; immunometabolism; respiratory disease

DOI:  https://doi.org/10.1097/IN9.0000000000000057
Sci Adv. 2025 Mar 07. 11(10): eads4957

Citrulline regulates macrophage metabolism and inflammation to counter aging in mice.

Zhangdan Xie, Moubin Lin, Beizi Xing, Hongmiao Wang, Haosong Zhang, Zimu Cai, Xinyu Mei, Zheng-Jiang Zhu.

Metabolic dysregulation and altered metabolite concentrations are widely recognized as key characteristics of aging. Comprehensive exploration of endogenous metabolites that drive aging remains insufficient. Here, we conducted an untargeted metabolomics analysis of aging mice, revealing citrulline as a consistently down-regulated metabolite associated with aging. Systematic investigations demonstrated that citrulline exhibited antiaging effects by reducing cellular senescence, protecting against DNA damage, preventing cell cycle arrest, modulating macrophage metabolism, and mitigating inflammaging. Long-term citrulline supplementation in aged mice yielded beneficial effects and ameliorated age-associated phenotypes. We further elucidated that citrulline acts as an endogenous metabolite antagonist to inflammation, suppressing proinflammatory responses in macrophages. Mechanistically, citrulline served as a potential inhibitor of mammalian target of rapamycin (mTOR) activation in macrophage and regulated the mTOR-hypoxia-inducible factor 1α-glycolysis signaling pathway to counter inflammation and aging. These findings underscore the significance of citrulline deficiency as a driver of aging, highlighting citrulline supplementation as a promising therapeutic intervention to counteract aging-related changes.

DOI: https://doi.org/10.1126/sciadv.ads4957
Nat Commun. 2025 Mar 06. 16(1): 2239

Oxidative phosphorylation is a key feature of neonatal monocyte immunometabolism promoting myeloid differentiation after birth.

Greta Ehlers, Annika Marie Tödtmann, Lisa Holsten, Maike Willers, Julia Heckmann, Jennifer Schöning, Maximilian Richter, Anna Sophie Heinemann, Sabine Pirr, Alexander Heinz, Christian Dopfer, Kristian Händler, Matthias Becker, Johanna Büchel, Achim Wöckel, Constantin von Kaisenberg, Gesine Hansen, Karsten Hiller, Joachim L Schultze, Christoph Härtel, Wolfgang Kastenmüller, Martin Vaeth, Thomas Ulas, Dorothee Viemann.

Neonates primarily rely on innate immune defense, yet their inflammatory responses are usually restricted compared to adults. This is controversially interpreted as a sign of immaturity or essential programming, increasing or decreasing the risk of sepsis, respectively. Here, combined transcriptomic, metabolic, and immunological studies in monocytes of healthy individuals reveal an inverse ontogenetic shift in metabolic pathway activities with increasing age. Neonatal monocytes are characterized by enhanced oxidative phosphorylation supporting ongoing myeloid differentiation. This phenotype is gradually replaced during early childhood by increasing glycolytic activity fueling the inflammatory responsiveness. Microbial stimulation shifts neonatal monocytes to an adult-like metabolism, whereas ketogenic diet in adults mimicking neonatal ketosis cannot revive a neonate-like metabolism. Our findings disclose hallmarks of innate immunometabolism during healthy postnatal immune adaptation and suggest that premature activation of glycolysis in neonates might increase their risk of sepsis by impairing myeloid differentiation and promoting hyperinflammation.

DOI: https://doi.org/10.1038/s41467-025-57357-w
Gut. 2025 Mar 07. pii: gutjnl-2024-333297. [Epub ahead of print]

24-Nor-ursodeoxycholic acid improves intestinal inflammation by targeting TH17 pathogenicity and transdifferentiation.

Ci Zhu, Nicole Boucheron, Osamah Al-Rubaye, Brian K Chung, Liv Wenche Thorbjørnsen, Thomas Köcher, Michael Schuster, Thierry Claudel, Emina Halilbasic, Victoria Kunczer, Fanziska Muscate, Lois L Cavanagh, Darina Waltenberger, Alexander Lercher, Anna Ohradanova-Repic, Philipp Schatzlmaier, Tatjana Stojakovic, Hubert Scharnagl, Andreas Bergthaler, Hannes Stockinger, Samuel Huber, Christoph Bock, Lukas Kenner, Tom H Karlsen, Wilfried Ellmeier, Michael Trauner.

   BACKGROUND: 24-Nor-ursodeoxycholic acid (NorUDCA) is a novel therapeutic bile acid for treating immune-mediated cholestatic liver diseases, such as primary sclerosing cholangitis (PSC).
OBJECTIVE: Since PSC strongly associates with T helper-type-like 17 (TH17)-mediated intestinal inflammation, we explored NorUDCA's immunomodulatory potential on TH17 cells.
DESIGN: NorUDCA's impact on TH17 differentiation was assessed using a CD4+TNaive adoptive transfer mouse model, and on intraepithelial TH17 pathogenicity and transdifferentiation using an αCD3 stimulation model combined with interleukin-17A-fate-mapping. Mechanistic studies used molecular and multiomics approaches, flow cytometry and metabolic assays with pathogenic (p) TH17. Pathogenicity of pTH17 exposed to NorUDCA in vitro was evaluated following adoptive transfer in intestinal tissues or the central nervous system (CNS). Key findings were validated in an αCD3-stimulated humanised NSG mouse model reconstituted with peripheral blood mononuclear cells from patients with PSC.
RESULTS: NorUDCA suppressed TH17 effector function and enriched regulatory T cell (Treg) abundance upon CD4+TNaive cell transfer. NorUDCA mitigated intraepithelial TH17 pathogenicity and decreased the generation of proinflammatory 'TH1-like-TH17' cells, and enhanced TH17 transdifferentiation into Treg and Tr1 (regulatory type 1) cells in the αCD3-model. In vivo ablation revealed that Treg induction is crucial for NorUDCA's anti-inflammatory effect on TH17 pathogenicity. Mechanistically, NorUDCA restrained pTH17 effector function and simultaneously promoted functional Treg formation in vitro, by attenuating a glutamine-mTORC1-glycolysis signalling axis. Exposure of pTH17 to NorUDCA dampened their pathogenicity and expansion in the intestine or CNS upon transfer. NorUDCA's impact on TH17 inflammation was corroborated in the humanised NSG mouse model.
CONCLUSION: NorUDCA restricts TH17 inflammation in multiple mouse models, potentiating future clinical applications for treating TH17-mediated intestinal diseases and beyond.

Keywords:  AUTOIMMUNE LIVER DISEASE; BILE ACID; INFLAMMATORY BOWEL DISEASE; INTESTINAL T CELLS; PRIMARY SCLEROSING CHOLANGITIS

DOI:  https://doi.org/10.1136/gutjnl-2024-333297
Science. 2025 Mar 07. 387(6738): eadn0953

Neonatal fungi promote lifelong metabolic health through macrophage-dependent β cell development.

Jennifer Hampton Hill, Rickesha Bell, Logan Barrios, Halli Baird, Kyla Ost, Morgan Greenewood, Josh K Monts, Erin Tracy, Casey H Meili, Tyson R Chiaro, Allison M Weis, Karen Guillemin, Anna E Beaudin, L Charles Murtaugh, W Zac Stephens, June L Round.

Loss of early-life microbial diversity is correlated with diabetes, yet mechanisms by which microbes influence disease remain elusive. We report a critical neonatal window in mice when microbiota disruption results in lifelong metabolic consequences stemming from reduced β cell development. We show evidence for the existence of a similar program in humans and identify specific fungi and bacteria that are sufficient for β cell growth. The microbiota also plays an important role in seeding islet-resident macrophages, and macrophage depletion during development reduces β cells. Candida dubliniensis increases β cells in a macrophage-dependent manner through distinctive cell wall composition and reduces murine diabetes incidence. Provision of C. dubliniensis after β cell ablation or antibiotic treatment improves β cell function. These data identify fungi as critical early-life commensals that promote long-term metabolic health.

DOI: https://doi.org/10.1126/science.adn0953
J Neuroinflammation. 2025 Mar 01. 22(1): 59

Lactate accumulation from HIF-1α-mediated PMN-MDSC glycolysis restricts brain injury after acute hypoxia in neonates.

Xiaogang Zhang, Laiqin Peng, Shuyi Kuang, Tianci Wang, Weibin Wu, Shaowen Zuo, Chunling Chen, Jiaxiu Ye, Guilang Zheng, Yuxiong Guo, Yumei He.

  Fetal intrauterine distress (FD) during delivery can cause fetal intrauterine hypoxia, posing significant risks to the fetus, mother, and newborns. While studies highlight the role of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in neonatal diseases and tumor hypoxia, their specific involvement in newborns experiencing fetal distress during delivery (FDNB) is not well understood. Here, we found elevated PMN-MDSC activation, increased glycolysis, enhanced lactate production, and upregulated HIF-1α expression in the blood of FDNB neonates compared to healthy newborns (NNB). Importantly, PMN-MDSC levels were inversely correlated with neuron-specific enolase (NSE), a marker for neurological injury. In neonatal mice subjected to acute hypoxia, a 48-h exposure led to a shift from exacerbation to amelioration of brain damage when compared with a 24-h period. This change was associated with a reduction in microglial activation, a decrease in the expression of inflammatory factors within the microglia, alongside increased peripheral PMN-MDSC activation. Depleting PMN-MDSCs led to heightened microglial activation and aggravated brain injury. Mechanistically, enhanced activation of PMN-MDSCs promotes HIF-1α accumulation while enhancing glycolysis and lactate release, thereby mitigating neonatal brain injury. Notably, lactate supplementation in hypoxic mice rescued brain damage caused by insufficient PMN-MDSC activation due to HIF-1α deficiency. Our study clarifies the role of lactate in peripheral PMN-MDSCs after acute hypoxia and its effects on microglial activation and subsequent brain injury.

Keywords:  Fetal intrauterine distress; Glycolysis; HIF-1α; Inflammatory factors expression; Lactate; Microglial activation; Polymorphonuclear myeloid-derived suppressor cells

DOI:  https://doi.org/10.1186/s12974-025-03385-8
Immunity. 2025 Feb 25. pii: S1074-7613(25)00070-6. [Epub ahead of print]

Bile acid receptor FXR promotes intestinal epithelial ferroptosis and subsequent ILC3 dysfunction in neonatal necrotizing enterocolitis.

Yuxin Zhang, Yuchao Jing, Juan He, Rui Dong, Tongyang Li, Fang Li, Xiaoqing Zheng, Gaoyu Liu, Ran Jia, Jin Xu, Fan Wu, Chunhong Jia, Jin Song, Lijuan Zhang, Pan Zhou, Haitao Wang, Zhi Yao, Qiang Liu, Ying Yu, Jie Zhou.

  Necrotizing enterocolitis (NEC) is a common pediatric emergency primarily afflicting preterm infants, yet its mechanisms remain to be fully understood. Here, we report that plasma fibroblast growth factor (FGF)19, a target of farnesoid X receptor (FXR), was positively correlated with the clinical parameters of NEC. NEC patients and the NEC murine model displayed abundant FXR in intestinal epithelial cells (IECs), which was restricted by microbiota-derived short-chain fatty acids (SCFAs) under homeostasis. Genetic deficiency of FXR in IECs caused remission of NEC. Mechanistically, FXR facilitated ferroptosis of IECs via targeting acyl-coenzyme A synthetase long-chain family member 4 (Acsl4). Lipid peroxides released by ferroptotic IECs suppressed interleukin (IL)-22 secretion from type 3 innate lymphoid cells (ILC3s), thereby exacerbating NEC. Intestinal FXR antagonist, ACSL4 inhibitor, and ferroptosis inhibitor ameliorated murine NEC. Furthermore, the elevated lipid peroxides in NEC patients were positively correlated with FGF19 and disease parameters. These observations demonstrate the therapeutic value of targeting intestinal FXR and ferroptosis in NEC treatment.

Keywords:  FXR; IECs; ILC3s; NEC; microbiota; neonatal intestine

DOI:  https://doi.org/10.1016/j.immuni.2025.02.003
ACS Nano. 2025 Mar 02.

Microneedles Loaded with Nitric-Oxide Driven Nanomotors Improve Force-Induced Efferocytosis Impairment and Sterile Inflammation by Revitalizing Macrophage Energy Metabolism.

Hao Tan, Shan Wang, Xinyi He, Guoyin Yang, Ye Zhu, Sihan Yang, Shengnan Yan, Chu Gong, Wenya Bai, Yun Hu, Jinlin Song, Leilei Zheng.

  Mechanical force initiates sterile inflammation, a process implicated in diverse physiological and pathological processes. The timely clearance of apoptotic cells by macrophages via efferocytosis is crucial for the proper resolution of sterile inflammation and for averting excessive tissue damage. Despite this, the specific role and underlying mechanisms of mechanical force on macrophage efferocytosis remain obscure. By integrating bioinformatics and metabolomics analyses, we uncovered how mechanical force disrupts the "arginine metabolism─TCA cycle─mitochondrial function" metabolic cascade, thereby impairing macrophage efferocytosis and intensifying sterile inflammation. Notably, we discovered that elevating l-arginine levels can ameliorate these crises by restoring energy metabolism. Leveraging this insight, we engineered a microneedle drug delivery system loaded with nitric-oxide driven nanomotors (MSN-LA@MNs) for targeted delivery of l-arginine. The active component, MSN-LA, exploits the heightened expression of inducible nitric oxide synthase (iNOS) in force-loaded tissues as a chemoattractant, harnessing NO generated from iNOS-catalyzed l-arginine for autonomous propulsion. In a force-induced rat orthodontic tooth movement (OTM) model, we confirmed that MSN-LA@MNs enhance macrophage efferocytosis and, under iNOS guidance, dynamically modulate sterile inflammation levels in OTM, thus facilitating the OTM process. Collectively, our findings elucidate previously unclear mechanistic links between force, macrophage efferocytosis, and sterile inflammation from a metabolic vantage point, offering a promising targeted strategy for modulating force-related biological processes such as OTM.

Keywords:  efferocytosis; energy metabolism; l-arginine; mechanical force; microneedle; nanomotor

DOI:  https://doi.org/10.1021/acsnano.5c01877
Nat Commun. 2025 Feb 28. 16(1): 2071

ACSS2 drives senescence-associated secretory phenotype by limiting purine biosynthesis through PAICS acetylation.

Li Yang, Jianwei You, Xincheng Yang, Ruishu Jiao, Jie Xu, Yue Zhang, Wen Mi, Lingzhi Zhu, Youqiong Ye, Ruobing Ren, Delin Min, Meilin Tang, Li Chen, Fuming Li, Pingyu Liu.

Senescence-associated secretory phenotype (SASP) mediates the biological effects of senescent cells on the tissue microenvironment and contributes to ageing-associated disease progression. ACSS2 produces acetyl-CoA from acetate and epigenetically controls gene expression through histone acetylation under various circumstances. However, whether and how ACSS2 regulates cellular senescence remains unclear. Here, we show that pharmacological inhibition and deletion of Acss2 in mice blunts SASP and abrogates the pro-tumorigenic and immune surveillance functions of senescent cells. Mechanistically, ACSS2 directly interacts with and promotes the acetylation of PAICS, a key enzyme for purine biosynthesis. The acetylation of PAICS promotes autophagy-mediated degradation of PAICS to limit purine metabolism and reduces dNTP pools for DNA repair, exacerbating cytoplasmic chromatin fragment accumulation and SASP. Altogether, our work links ACSS2-mediated local acetyl-CoA generation to purine metabolism through PAICS acetylation that dictates the functionality of SASP, and identifies ACSS2 as a potential senomorphic target to prevent senescence-associated diseases.

DOI: https://doi.org/10.1038/s41467-025-57334-3
Mediators Inflamm. 2025 ;2025 6608718

Interleukins-27 Aggravates Liver Injury by Impairing the Antimicrobial Response of Macrophages via the Promotion of Mitochondrial Dysfunction in the Context of Sepsis.

Yuehua You, Yuyan Li, Lin Ye, Fang Xu, Jing Fan.

  Background and Aims: Plasma interleukin (IL)-27 is an important mediator of acute hepatic injury (AHI) associated with sepsis. Mitochondria contribute to the proper regulation of macrophage phagocytosis. In this study, we investigated the effect of IL-27 on mitochondrial function and the antimicrobial response of macrophages in sepsis-associated AHI. Methods: Wild-type (WT) and IL-27 receptor WSX-1 deficient (IL-27R-/-) mice underwent cecal ligation and puncture (CLP). The severity of hepatic injury, inflammatory cytokine levels, hepatic pyroptosis, and bacterial load in the liver and blood were assessed 24 h after CLP. In vitro, RAW264.7 cells and peritoneal macrophages were treated with lipopolysaccharide (LPS) and/or IL-27. The phagocytosis and killing functions of macrophages were detected. Mitochondrial function and mitophagy were detected using western blot, glutathione (GSH)/malondialdehyde (MDA) content measurement, fluorescence staining, and JC-1 staining in vivo and in vitro. After treatment with nicotinamide mononucleotide (NMN, NAD + precursor), a pharmacologic agent that improves mitochondrial function, the inflammatory response, hepatic injury, and hepatic pyroptosis were assessed. Results: IL-27R-/- mice exhibited a marked reduction in hepatic injury, pyroptosis (based on cleaved GSDMD and cleaved Caspases 1 protein levels), and systemic inflammation (based on serum IL-6, IL-10, and TNF-α levels) compared to WT mice following CLP. After CLP, mice lacking IL-27R displayed significantly higher bacterial clearance and greater local infection control. Subsequent studies demonstrated that IL-27 directly impaired the LPS-induced bacterial phagocytosis, killing capacity, and mitochondrial function of macrophages. Finally, enhanced mitochondrial function using NMN in vivo significantly alleviated pathological liver injury and inflammation. Conclusions: These findings indicated that IL-27 impairs the bacterial phagocytosis capacity of macrophages by aggravating mitochondrial dysfunction to aggravate AHI during sepsis.

Keywords:  AHI; IL-27; macrophages; mitochondrial dysfunction; sepsis

DOI:  https://doi.org/10.1155/mi/6608718
Acta Pharm Sin B. 2025 Jan;15(1): 542-556

Synergistic metabolic modulation of fibroblast-like synoviocytes via targeted dual prodrug nanoparticles to mitigate rheumatoid arthritis.

Shaobing Li, Juntao Lin, Chengxinqiao Wang, Junhan Liu, Yupeng Wang, Yan Chen, Dongfang Zhou.

  Elevated glucose metabolism is a prominent characteristic of fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA). However, the efficacy of inhibiting a single target of glucose metabolism in FLS using small molecular inhibitors is limited for RA treatment. Herein, the synergistic inhibition of FLS' survival, proliferation, and activation by combining two glucose metabolism inhibitors, diclofenac (DC) and lonidamine (LND) was first verified. Subsequently, DC and LND were individually conjugated to cystamine-modified hyaluronic acid (HA) to prepare two polymer-prodrug conjugates. A HAP-1 peptide-modified dual polymer-prodrug conjugates-assembled nanoparticles system (HAP-1NPDC+LND) was further tailored in the optimal synergistic ratio for targeted and synergistic metabolic modulation of FLS to alleviate RA symptoms. Upon targeted uptake by FLS in inflamed joints, HAP-1NPDC+LND released DC and LND within the intracellular reductive microenvironment, where DC hinders glucose uptake and LND suppresses glycolytic enzymes to eliminate FLS synergistically. Additionally, the secretion of lactic acid and pro-inflammatory factors from FLS were reduced, thereby disrupting the crosstalk between FLS and pro-inflammatory macrophages. Finally, HAP-1NPDC+LND demonstrated promising efficacy in a mouse model of collagen-induced arthritis (CIA). Overall, this research provides valuable insights into novel therapeutic strategies for the safe and effective of treatment RA through targeted and synergistic metabolic modulation of FLS.

Keywords:  Dual prodrug nanoparticles; Fibroblast-like synoviocytes; Glucose transporter member 1; Glycolytic enzyme; Lactic acid; Metabolic modulation; Rheumatoid arthritis; Synovial microenvironment

DOI:  https://doi.org/10.1016/j.apsb.2024.11.007
Precis Clin Med. 2025 Mar;8(1): pbaf002

Epstein-Barr virus infection exacerbates ulcerative colitis by driving macrophage pyroptosis via the upregulation of glycolysis.

Chunxiang Ma, Kexin Chen, Lili Li, Mingshan Jiang, Zhen Zeng, Fang Yin, Jing Yuan, Yongbin Jia, Hu Zhang.

   Background: Epstein-Barr virus (EBV) infection is associated with clinical symptoms, treatment response, need for surgical intervention, and an enhanced likelihood of lymphoma among patients with ulcerative colitis (UC). However, existing studies have primarily concentrated on the epidemiological and clinical associations between EBV and UC, leaving the mechanisms by which EBV exacerbates colitis poorly understood.
Methods: Clinical specimens of UC patients with EBV infection and a mouse model of dextran sulfate sodium-induced colitis with concurrent murine γ-herpesvirus 68 (MHV-68) infection were utilized to investigate the relationship between EBV infection and macrophage pyroptosis. In vivo, adoptive transfer of MHV-68-induced macrophages and macrophage depletion were performed to elucidate the underlying mechanisms. In vitro, myeloid leukemia mononuclear cells of human (THP-1) and macrophages derived from mouse bone marrow (BMDMs) were stimulated with EBV and MHV-68, respectively, to assess macrophage pyroptosis and glycolysis.
Results: EBV-induced activation of macrophage pyroptosis was positively correlated with clinical disease activity in UC patients. Furthermore, MHV-68 infection activated pyroptosis by upregulating gasdermin D, NLRP3, interleukin-1β, and interleukin-18 in colonic tissues and peritoneal macrophages of mice with colitis. In vitro, EBV and MHV-68 also mediated activation of pyroptosis in human THP-1 cells and mouse BMDMs, respectively. Additionally, the adoptive transfer of MHV-68-induced BMDMs aggravated murine colitis, whereas macrophage depletion attenuated MHV-68-induced intestinal injury. Mechanistically, MHV-68 promoted macrophage pyroptosis by upregulating glycolysis, while the glycolysis inhibitor, 2-deoxy-D-glucose, blocked this process in vitro.
Conclusion: EBV infection exacerbates UC by driving macrophage pyroptosis through upregulation of glycolysis, indicating a potential therapeutic approach to mitigate EBV-induced intestinal inflammation.

Keywords:  Epstein-Barr virus; macrophages; pyroptosis; glycolysis; ulcerative colitis

DOI:  https://doi.org/10.1093/pcmedi/pbaf002
J Neurochem. 2025 Mar;169(3): e70030

Metabolic Reprogramming in Primary Microglial Cell and Extracellular Vesicle Triggered by Aβ Exposure.

Seong-Hun Bong, Hayoung Choi, Hyun-Ho Song, Dong Kyu Kim, Inhee Mook-Jung, Do Yup Lee.

  Microglia, key immune cells in the brain, play a pivotal role in brain homeostasis and immune responses. Emerging evidence suggests their critical involvement in Alzheimer's disease (AD) pathogenesis and propagation. The propagation of AD pathology is related to the extracellular matrix of microglia, including extracellular vesicles (EV). Recently, microglia-derived EVs are implicated in inflammatory processes and neuronal death. This study aimed to extensively profile and propose the metabolic role of microglial EVs in AD. Accordingly, we determined the significant alterations of the EV metabolome associated with the metabolites in primary microglial cells. Aβ exposure induced significant metabolic alteration of 39, 18, and 28 metabolites in microglial cells, cultured media, and EVs, respectively. Aβ exposure triggered common alteration of key metabolic pathways between microglial cells and EVs, including purine, amino acid, and fatty acid metabolisms. While most of the common metabolites showed the same directional changes among the microglial system, N-acetyl aspartic acid displayed the opposite directional change in EVs. N-acetyl aspartic acid decreased 2.3-fold and twofold in microglial cells and media, respectively, but increased 3.5-fold in EVs under Aβ exposure. Moreover, mediation analysis proposed key EV metabolites that were directly affected by the metabolic dysregulation of Aβ-exposed microglial cells. The up-regulation of cysteic acid in EVs was mediated by up-regulated IMP in microglial cells. The down-regulation of 1-16:0-lysoPE in EVs was mediated by stearoyl-L-carnitine in microglial cells. Our study sheds new light on the role of microglia and EVs in neurodegenerative diseases, offering promising avenues for future therapeutic interventions.

Keywords:  Alzheimer's disease; Anaplerosis; extracellular vesicle; metabolomics; microglial cell

DOI:  https://doi.org/10.1111/jnc.70030
Cell Rep. 2025 Mar 06. pii: S2211-1247(25)00146-9. [Epub ahead of print]44(3): 115375

iMetAct: An integrated systematic inference of metabolic activity for dissecting tumor metabolic preference and tumor-immune microenvironment.

Binxian Wang, Chao Huang, Xuan Liu, Zhenni Liu, Yilei Zhang, Wei Zhao, Qiuran Xu, Ping-Chih Ho, Zhengtao Xiao.

  Metabolic enzymes play a central role in cancer metabolic reprogramming, and their dysregulation creates vulnerabilities that can be exploited for therapy. However, accurately measuring metabolic enzyme activity in a high-throughput manner remains challenging due to the complex, multi-layered regulatory mechanisms involved. Here, we present iMetAct, a framework that integrates metabolic-transcription networks with an information propagation strategy to infer enzyme activity from gene expression data. iMetAct outperforms expression-based methods in predicting metabolite conversion rates by accounting for the effects of post-translational modifications. With iMetAct, we identify clinically significant subtypes of hepatocellular carcinoma with distinct metabolic preferences driven by dysregulated enzymes and metabolic regulators acting at both the transcriptional and non-transcriptional levels. Moreover, applying iMetAct to single-cell RNA sequencing data allows for the exploration of cancer cell metabolism and its interplay with immune regulation in the tumor microenvironment. An accompanying online platform further facilitates tumor metabolic analysis, patient stratification, and immune microenvironment characterization.

Keywords:  CP: Cancer; CP: Metabolism; hepatocellular carcinoma; information propagation; metabolic enzyme activity; tumor stratification; tumor-immune microenvironment

DOI:  https://doi.org/10.1016/j.celrep.2025.115375
Adv Healthc Mater. 2025 Mar 05. e2405097

Matrix Viscoelasticity Orchestrates Osteogenesis via Mechanotransduction Mediated Metabolic Switch in Macrophages.

Dihao Tao, Hanzhe Wang, Shiping Chang, Jiayu Cheng, Ningning Da, Li Zhang, Jianhua Yang, Wenzhe Wang, Feng Xu, Bei Li.

  Understanding the interplay between extracellular matrix (ECM) mechanics and macrophage cellular processes is crucial for bone regeneration. While ECM stiffness has been extensively studied, the role of ECM viscoelasticity (e.g., stress relaxation) in the bone marrow niche and its effects on macrophage function remain unclear. Here, this study reveals how matrix viscoelasticity orchestrates osteogenesis by modulating macrophage metabolism through vasodilator-stimulated phosphoprotein (VASP) / hypoxia-inducible factor 1 alpha (HIF1α) signaling. In the rapid maxillary expansion (RME) model, significant stress relaxation occurs in regenerated bone marrow during the initial 17 days, coinciding with increased transforming growth factor-beta 1 (TGF-β1+) F4/80+ macrophages. Fast stress relaxation enhances macrophage recruitment of mesenchymal stem cells (MSCs) by upregulating TGF-β1. Using a hydrogel-macrophage system mimicking bone marrow viscoelasticity, cranial defect regeneration is significantly improved. Moreover, fast stress relaxation shifts macrophage metabolism from glycolysis to oxidative phosphorylation (OXPHOS) via VASP/HIF1α signaling, facilitating a reparative phenotype. These findings elucidate the relationship between ECM viscoelasticity and macrophage metabolism, suggesting new therapeutic avenues for bone regeneration through mechanomedicine.

Keywords:  OXPHOS; bone regeneration; glycolysis; macrophages; mechanical microenvironment; mechanomedicine

DOI:  https://doi.org/10.1002/adhm.202405097
Redox Biol. 2025 Mar 01. pii: S2213-2317(25)00088-6. [Epub ahead of print]81 103575

Dietary oxidized lipids in redox biology: Oxidized olive oil disrupts lipid metabolism and induces intestinal and hepatic inflammation in C57BL/6J mice.

Yifan Bao, Magdalena Osowiecka, Christiane Ott, Vasiliki Tziraki, Lukas Meusburger, Claudia Blaßnig, Daniela Krivda, Petra Pjevac, Joana Séneca, Matthias Strauss, Christina Steffen, Verena Heck, Soner Aygün, Kalina Duszka, Kevin Doppelmayer, Tilman Grune, Marc Pignitter.

  Olive oil, rich in oleic acid, is often regarded as a healthier alternative to animal fats high in saturated fatty acids and plant oils rich in oxidizable polyunsaturated fatty acids. However, the redox biological implications and health effects of oxidized olive oil (ox-OO) remain underexplored. Our study investigated its impact on lipid metabolism, intestinal and hepatic inflammation, and gut microbiota. Female C57BL/6J mice were fed either a standard normal (NFD), high-fat diet (HFD), an NFD-ox-OO or HFD-ox-OO, in which ox-OO (180 °C heating, 10 min) was the sole lipid source. Inflammation was assessed using macrophage marker F4/80 immunohistochemical (IHC) staining. Gene expression of inflammatory and lipid metabolism markers (IL-10, NF-kBp65, IL-1β, TNFα, TLR4, COX2, PPARα, PPARγ, CPT1a, SCAD, MCAD, LCAD) was analyzed by qRT-PCR. Soluble epoxide hydrolase (sEH) protein expression was measured using IHC. Oxylipin and carnitine profiles were determined by LC-MS/MS. Gut microbiota was analyzed by 16S rRNA sequencing. Ox-OO disrupted redox homeostasis, leading to lipid metabolic dysfunction in the intestines and liver. In the duodenum and proximal jejunum, ox-OO decreased the levels of anti-inflammatory oxylipins and increased pro-inflammatory mediators, leading to inflammation. In the ileum and colon, ox-OO caused lipid metabolic dysregulation and inflammation. Colon inflammation was linked to inhibited mitochondrial β-oxidation and decreased short-chain fatty acid-producing microbiomes. Notably, redox imbalances were further implicated by the identification of 9,10-epoxy-stearic acid, a novel inflammatory lipid mediator oxidized from dietary oleic acid, which upregulated sEH. Ox-OO affects lipid metabolism and may contribute to inflammation in the gut and liver, raising questions about the assumption that olive oil is always beneficial and suggesting possible risks linked to oxidized oleic acid.

Keywords:  9,10-Epoxy-stearic acid; Gut microbiota; Inflammation; Lipid metabolic dysfunction; Oxidized olive oil

DOI:  https://doi.org/10.1016/j.redox.2025.103575
Immunity. 2025 Feb 25. pii: S1074-7613(25)00078-0. [Epub ahead of print]

The polyamine-regulating enzyme SSAT1 impairs tissue regulatory T cell function in chronic cutaneous inflammation.

Teresa Neuwirth, Daniel Malzl, Katja Knapp, Panagiota Tsokkou, Lisa Kleissl, Anna Gabriel, Baerbel Reininger, Christian Freystätter, Nara Marella, Ana P Kutschat, Elisabeth Ponweiser, Arvand Haschemi, Davide Seruggia, Jörg Menche, Erwin F Wagner, Georg Stary.

  Regulatory T (Treg) cells are a critical immune component guarding against excessive inflammation. Treg cell dysfunction can lead to chronic inflammatory diseases with current therapies aimed at inhibiting effector T cells rather than rescuing Treg cell function. We utilized single-cell RNAsequencing data from patients with chronic inflammation to identify SAT1, the gene encoding spermidine/spermine N1-acetyltransferase (SSAT), as a driver of skin-resident Treg cell dysfunction. CRISPRa-driven SAT1 expression in human skin-derived Treg cells impaired their suppressive function and induced a pro-inflammatory phenotype. During cutaneous type-17 inflammation, keratinocyte 4-1BBL induces SAT1 on Treg cells. In a mouse model of psoriasis, pharmacological inhibition of SSAT rescued Treg cell number and function. Together, these data show that SAT1 expression has severe functional consequences on Treg cells and suggest a therapeutic target to treat chronic inflammatory disease.

Keywords:  chronic inflammation; polyamine metabolism; psoriasis; regulatory T cells

DOI:  https://doi.org/10.1016/j.immuni.2025.02.011
Commun Biol. 2025 Mar 07. 8(1): 384

Metabolic crosstalk between the mitochondrion and the nucleus is essential for Toxoplasma gondii infection.

Hongxi Zhang, Nuo Ji, Shuxin Su, Meng Zhao, Huiyu Du, Lakesh Kumar Sahoo, Yi Wu, Yaoyu Feng, Nishith Gupta, Lihua Xiao, Ningbo Xia.

Toxoplasma gondii, an intracellular pathogenic protist with a remarkable ability to infect a wide range of host cells, displays an equally exceptional design of its carbon metabolism. There are, however, critical gaps in our understanding of the metabolic network in T. gondii. We characterized the mito-nuclear metabolism and organelle coupling during its acute infection (lytic cycle). The major enzymes of the TCA cycle, i.e., citrate synthase (CS1), succinyl-CoA synthase alpha subunit (SCSα), succinate dehydrogenase (SDHA) and FAD malate dehydrogenase (MDH-FAD) located in the parasite mitochondrion support its asexual reproduction but are not needed for its survival. The SCSα and SDHA mutants are nearly avirulent in a mouse model, and they can protect the host against a lethal challenge infection. Genetic deletion of MDH-FAD dysregulated glucose-derived carbon flux, leading to a collapse of the mitochondrial membrane potential. The parasite also harbors a cytosolic isoform of MDH and a nuclear malic enzyme (ME) contributing to malate oxidation; however, only the latter is essential for the lytic cycle. Expression of ME in the nucleus is crucial for the parasite development. Besides, conditional knockdown of ME impairs the histone acetylation and disrupts the expression of several genes in tachyzoites. Our work discloses novel network design features of T. gondii and highlights the therapeutic and vaccination potential of the parasite metabolism.

DOI: https://doi.org/10.1038/s42003-025-07823-4
Sci Adv. 2025 Mar 07. 11(10): eadq4266

Isocyanic acid-mediated NLRP3 carbamoylation reduces NLRP3-NEK7 interaction and limits inflammasome activation.

Zhenxing Zhang, Chao Chen, Caiyun Liu, Pengkai Sun, Ping Liu, Shu Fang, Xinjian Li.

Isocyanic acid, as a reactive metabolite synthesized by the enzyme LACC1, can carbamoylate the ε-amino group of lysine residues in proteins. However, the role of isocyanic acid in inflammatory response remains elusive. Herein, we reveal that lipopolysaccharide stimulation increases LACC1-dependent isocyanic acid production, which attenuates inflammation by limiting the NLRP3 inflammasome activation in macrophages primed with lipopolysaccharide for 8 hours. Mechanistically, isocyanic acid directly carbamoylates NLRP3 at lysine-593 to disrupt NLRP3-NEK7 interaction, a key step in assembly of active NLRP3 inflammasome. Abrogation of isocyanic acid biosynthesis by LACC1/Lacc1 knockout or expression of K593 carbamoylation (K593ca)-deficient NLRP3 mutant promotes macrophagic inflammatory response in vitro. Furthermore, Lacc1-/- mice and mice harboring K593ca-deficient NLRP3 mutation manifest exacerbated inflammatory response in vivo. Hence, our findings identify isocyanic acid as an endogenous immunoregulatory metabolite that limits NLRP3-driven inflammation and provide valuable insights into the regulation of NLRP3 inflammasome activation, governed by metabolites.

DOI: https://doi.org/10.1126/sciadv.adq4266
PLoS One. 2025 ;20(3): e0318267

Intracellular accumulation of free cholesterol in macrophages triggers a PARP1 response to DNA damage and PARP1 impairs lipopolysaccharide-induced inflammatory response.

Kenneth K Y Ting, Hisham M Ibrahim, Nitya Gulati, Yufeng Wang, Jonathan V Rocheleau, Myron I Cybulsky.

The formation of macrophage (Mφ) foam cells is a hallmark of atherosclerosis, yet how the process of lipid loading can modulate Mφ inflammatory responses by rewiring their intracellular metabolic circuits is not well understood. Our previous studies have shown that the accumulation of oxidized LDL (oxLDL) or free cholesterol in Mφs impaired their inflammatory response by suppressing HIF-1α-mediated glycolysis and upregulating NRF2 antioxidative response. However, it remains unclear if other metabolic processes are also contributory. In this study, we found that the accumulation of free cholesterol, but not oxLDL, in primary murine thioglycolate-elicited peritoneal Mφs (PMφs) enhanced a PARP1-dependent response associated with repair of DNA damage, which was characterized by poly ADP-ribosylation of proteins, phosphorylation of histone 2A.X and consumption of NAD + . Both oxLDL and cholesterol enhanced the PARP1 response after LPS stimulation. Treatment of PMφs with mitoTEMPO, a specific mitochondrial reactive oxygen species (mtROS) scavenger, alleviated mtROS during cholesterol loading, blocked the PARP1 response and partially restored LPS- induced inflammatory gene expression. In contrast to inhibition of PARP1 enzymatic activity, knockdown of PARP1 expression in RAW264.7 Mφs with siRNA elevated LPS-induced inflammatory gene expression. Overall, our study suggests that cholesterol accumulation triggers a PARP1 response to DNA damage in Mφs and that PARP1 inhibits LPS-mediated inflammation through a non-enzymatic function.

DOI: https://doi.org/10.1371/journal.pone.0318267
Cancer Cell. 2025 Feb 21. pii: S1535-6108(25)00056-X. [Epub ahead of print]

Metabolic engineering to facilitate anti-tumor immunity.

Tanya Schild, Patrick Wallisch, Yixuan Zhao, Ya-Ting Wang, Lyric Haughton, Rachel Chirayil, Kaitlyn Pierpont, Kevin Chen, Sara Nunes-Violante, Justin Cross, Elisa de Stanchina, Craig B Thompson, David A Scheinberg, Justin S A Perry, Kayvan R Keshari.

  Fructose consumption is elevated in western diets, but its impact on anti-tumor immunity is unclear. Fructose is metabolized in the liver and small intestine, where fructose transporters are highly expressed. Most tumors are unable to drive glycolytic flux using fructose, enriching fructose in the tumor microenvironment (TME). Excess fructose in the TME may be utilized by immune cells to enhance effector functions if engineered to express the fructose-specific transporter GLUT5. Here, we show that GLUT5-expressing CD8+ T cells, macrophages, and chimeric antigen receptor (CAR) T cells all demonstrate improved effector functions in glucose-limited conditions in vitro. GLUT5-expressing T cells show high fructolytic activity in vitro and higher anti-tumor efficacy in murine syngeneic and human xenograft models in vivo, especially following fructose supplementation. Together, our data demonstrates that metabolic engineering through GLUT5 enables immune cells to efficiently utilize fructose and boosts anti-tumor immunity in the glucose-limited TME.

Keywords:  CAR-T; fructose; macrophages; metabolic engineering; slc2a5; t cell

DOI:  https://doi.org/10.1016/j.ccell.2025.02.004
Eur J Cancer. 2025 Feb 28. pii: S0959-8049(25)00113-3. [Epub ahead of print]220 115332

Immunometabolism of tumor-associated macrophages: A therapeutic perspective.

Adelya F Karimova, Adelya R Khalitova, Roman Suezov, Nikita Markov, Yana Mukhamedshina, Albert A Rizvanov, Magdalena Huber, Hans-Uwe Simon, Anna Brichkina.

  Tumor-associated macrophages (TAMs) play a pivotal role in the tumor microenvironment (TME), actively contributing to the formation of an immunosuppressive niche that fosters tumor progression. Consequently, there has been a growing interest in targeting TAMs as a promising avenue for cancer therapy. Recent advances in the field of immunometabolism have shed light on the influence of metabolic adaptations on macrophage physiology in the context of cancer. Here, we discuss the key metabolic pathways that shape the phenotypic diversity of macrophages. We place special emphasis on how metabolic reprogramming impacts the activation status of TAMs and their functions within the TME. Additionally, we explore alterations in TAM metabolism and their effects on phagocytosis, production of cytokines/chemokines and interaction with cytotoxic T and NK immune cells. Moreover, we examine the application of nanomedical approaches to target TAMs and assess the clinical significance of modulating the metabolism of TAMs as a strategy to develop new anti-cancer therapies. Taken together, in this comprehensive review article focusing on TAMs, we provide invaluable insights for the development of effective immunotherapeutic strategies and the enhancement of clinical outcomes for cancer patients.

Keywords:  Immunometabolism; Nanomedicine; Tumor immunology; Tumor-associated macrophages

DOI:  https://doi.org/10.1016/j.ejca.2025.115332
Cardiovasc Res. 2025 Mar 04. pii: cvaf032. [Epub ahead of print]

Targeting the PDK/PDH axis modulates neutrophil and smooth muscle cell pathological responses and prevents abdominal aortic aneurysm formation.

S Griepke, A Grentzmann, G L Tripodi, J Hansen, M P Fonseca, M D Nilsson, Y Tallouzi, E Grupe, P S Jensen, H C Beck, G Temprano-Sagrera, M Sabater-Lleal, M Burton, M Dembic, M Thomassen, M J Forteza, M G Terp, J S Lindholt, L M Rasmussen, L B Steffensen, J Stubbe, D F J Ketelhuth.

AIMS: Abdominal aortic aneurysm (AAA) is a life-threatening condition where inflammation plays a key role. Currently, AAA treatment relies exclusively on surgical interventions, and no guideline drug therapy to prevent aneurysm growth or rupture is available. Pharmacological reprogramming of immune cell metabolism, through the modulation of the pyruvate dehydrogenase kinase/pyruvate dehydrogenase (PDK/PDH) axis, has been identified as an attractive strategy to combat inflammation. Here we aimed, for the first time, to investigate the role of the PDK/PDH axis in AAA and its potential as a therapeutic target.
METHODS AND RESULTS: Analysis of three separate transcriptome datasets revealed that the expression of PDK isoenzymes is skewed in human AAA. Thus, human AAA homogenates showed increased levels of phosphorylated PDH-Ser293 and lactate compared to controls, confirming a metabolic deviation. In mice subjected to porcine pancreatic elastase (PPE)-induced AAA, treatment with dichloroacetate (DCA), a pan inhibitor of PDK isoenzymes, prevented aortic dilation, reducing the increase in inner aortic diameter by approximately 58% compared to controls. Further analysis showed that DCA treatment upregulated contractile VSMC-related genes and downregulated neutrophil-related genes in the mice. In line with the previous, PDK-inhibition prevented elastin breakdown, preserved aortic alpha-smooth muscle actin and collagen expression, and decreased neutrophil infiltration and neutrophil extracellular traps (NET) release. Thus, treating VSMC with DCA or PDK1-siRNA revealed that the PDK/PDH axis regulates their dedifferentiation, influencing contractile gene expression and proliferation. Moreover, we found that DCA-induced PDK inhibition inhibited neutrophil NET release in vivo and in vitro.
CONCLUSION: We show that the PDK/PDH axis is skewed in human AAA. Through the inhibition of PDK, in vitro and in vivo, we demonstrated that the PDK/PDH axis is a key regulator of vascular- and neutrophil-associated pathological responses with AAA formation. Our study pinpoints immunometabolic reprogramming using PDK inhibitors as an attractive strategy to fight AAA disease.

DOI: https://doi.org/10.1093/cvr/cvaf032
Biochim Biophys Acta Mol Basis Dis. 2025 Mar 03. pii: S0925-4439(25)00101-2. [Epub ahead of print] 167756

Sodium butyrate alleviates colitis by inhibiting mitochondrial ROS mediated macrophage pyroptosis.

Guoqiang Fan, Yaxin Liu, Limei Tao, Danping Wang, Yizhu Huang, Xiaojing Yang.

  Inflammatory bowel disease (IBD) is a chronic inflammatory bowel disease with unclear causes and limited treatment options. Sodium butyrate (NaB), a byproduct of dietary fiber in the intestine, has demonstrated efficacy in treating inflammation. However, the precise anti-inflammatory mechanisms of NaB in colon inflammation remain largely unexplored. This study aims to investigate the effects of NaB on dextran sulfate sodium (DSS)-induced colitis in rats. The findings indicate that oral administration of NaB effectively prevent colitis and reduce levels of serum or colon inflammatory factors. Additionally, NaB demonstrated in vitro inhibition of RAW264.7 inflammation cytokines induced by LPS, along with suppression of the ERK and NF-κB signaling pathway activation. Moreover, NaB mitigated LPS and Nigericin-induced RAW264.7 pyroptosis by reducing indicators of mitochondrial damage, including increased mitochondrial membrane potential (JC-1) levels and decreased Mito-ROS production. NaB increases ZO-1 and Occludin expression in CaCo2 cells by inhibiting RAW264.7 pyroptosis. These results suggest that NaB could be utilized as a therapeutic agent or dietary supplement to alleviate colitis.

Keywords:  Colitis; Mitochondria damage; Pyroptosis; RAW264.7 cells; Sodium butyrate

DOI:  https://doi.org/10.1016/j.bbadis.2025.167756
Am J Physiol Endocrinol Metab. 2025 Mar 06.

Discovery of A Novel Regulator, 3β-Sulfate-5-Cholestenoic Acid, of Lipid Metabolism and Inflammation.

Yaping Wang, Arun J Sanyal, Phillip Hylemon, Shunlin Ren.

  Mitochondrial oxysterols, cholestenoic acid (CA), 25-hydroxycholesterol (25HC), and 27-hydroxycholesterol (27HC), are potent regulators involved in many important biological events. This study aimed to investigate the metabolic pathways of these oxysterols and their roles between hepatocytes and macrophages. LC-MS-MS analysis showed a novel regulatory molecule, 3β-sulfate-5-cholestenoic acid (3SCA), following addition of CA in media culturing hepatocytes. Further study showed that 3SCA could also derived from 27HC. As comparison, 25HC was converted to 25HC3S, of which mostly remained in the cells and nuclei. Functional study showed that 3SCA significantly downregulated the expression of genes involved in lipid metabolism in hepatocytes and suppressed gene expression of pro-inflammatory cytokines induced by LPS in human macrophages. Based on the results, we conclude that 3SCA acts as a secretory regulator for the regulation of lipid metabolism and inflammatory responses in hepatocytes and macrophages. These findings shed light on understanding the unique metabolic pathways of these oxysterols and their possible roles in liver tissues.

Keywords:  Cholestenoic acid; Inflammation; LPS; Lipids; Liver; Mitochondria; Monohydroxy bile acid; Oxysterol sulfation; Oxysterols

DOI:  https://doi.org/10.1152/ajpendo.00426.2024
Front Immunol. 2025 ;16 1534009

Acute hypoxia modulate macrophage phenotype accompanied with transcriptome re-programming and metabolic re-modeling.

Binda Sun, Yao Long, Gang Xu, Jian Chen, Gang Wu, Bao Liu, Yuqi Gao.

   Introduction: Macrophages, which tend to aggregate in the hypoxic regions of tissues, have a significant impact on disease progression and outcome because of their plastic responsiveness to hypoxia, particularly in the early stages. Understanding macrophages'participation in hypoxia-related disorders requires demonstrating the impact of acute hypoxia on their survival, phenotype, and function.
Methods: Here we conducted a systematic evaluation of macrophage responses to hypoxia over 24 and 48 h including cell growth and activity, inflamatory response, macrophage polarization and transcriptional and metabolic changes.
Results: We found that acute hypoxia suppresses macrophage proliferation and phagocytosis function with a parallel change of transcriptome re-programming and metabolic re-modeling. Although macrophages accumulate transcriptome heterogeneity based on oxygen concentration and culture period, genes involved in hypoxia response, chemotaxis, and glycolytic process were commonly altered during acute hypoxia. Furthermore, the pro-inflammatory response of macrophages was activated during acute hypoxia concomitantly with an enhanced anti-inflammatory regulatory mechanism characterized by increased M2 macrophage population and anti-inflammatory metabolite itaconic acid. Aside from increased glycolysis, the key intermediates in the pentose phosphate pathway significantly increased, such as fructose 1,6-bisphosphate (fold change: 7.8), 6-phosphogluconate (fold change: 6.1), and ribose 5-phosphate (fold change: 3.9), which indicated that the pentose phosphate pathway was an important compensatory metabolic regulation that rules for the response of macrophages to acute hypoxia.
Discussion: These findings highlight that acute hypoxia suppresses macrophage viability and phagocytosis, while acute hypoxia modifies the transcriptome and metabolome in specific inflammatory responses and metabolic pathways to facilitate the adaptation of macrophage in hypoxic conditions.

Keywords:  acute hypoxia; macrophage; metabolic remodeling; pentose phosphate pathway; transcriptome reprogramming

DOI:  https://doi.org/10.3389/fimmu.2025.1534009