bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2025–02–16
twenty-one papers selected by
Dylan Ryan, University of Cambridge
  1. Neuroinflammation and immunometabolism in neurodegenerative diseases.
  2. Metabolic T-cell phenotypes - from bioenergetics to function.
  3. Acsbg1 regulates differentiation and inflammatory properties of CD4+ T cells.
  4. Role of amino acid metabolism in tumor immune microenvironment of colorectal cancer.
  5. Apabetalone alleviates ligature-induced periodontitis by inhibiting M1 macrophage polarization via an immunometabolic shift.
  6. Starve a cold or feed a fever? Identifying cellular metabolic changes following infection and exposure to SARS-CoV-2.
  7. ACC1 is a Dual Metabolic-Epigenetic Regulator of Treg Stability and Immune Tolerance.
  8. Examining the Impact of Microglia on Ischemic Stroke With an Emphasis on the Metabolism of Immune Cells.
  9. Mechanical force receptor Piezo1 regulates TH9 cell differentiation.
  10. Tumor extracellular vesicle-derived PD-L1 promotes T cell senescence through lipid metabolism reprogramming.
  11. Recent advances in nutritional metabolism studies on SARS-CoV-2 infection.
  12. Metabolic reprogramming of macrophages by a nano-sized opsonization strategy to restore M1/M2 balance for osteoarthritis therapy.
  13. Itaconate promotes mitophagy to inhibit neuronal ferroptosis after subarachnoid hemorrhage.
  14. Early-age efferocytosis directs macrophage arachidonic acid metabolism for tissue regeneration.
  15. Citrulline inhibits Clostridioides difficile infection with anti-inflammatory effects.
  16. Inositol polyphosphate multikinase regulates Th1 and Th17 cell differentiation by controlling Akt-mTOR signaling.
  17. Stearoyl-CoA Desaturase 1 Regulates Metabolism and Inflammation in Mouse Perivascular Adipose Tissue in Response to a High-Fat Diet.
  18. Gut bacterial L-lysine alters metabolism and histone methylation to drive dendritic cell tolerance.
  19. Fluoxetine promotes IL-10-dependent metabolic defenses to protect from sepsis-induced lethality.
  20. Multi-omics reveals immune response and metabolic profiles during high-altitude mountaineering.
  21. Mitochondria-loading erythrocytes transfer mitochondria to ameliorate inflammatory bone loss.
  1. Curr Opin Neurol. 2025 Feb 13.
    Neuroinflammation and immunometabolism in neurodegenerative diseases.
    Neha Lonkar, Eicke Latz, Róisín M McManus.
       PURPOSE OF REVIEW: Immunometabolism is an emerging field of research investigating the ability of immune cells to modulate their metabolic activity for optimal function. While this has been extensively examined in peripheral immune cells like macrophages, only recently have these studies been extended to assess the immunometabolic activity of microglia, the innate immune cells of the brain.
    RECENT FINDINGS: Microglia are highly metabolically flexible and can utilize different nutrients for their diverse functions. Like other immune cells, they undergo metabolic reprogramming on immune stimulation and in inflammatory, neurodegenerative conditions such as Alzheimer's disease (AD). In recent years, researchers have looked at the intricate mechanisms that modulate microglial activity and have uncovered key links between altered metabolism, neuroinflammation, and the involvement of disease-associated risk genes.
    SUMMARY: This review highlights the recent studies that have significantly contributed to our understanding of the metabolic dysregulation observed in activated microglia in conditions such as AD, unveiling novel targets for therapeutic intervention.
    DOI:  https://doi.org/10.1097/WCO.0000000000001356
  2. Am J Physiol Cell Physiol. 2025 Feb 13.
    Metabolic T-cell phenotypes - from bioenergetics to function.
    Nouria Jantz-Naeem, Nese Guvencli, Romy Böttcher-Loschinski, Martin Böttcher, Dimitrios Mougiakakos, Sascha Kahlfuss.
      It is well known that T cell metabolism and function are intimately linked. Metabolic reprogramming is a dynamic process that provides the necessary energy and biosynthetic precursors while actively regulating the immune response of T cells. As such, aberrations and dysfunctions in metabolic (re)programming, resulting in altered metabolic endotypes, may have an impact on disease pathology in various contexts. With the increasing demand for personalized and highly specialized medicine and immunotherapy, understanding metabolic profiles and T cell subset dependence on specific metabolites will be crucial to harness the therapeutic potential of immunometabolism and T cell bioenergetics. In this review, we dissect metabolic alterations in different T cell subsets in autoimmune and viral inflammation, T cell and non-T cell malignancies, highlighting potential anchor points for future treatment and therapeutic exploitation.
    Keywords:  Autoimmunity; Cancer; Immunometabolism; T cells; Viral infection
    DOI:  https://doi.org/10.1152/ajpcell.00478.2024
  3. Eur J Microbiol Immunol (Bp). 2025 Feb 12.
    Acsbg1 regulates differentiation and inflammatory properties of CD4+ T cells.
    Martina Palatella, Friederike Kruse, Silke Glage, André Bleich, Marina Greweling-Pils, Jochen Huehn.
      Epigenetic modifications are critical for the regulation of CD4+ T cell differentiation and function. Previously, we identified Acyl-CoA Synthetase Bubble Gum 1 (Acsbg1), a gene involved in fatty acid metabolism, as part of an epigenetic signature that was selectively demethylated in ex vivo isolated T helper 17 (TH17) cells. However, its functional relevance for CD4+ T cells remains incompletely understood. Here, we used in vitro differentiation assays and the adoptive transfer colitis model to investigate the role of Acsbg1 in the differentiation and function of TH1, TH17, and regulatory T (Treg) cells. In vitro, Acsbg1 was expressed in both TH17 and in vitro-induced Treg (iTreg) cells, whereas TH1 cells lacked Acsbg1 expression. Accordingly, Acsbg1 deficiency resulted in impaired TH17 and iTreg differentiation, whereas TH1 differentiation was unaffected. In vivo, upon adoptive transfer of Acsbg1⁻/⁻ Tnaïve cells, immunodeficient recipient mice exhibited an exacerbated colitis, characterized by an altered balance of TH17 and Treg cells, indicating that Acsbg1 expression is essential for optimal TH17 and Treg cell differentiation and function. Our findings highlight the importance of fatty acid (FA) metabolism in maintaining immune homeostasis by regulating T cell differentiation and provide novel insights into the metabolic targeting of inflammatory diseases.
    Keywords:  Acsbg1; Th17; Treg; colitis; fatty acid metabolism; mucosal immunology
    DOI:  https://doi.org/10.1556/1886.2025.00003
  4. Am J Cancer Res. 2025 ;15(1): 233-247
    Role of amino acid metabolism in tumor immune microenvironment of colorectal cancer.
    Minjing Zhu, Yanyan Hu, Yangjia Gu, Xuedan Lin, Xiang Jiang, Chaoju Gong, Zejun Fang.
      This review investigates the role of amino acid metabolism in the tumor microenvironment of colorectal cancer (CRC) and explores potential targeted therapeutic strategies. The paper synthesized current research on amino acid metabolism in the colorectal cancer tumor microenvironment, focusing on amino acids such as tryptophan, methionine, glutamine, and arginine. It examined their impact on tumor growth, immune evasion, and patient prognosis, as well as the metabolic reprogramming of tumor cells and complex tumor microenvironment interactions. Aberrant amino acid metabolism was a hallmark of colorectal cancer, influencing tumor proliferation, survival, and invasiveness. Key findings included: Tryptophan metabolism via the kynurenine and serotonin pathways significantly affected immune response and tumor progression in CRC. Methionine influenced T cell function and DNA methylation, playing a critical role in tumor development. Glutamine was extensively used by tumor cells for energy metabolism and supported immune cell function. Arginine metabolism impacted CD8+ T cell functionality and tumor growth. The review also discussed the dual roles of immune cells in the tumor microenvironment and the potential of targeting amino acid metabolic pathways for CRC treatment. In conclusion, amino acid metabolism significantly impacts the colorectal cancer tumor microenvironment and immunity. Understanding these metabolic pathways provides valuable insights into CRC pathogenesis and identifies potential therapeutic targets. Future research should focus on developing treatments that disrupt these metabolic processes to improve patient outcomes in CRC.
    Keywords:  Colorectal cancer; amino acid metabolism; immune evasion; therapeutic targets; tumor microenvironment
    DOI:  https://doi.org/10.62347/ZSOO2247
  5. Int Immunopharmacol. 2025 Feb 12. pii: S1567-5769(25)00269-3. [Epub ahead of print]150 114279
    Apabetalone alleviates ligature-induced periodontitis by inhibiting M1 macrophage polarization via an immunometabolic shift.
    Tianying Bian, Hu Li, Haohao Liu, Mudi Guo, Yiding Zhang, Pinli Hu, Meihua Chen.
       OBJECTIVES: To explore the effects and biological mechanism of apabetalone on periodontal inflammation by regulating glycolysis and metabolites.
    METHODS: A ligature-induced periodontitis model was established in mice and apabetalone was administered on the ligation silk for two weeks. Inflammation levels and alveolar bone absorption were explored using micro-computed tomography and histopathological analysis. To observe the role of apabetalone in macrophage polarization and the macrophage-mediated immune microenvironment, a Luminex assay, quantitative real-time polymerase chain reaction, a conditioned medium experiment, a Seahorse extracellular flux assay and quantitative metabolomics were used for molecular biological analysis.
    RESULTS: Apabetalone-treated mice exhibited ameliorated alveolar bone loss and inflammatory infiltration in the periodontium. Furthermore, apabetalone significantly inhibited the production of proinflammatory cytokines and suppressed the levels of M1-specific biomarkers both in vivo and in vitro. Apabetalone also promoted the osteogenic potential of mouse periodontal ligament cells in a macrophage-mediated microenvironment. Apabetalone restrained LPS-induced glucose uptake and lactic acid production. Apabetalone inhibited glycolysis by suppressing the transcription and protein expression of hexokinase 2, glucose transporter 1 and phosphofructokinase-2/fructose-2,6- bisphosphatase 3 (PFKFB3) in a dose-dependent manner. Quantitative analysis of certain carbohydrates involved in energy metabolism revealed that apabetalone reserved the disruption of the tricarboxylic acid (TCA) cycle and inhibited glycolysis and the pentose phosphate pathway. In addition, apabetalone increased the oxygen consumption rate.
    CONCLUSION: Collectively, these findings indicate that apabetalone improves the periodontal immune microenvironment by regulating metabolites in macrophages. Apabetalone exerts anti-inflammatory and osteo-protective effects by replenishing the broken TCA cycle and suppressing glycolysis. Apabetalone is a potential candidate for the treatment of periodontitis.
    Keywords:  Apabetalone; Glycolysis; Macrophage polarization; Metabolic reprogramming; Periodontitis
    DOI:  https://doi.org/10.1016/j.intimp.2025.114279
  6. PLoS One. 2025 ;20(2): e0305065
    Starve a cold or feed a fever? Identifying cellular metabolic changes following infection and exposure to SARS-CoV-2.
    Emma K Loveday, Hope Welhaven, Ayten Ebru Erdogan, Kyle S Hain, Luke F Domanico, Connie B Chang, Ronald K June, Matthew P Taylor.
      Viral infections induce major shifts in cellular metabolism elicited by active viral replication and antiviral responses. For the virus, harnessing cellular metabolism and evading changes that limit replication are essential for productive viral replication. In contrast, the cellular response to infection disrupts metabolic pathways to prevent viral replication and promote an antiviral state in the host cell and neighboring bystander cells. This competition between the virus and cell results in measurable shifts in cellular metabolism that differ depending on the virus, cell type, and extracellular environment. The resulting metabolic shifts can be observed and analyzed using global metabolic profiling techniques to identify pathways that are critical for either viral replication or cellular defense. SARS-CoV-2 is a respiratory virus that can exhibit broad tissue tropism and diverse, yet inconsistent, symptomatology. While the factors that determine the presentation and severity of SARS-CoV-2 infection remain unclear, metabolic syndromes are associated with more severe manifestations of SARS-CoV-2 disease. Despite these observations a critical knowledge gap remains between cellular metabolic responses and SARS-CoV-2 infection. Using a well-established untargeted metabolomics analysis workflow, we compared SARS-CoV-2 infection of human lung carcinoma cells. We identified significant changes in metabolic pathways that correlate with either productive or non-productive viral infection. This information is critical for characterizing the factors that contribute to SARS-CoV-2 replication that could be targeted for therapeutic interventions to limit viral disease.
    DOI:  https://doi.org/10.1371/journal.pone.0305065
  7. Mol Metab. 2025 Feb 08. pii: S2212-8778(25)00018-3. [Epub ahead of print] 102111
    ACC1 is a Dual Metabolic-Epigenetic Regulator of Treg Stability and Immune Tolerance.
    Philipp Stüve, Gloria J Godoy, Fernando N Ferreyra, Florencia Hellriegel, Fatima Boukhallouk, Yu-San Kao, Tushar H More, Anne-Marie Matthies, Tatiana Akimova, Wolf-Rainer Abraham, Volkhard Kaever, Ingo Schmitz, Karsten Hiller, Matthias Lochner, Benoît L Salomon, Ulf H Beier, Michael Rehli, Tim Sparwasser, Luciana Berod.
       OBJECTIVE: Regulatory T cells (Tregs) are essential in maintaining immune tolerance and controlling inflammation. Treg stability relies on transcriptional and post-translational mechanisms, including histone acetylation at the Foxp3 locus and FoxP3 protein acetylation. Additionally, Tregs depend on specific metabolic programs for differentiation, yet the underlying molecular mechanisms remain elusive. We aimed to investigate the role of acetyl-CoA carboxylase 1 (ACC1) in the differentiation, stability, and function of regulatory T cells (Tregs).
    METHODS: We used either T cell-specific ACC1 knockout mice or ACC1 inhibition via a pharmacological agent to examine the effects on Treg differentiation and stability. The impact of ACC1 inhibition on Treg function was assessed in vivo through adoptive transfer models of Th1/Th17-driven inflammatory diseases.
    RESULTS: Inhibition or genetic deletion of ACC1 led to an increase in acetyl-CoA availability, promoting enhanced histone and protein acety lation, and sustained FoxP3 transcription even under inflammatory conditions. Mice with T cell-specific ACC1 deletion exhibited an enrichment of double positive RORγt+FoxP3+ cells. Moreover, Tregs treated with an ACC1 inhibitor demonstrated superior long-term stability and an enhanced capacity to suppress Th1/Th17-driven inflammatory diseases in adoptive transfer models.
    CONCLUSIONS: We identified acetyl-CoA carboxylase 1 (ACC1) as a metabolic checkpoint in Treg biology. Our data demonstrate that ACC1 inhibition promotes Treg differentiation and long-term stability in vitro and in vivo. Thus, ACC1 serves as a dual metabolic and epigenetic hub, regulating immune tolerance and inflammation by balancing de novo lipid synthesis and protein acetylation.
    Keywords:  ACC1; Acetylation; Adoptive Treg transfer; Epigenetic regulation; Fatty acid synthesis; Treg stability
    DOI:  https://doi.org/10.1016/j.molmet.2025.102111
  8. CNS Neurosci Ther. 2025 Feb;31(2): e70229
    Examining the Impact of Microglia on Ischemic Stroke With an Emphasis on the Metabolism of Immune Cells.
    Jing Lv, Yang Jiao, Xinya Zhao, Xin Kong, Yanwei Chen, Lu Li, Xuyang Chen, Xufeng Tao, Deshi Dong.
       BACKGROUND: Ischemic stroke, a major cause of disability and the second leading cause of death, poses a significant public health challenge. Post-stroke inflammation can harm the blood-brain barrier and worsen neurological deficits, which are key factors in neuronal damage in patients with ischemic stroke. Microglia are crucial in the central nervous system, involved in inflammation, neuronal damage, and repair after cerebral ischemia. While cellular immune metabolism has been widely studied, its role in ischamic stroke remains unclear.
    AIM: This review aims to examine how inflammation affects the phenotypic characteristics of immune cells after ischemic stroke and to explore the effects of the immune metabolic microenvironment on the phenotypic profiles and functions of microglia in ischemic stroke.
    METHOD: The review refers to the available literature in PubMed, searching for critical terms related to Ischemic stroke, neuroinflammation, microglia, and immunometabolism.
    RESULT: In this review, we found that during stroke progression, microglia can dynamically switch between pro-inflammatory and anti-inflammatory phenotypes. Microglial glycometabolism includes oxidative phosphorylation and glycolysis, and lipid metabolism involves lipid synthesis and breakdown. Modulating the production of inflammatory mediator precursors can induce an anti-inflammatory phenotype in microglia.
    CONCLUSION: Thus, studying microglial metabolic pathways and their products may offer new insights for ischemic stroke treatment.
    Keywords:  immunometabolism; ischemic stroke; microglia; neuroinflammation
    DOI:  https://doi.org/10.1111/cns.70229
  9. Cell Rep. 2025 Jan 28. pii: S2211-1247(24)01487-6. [Epub ahead of print]44(1): 115136
    Mechanical force receptor Piezo1 regulates TH9 cell differentiation.
    Qiuli Yang, Yejin Cao, Likun Wang, Yingjie Dong, Longhao Zhao, Zi Geng, Yujing Bi, Guangwei Liu.
      Interleukin (IL)-9-producing CD4+ T cells (TH9) are essential for mediating antitumor immunity, but the mechanisms of TH9 cell differentiation remain unclear. Here, we found that the mechanical force receptor Piezo1 is critical for regulating TH9 cell differentiation. Piezo1 deficiency in CD4+ T cells intrinsically inhibited TH9 cell differentiation, whereas ectopic Piezo1 expression promoted this process. Notably, Piezo1 deficiency inhibited TH9 cell differentiation and contributed to tumor development. Mechanistically, Piezo1 deficiency inhibits TH9 cell differentiation mainly through the SIRT3-succinate dehydrogenase A (SDHA)-oxidative phosphorylation (OXPHOS) pathway. SIRT3 deficiency or blockade of SDHA-OXPHOS signaling activity reversed the TH9 cell differentiation induced by Piezo1 deficiency. Moreover, HIF1α signaling is responsible for the TH9 cell differentiation induced by Piezo1 deficiency. Thus, our findings identify a redox metabolism signaling mechanism regulated by the mechanical force receptor Piezo1 that limits the mitochondrial SIRT3-SDHA-dependent OXPHOS pathway and triggers HIF1α-IL-9 to reprogram TH9 cell differentiation, with implications for future immunotherapy approaches.
    Keywords:  CP: Cell biology; CP: Immunology; Piezo1; T cell differentiation; T(H)9; allergic airway inflammation; antitumor immunity; cancer; helper T cells; metabolism; tumor
    DOI:  https://doi.org/10.1016/j.celrep.2024.115136
  10. Sci Transl Med. 2025 Feb 12. 17(785): eadm7269
    Tumor extracellular vesicle-derived PD-L1 promotes T cell senescence through lipid metabolism reprogramming.
    Feiya Ma, Xia Liu, Yuanqin Zhang, Yan Tao, Lei Zhao, Hazar Abusalamah, Cody Huffman, R Alex Harbison, Sidharth V Puram, Yuqi Wang, Guangyong Peng.
      The limited success of cancer immunotherapy has posed challenges in treating patients with cancer. However, promising strides could be made with a deeper understanding of the factors that cause T cell dysfunction within the tumor microenvironment and by developing effective strategies to counteract tumor-induced immune suppression. Here, we report that tumor-derived extracellular vesicles (tEVs) can induce senescence and suppression in T cells. Programmed death ligand 1 (PD-L1), a key component within tEVs, induced DNA damage and hyperactive lipid metabolism in both human and mouse T cells. This caused an elevated expression of lipid metabolic enzymes and an increase in cholesterol and lipid droplet formation, leading to cellular senescence. At a molecular level, PD-L1 derived from tEVs activated the cAMP-response element binding protein (CREB) and signal transducer and activator of transcription (STAT) signaling, which promoted lipid metabolism and facilitated senescence in human and mouse T cells. Inhibiting EV synthesis in tumors or blocking CREB signaling, cholesterol synthesis, and lipid droplet formation in effector T cells averted the tEV-mediated T cell senescence in vitro and in vivo in cell adoptive transfer and melanoma mouse models. The same treatments also bolstered the antitumor efficacy of adoptive transfer T cell therapy and anti-PD-L1 checkpoint immunotherapy in both human and mouse melanoma models. These studies identified mechanistic links between tumor-mediated immune suppression and potential immunotherapy resistance, and they provide new strategies for cancer immunotherapy.
    DOI:  https://doi.org/10.1126/scitranslmed.adm7269
  11. Infect Med (Beijing). 2025 Mar;4(1): 100162
    Recent advances in nutritional metabolism studies on SARS-CoV-2 infection.
    Yufen Jiang, Linle Xu, Xuexing Zheng, Hongbo Shi.
      In the context of the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), metabolic research has become crucial for in-depth exploration of viral infection mechanisms and in searching for therapeutic strategies. This paper summarizes the interrelationships between carbohydrate, lipid, and amino acid metabolism and COVID-19 infection, discussing their roles in infection progression. SARS-CoV-2 infection leads to insulin resistance and increased glycolysis, reducing glucose utilization and shifting metabolism to use fat as an energy source. Fat is crucial for viral replication, and imbalances in amino acid metabolism may interfere with immune regulation. Consequently, metabolic changes such as hyperglycemia, hypolipidemia, and deficiency of certain amino acids following SARS-CoV-2 infection can contribute to progression toward severe conditions. These metabolic pathways not only have potential value in prediction and diagnosis but also provide new perspectives for the development of therapeutic strategies. By monitoring metabolic changes, infection severity can be predicted early, and modulating these metabolic pathways may help reduce inflammatory responses, improve immune responses, and reduce the risk of thrombosis. Research on the relationship between metabolism and SARS-CoV-2 infection provides an important scientific basis for addressing the global challenge posed by COVID-19, however, further studies are needed to validate these findings and provide more effective strategies for disease control.
    Keywords:  Amino acid metabolism; Carbohydrate metabolism; Lipid metabolism; SARS-CoV-2
    DOI:  https://doi.org/10.1016/j.imj.2025.100162
  12. J Control Release. 2025 Feb 11. pii: S0168-3659(25)00111-7. [Epub ahead of print]380 469-489
    Metabolic reprogramming of macrophages by a nano-sized opsonization strategy to restore M1/M2 balance for osteoarthritis therapy.
    Ruijie Chen, Shimin Zheng, Xinyu Zhao, Huirong Huang, Yitianhe Xu, Chenyu Qiu, Shengjie Li, Xindan Liang, Pengfei Mao, Yuqi Yan, Yinhao Lin, Shengnan Song, Wenjing Cai, Haoxiong Guan, Yinsha Yao, Wanling Zhu, Xianbao Shi, Vadivel Ganapathy, Longfa Kou.
      Osteoarthritis is a chronic and progressive joint disease accompanied by cartilage degeneration and synovial inflammation. It is associated with an imbalance of synovial macrophage M1/M2 ratio tilting more towards the pro-inflammatory M1 than the anti-inflammatory M2. The M1-macrophages rely on aerobic glycolysis for energy whereas the M2-macrophages derive energy from oxidative phosphorylation. Therefore, inhibiting aerobic glycolysis to induce metabolic reprogramming of macrophages and consequently promote the shift from M1 type to M2 type is a therapeutic strategy for osteoarthritis. Here we developed a macrophage-targeting strategy based on opsonization, using nanoparticles self-assembled to incorporate Chrysin (an anti-inflammatory flavonoid) and V-9302 (an inhibitor of glutamine uptake), and the outer layer modified by immunoglobulin IgG by electrostatic adsorption into IgG/Fe-CV NPs. In vitro studies showed that IgG/Fe-CV NPs effectively target M1 macrophages and inhibit HIF-1α and GLUT-1 essential for aerobic glycolysis and promote polarization from M1 to M2-type macrophages. In vivo, IgG/Fe-CV NPs inhibit inflammation and protect against cartilage damage. The metabolic reprogramming strategy with IgG/Fe-CV NPs to shift macrophage polarization from inflammatory to anti-inflammatory phenotype by inhibiting aerobic glycolysis and glutamine delivery may open up new avenues to treat osteoarthritis.
    Keywords:  Aerobic glycolysis; HIF-1α; Macrophage reprogramming; Opsonization; Osteoarthritis
    DOI:  https://doi.org/10.1016/j.jconrel.2025.02.005
  13. Apoptosis. 2025 Feb 09.
    Itaconate promotes mitophagy to inhibit neuronal ferroptosis after subarachnoid hemorrhage.
    Guijun Wang, Zhijie Li, Wenrui Han, Qi Tian, Chengli Liu, Shengming Jiang, Xi Xiang, Xincan Zhao, Lei Wang, Jianming Liao, Mingchang Li.
      Subarachnoid hemorrhage (SAH), representing 5-10% of all stroke cases, is a cerebrovascular event associated with a high mortality rate and a challenging prognosis. The role of IRG1-regulated itaconate in bridging metabolism, inflammation, oxidative stress, and immune response is pivotal; however, its implications in the early brain injury following SAH remain elusive. The SAH nerve inflammation model was constructed by Hemin solution and BV2 cells. In vitro and in vivo SAH models were established by intravascular puncture and Hemin solution treatment of HT22 cells. To explore the relationship between IRG1 and neuroinflammation by interfering the expression of Irg1 in BV2 cells. By adding itaconate and its derivatives to explore the relationship between mitophagy and ferroptosis. IRG1 knockdown increased the expression of inflammatory factors and induced the transformation of microglia to pro-inflammatory phenotype after SAH; Itaconate and itaconate derivative 4-OI can reduce oxidative stress and lipid peroxidation level in neuron after SAH, and reduce EBI after SAH; IRG1/ itaconate promotes mitophagy through PINK1/Parkin signaling pathway to inhibit neuronal ferroptosis. IRG1 can improve nerve inflammation after SAH, M2 of microglia induced polarization. IRG1/ Itaconate participates in mitophagy through PINK1/Parkin to alleviate neuronal ferroptosis after SAH and play a neuroprotective role.
    Keywords:  Ferroptosis; IRG1; Itaconate; Mitophagy; Subarachnoid hemorrhage
    DOI:  https://doi.org/10.1007/s10495-025-02077-1
  14. Immunity. 2025 Feb 11. pii: S1074-7613(24)00533-8. [Epub ahead of print]58(2): 344-361.e7
    Early-age efferocytosis directs macrophage arachidonic acid metabolism for tissue regeneration.
    Connor Lantz, Amanda Becker, Matthew DeBerge, Mallory Filipp, Kristofor Glinton, Aparnaa Ananthakrishnan, Jessica Urbanczyk, Madeline Cetlin, Afnan Alzamroon, Ahmed Abdel-Latif, Matthew Spite, Zhi-Dong Ge, Edward B Thorp.
      In response to organ injury in adults, macrophages often promote scarring, yet during early life, they are required for tissue regeneration. To elucidate the mechanisms underlying age-associated regeneration, we compared the macrophage injury response in newborn versus adult hearts. Single-cell analysis revealed an accumulation of tissue-resident macrophages in neonates that were selectively polarized for apoptotic cell recognition and uptake (efferocytosis). Ablation of the apoptotic cell recognition receptor Mertk in newborns prevented cardiac regeneration. These findings could be attributed to reprogramming of macrophage gene expression that was required for biosynthesis of the eicosanoid thromboxane A2, which unexpectedly activated parenchymal cell proliferation. Markers of thromboxane A2 production were suppressed in adult macrophages after efferocytosis. Moreover, macrophage-neighboring neonatal cardiomyocytes expressed the thromboxane A2 receptor, whose activation induced a metabolic shift that supported cellular proliferation. Our data reveal a fundamental age-defined macrophage response in which lipid mitogens produced during efferocytosis support receptor-mediated tissue regeneration.
    Keywords:  aging; arachidonic acid; efferocytosis; heart; immunometabolism; macrophage; proliferation; regeneration; thromboxane
    DOI:  https://doi.org/10.1016/j.immuni.2024.11.018
  15. Cell Mol Gastroenterol Hepatol. 2025 Feb 07. pii: S2352-345X(25)00015-3. [Epub ahead of print] 101474
    Citrulline inhibits Clostridioides difficile infection with anti-inflammatory effects.
    Ying Xie, Sophie Irwin, Becca Nelson, Mieke van Daelen, Lindsey Fontenot, Jonathan P Jacobs, Monica Cappelletti, Hanping Feng, Yiling Li, Hon Wai Koon.
       BACKGROUND AND AIMS: Clostridioides difficile infection (CDI) causes colitis and diarrhea. C. difficile bacterium produces toxins A and B, which cause intestinal inflammation. A metabolomics analysis discovered fecal metabolites with anti-inflammatory effects in CDI. We aimed to identify an anti-CDI metabolite that can inhibit CDI-mediated colitis and prevent recurrence.
    METHODS: Fresh human colonic tissues and primary human cells were used to determine metabolite effects. Humanized C. difficile-infected HuCD34-NCG mice and antibiotics-treated human gut microbiota-treated (ABX+HGM) hamsters were used to simulate the human environment.
    RESULTS: High-throughput screening and fecal metabolomics analysis identified anti-inflammatory metabolites. Compared to other tested metabolites, citrulline preserved the mucosal integrity of toxin-exposed fresh human colonic tissues with reduced macrophage inflammatory protein 1 alpha (MIP-1α) and increased interleukin-10 (IL-10) expression. Oral citrulline treatment alleviated cecal inflammation in hamsters infected with C. difficile ribotype 027. This was accomplished by the augmented expression of cecal IL-10 and the diminished level of cecal MIP-1α. Citrulline and vancomycin synergistically prevented recurrence in the infected ABX+HGM hamsters. In C57BL/6J mice infected with C. difficile VPI10463, citrulline ameliorated colitis by reducing colonic Ccl3 mRNA expression. In immunologically humanized HuCD34-NCG mice infected with toxin B-expressing C. difficile ribotype 017, citrulline ameliorated colitis with increased human IL-10 expression in colonic macrophages. Citrulline suppressed MIP-1α secretion and GSK3α/β dephosphorylation in the toxin A-exposed human colonic epithelial cells and promoted IL-10 expression in toxin B-exposed human macrophages and heat shock protein 27 phosphorylation.
    CONCLUSION: Citrulline exerts anti-inflammatory effects in the intestines against C. difficile toxins and inhibits CDI recurrence in mice and hamsters.
    Keywords:  inflammation; metabolite; microbiome
    DOI:  https://doi.org/10.1016/j.jcmgh.2025.101474
  16. Cell Rep. 2025 Feb 12. pii: S2211-1247(25)00052-X. [Epub ahead of print]44(2): 115281
    Inositol polyphosphate multikinase regulates Th1 and Th17 cell differentiation by controlling Akt-mTOR signaling.
    Chae Min Yuk, Sehoon Hong, Dongeon Kim, Mingyo Kim, Hyun-Woo Jeong, Seung Ju Park, Hyungyu Min, Wooseob Kim, Jongbu Lim, Hyo Dam Kim, Sang-Gyu Kim, Rho Hyun Seong, Seyun Kim, Seung-Hyo Lee.
      Activated proinflammatory T helper (Th) cells, including Th1 and Th17 cells, drive immune responses against pathogens and contribute to autoimmune diseases. We show that the expression of inositol polyphosphate multikinase (IPMK), an enzyme essential for inositol phosphate metabolism, is highly induced in Th1 and Th17 subsets. Deletion of IPMK in CD4+ T cells leads to diminished Th1- and Th17-mediated responses, reducing resistance to Leishmania major and attenuating experimental autoimmune encephalomyelitis. IPMK-deficient CD4+ T cells show impaired activation and Th17 differentiation, linked to the decreased activation of Akt, mTOR, and STAT3. Mechanistically, IPMK functions as a phosphatidylinositol 3-kinase to regulate phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3) production, promoting T cell activation and effector functions. In IPMK-deficient CD4+ T cells, T cell receptor-stimulated PtdIns(3,4,5)P3 generation is abolished by wortmannin, suggesting IPMK acts in a wortmannin-sensitive manner. These findings establish IPMK as a critical regulator of Th1 and Th17 differentiation, underscoring its role in maintaining immune homeostasis.
    Keywords:  CD4(+) T cell differentiation; CD4(+) T cells; CP: Immunology; CP: Metabolism; EAE; IPMK; Leishmania major infection; PIP3-Akt-mTOR signaling; STAT3 signaling; Th1 cells; Th17 cells; experimental autoimmune encephalomyelitis; inositol polyphosphate multikinase
    DOI:  https://doi.org/10.1016/j.celrep.2025.115281
  17. J Cell Physiol. 2025 Feb;240(2): e31510
    Stearoyl-CoA Desaturase 1 Regulates Metabolism and Inflammation in Mouse Perivascular Adipose Tissue in Response to a High-Fat Diet.
    Adrian Sowka, Volodymyr V Balatskyi, Viktor O Navrulin, James M Ntambi, Pawel Dobrzyn.
      The dysregulation of perivascular adipose tissue (PVAT) is a key contributor to obesity-induced vascular dysfunction. Mouse periaortic adipose tissue is divided into two parts: thoracic perivascular adipose tissue (TPVAT) and abdominal perivascular adipose tissue (APVAT). These two parts have different physiological properties, which translate into different effects on the vascular wall in the onset of metabolic syndrome. Stearoyl-CoA desaturase 1 (SCD1) is an enzyme that is involved in the synthesis of monounsaturated fatty acids and has been shown to play an important role in metabolic syndrome, including vascular homeostasis. Despite a considerable focus on the role of SCD1 in the development of vascular disorders, there is currently a lack of knowledge of the relationship between SCD1 and PVAT. The present study investigated effects of SCD1 deficiency on lipolysis, β-oxidation, mitochondrial dynamics, and inflammation in mouse TPVAT and APVAT under high-fat diet (HFD) feeding conditions. We found lower triglyceride levels in PVAT in SCD1-/- mice both in vitro and in vivo compared with wildtype perivascular adipocytes, attributable to activated lipolysis and β-oxidation. Moreover, PVAT in HFD-fed SCD1-/- mice was characterized by higher levels of oxidative phosphorylation complexes and mitochondrial respiratory potential and alterations of mitochondrial morphology compared with wildtype mice. Furthermore, TPVAT and APVAT in SCD1-/- mice showed signs of greater pro-inflammatory macrophage polarization and higher inflammatory markers that were induced by a HFD. This may be related to the accumulation free fatty acids and diacylglycerols, which are enriched in saturated fatty acids. These findings elucidate the role of SCD1 in maintaining vascular integrity.
    Keywords:  PVAT; fatty acids; inflammation; lipid metabolism; mitochondria
    DOI:  https://doi.org/10.1002/jcp.31510
  18. Cell Rep. 2025 Jan 28. pii: S2211-1247(24)01476-1. [Epub ahead of print]44(1): 115125
    Gut bacterial L-lysine alters metabolism and histone methylation to drive dendritic cell tolerance.
    Qiang Tang, Guangyue Fan, Xianping Peng, Xinyu Sun, Xueting Kong, Lisong Zhang, Chunze Zhang, Yandi Liu, Jianming Yang, Kaiyuan Yu, Chunhui Miao, Zhi Yao, Long Li, Zhi-Song Zhang, Quan Wang.
      Dendritic cells (DCs) are responsible for maintaining tolerance to harmless antigens in the gut; however, the mechanism by which bacterial metabolites induce DC tolerance remains to be studied. Here, we observed that gut commensal bacterium-derived L-lysine stimulated the serine, glycine, one-carbon (SGOC) metabolism through the adenosine monophosphate (AMP)-activated protein kinase (AMPK)/acetyl-coenzyme A (AcCoA)-mechanistic target of rapamycin (mTOR) axis in DCs. This activation led to an increase in S-adenosyl methionine (SAM) and disruptor of telomeric silencing 1-like (DOT1L) expression, resulting in enhanced dimethylation on H3 lysine 79 (H3K79me2) enrichment at Tgfb and signal transducers and activator of transcription 3 (Stat3) gene promoters, which promote immune tolerance characteristics in DCs. The lysine-induced DC tolerance in restoring homeostasis was demonstrated using mouse models of immune-inflammatory diseases and phosphoglycerate dehydrogenase (Phgdh) conditional knockout mice. The single-cell RNA sequencing (scRNA-seq) analysis revealed that L-lysine restored homeostasis during inflammatory disorders by switching DCs to a tolerance state in vivo. Moreover, the enzyme by which bacteria effectively produce L-lysine is identified. The study reveals an unknown mechanism for regulating immune homeostasis through the intricate interplay of bacterial L-lysine, SGOC metabolism, histone methylation, and DC tolerance.
    Keywords:  CP: Immunology; CP: Microbiology; H3K79me2; L-lysine; SGOC metabolism; dendritic cell; immune tolerance
    DOI:  https://doi.org/10.1016/j.celrep.2024.115125
  19. Sci Adv. 2025 Feb 14. 11(7): eadu4034
    Fluoxetine promotes IL-10-dependent metabolic defenses to protect from sepsis-induced lethality.
    Robert M Gallant, Karina K Sanchez, Emeline Joulia, Jessica M Snyder, Christian M Metallo, Janelle S Ayres.
      Selective serotonin reuptake inhibitors (SSRIs) are some of the most prescribed drugs in the world. While they are used for their ability to increase serotonergic signaling in the brain, SSRIs are also known to have a broad range of effects beyond the brain, including immune and metabolic effects. Recent studies have demonstrated that SSRIs are protective in animal models and humans against several infections, including sepsis and COVID-19; however, the mechanisms underlying this protection are largely unknown. Here, we mechanistically link two previously described effects of the SSRI fluoxetine in mediating protection against sepsis. We show that fluoxetine-mediated protection is independent of peripheral serotonin and instead increases levels of circulating interleukin-10 (IL-10). IL-10 is necessary for protection from sepsis-induced hypertriglyceridemia, preventing cardiac effects including impairment of glucose oxidation, ectopic lipid accumulation, ventricular stretch and possibly cardiac failure. Our work reveals a beneficial "off-target" effect of fluoxetine, and reveals a protective immunometabolic defense mechanism with therapeutic potential.
    DOI:  https://doi.org/10.1126/sciadv.adu4034
  20. Cell Rep. 2025 Jan 28. pii: S2211-1247(24)01485-2. [Epub ahead of print]44(1): 115134
    Multi-omics reveals immune response and metabolic profiles during high-altitude mountaineering.
    Jianhua Yin, Jingzhi Lv, Shichen Yang, Yang Wang, Zhuoli Huang, Xue Wang, Guixue Hou, Wenwen Zhou, Ying Liu, Weikai Wang, Xiumei Lin, Yunting Huang, Yuhui Zheng, Chen Wei, Yue Yuan, Yaling Huang, Chang Liu, Haoran Tao, Huanhuan Liu, Ruquan Liu, Yan Zhang, Guodan Zeng, Feiyun Quan, Xinyue Zhu, Peng Gao, Jun Xie, Longqi Liu, Jun Cao, Chuanyu Liu, Xin Jin, Jian Wang.
      The physiological perturbations induced by high-altitude exposure in mountain climbers, manifesting as immunological and metabolic deviations, have been previously reported but are not fully understood. In this study, we obtain multi-omic profiles of climbers' blood samples, including single-cell transcriptomic analysis of 375,722 immune cells, and plasma metabolomics and lipidomics. Longitudinal analysis reveals dynamic immune response profiles, during the acclimatization period, characterized by the downregulation of inflammatory responses in myeloid cell subsets and by the enhancement of immune effector processes in cytotoxic CD8+ T, γδT, and CD16+ natural killer cells. In contrast, during extreme-altitude mountaineering, the activation of inflammatory responses and impairment of immune effector function are observed, concomitant with an increased cellular response to hypoxia and oxidative stress pathways. Furthermore, glycolysis and antioxidant gene expression are upregulated during extreme-altitude mountaineering. Plasma metabolic analysis reveals significant alterations, involving enhanced glutamine and fatty acid metabolism.
    Keywords:  CP: Immunology; CP: Metabolism; HIF1A; high-altitude mountaineering; hypoxia; immune response; metabolism; mountain climber; single-cell RNA sequencing
    DOI:  https://doi.org/10.1016/j.celrep.2024.115134
  21. Acta Biomater. 2025 Feb 10. pii: S1742-7061(25)00106-0. [Epub ahead of print]
    Mitochondria-loading erythrocytes transfer mitochondria to ameliorate inflammatory bone loss.
    Shi Cheng, Lu Zhou, Wu-Yin Wang, Meng-Jie Zhang, Qi-Chao Yang, Wen- Da Wang, Kong-Huai Wang, Zhi-Jun Sun, Lu Zhang.
      Inflammatory diseases frequently result in bone loss, a condition for which effective therapeutic interventions are lacking. Mitochondrial transfer and transplantation hold promise in tissue repair and disease treatments. However, the application of mitochondrial transfer in alleviating disorders has been limited due to its uncontrollable nature. Moreover, a key challenge in this field is maintaining the quality of isolated mitochondria (Mito), as dysfunctional Mito can exacerbate disease progression. Therefore, we employ Mito loading erythrocytes (named MiLE) to achieve maintenance of mitochondrial quality. In addition, MiLE can be cryopreserved, allowing for long-term preservation of mitochondrial quality and facilitating the future application of mitochondrial transfer. In the inflammatory microenvironment, MiLE supplying Mito as well as O2 to macrophages. By undergoing metabolic reprogramming, MiLE suppresses lipopolysaccharide-induced osteoclast differentiation and promotes macrophage polarization from M1 to M2 phenotype, ultimately ameliorating inflammatory bone destruction. In summary, this work tackles the challenges of uncontrollable mitochondrial transfer and mitochondrial quality maintenance, and offers an opportunity for future exploration of organelle transplantation. STATEMENT OF SIGNIFICANCE: The application of mitochondrial transfer for the alleviation of pathologies has been hindered by the intrinsic limitations in terms of control and selectivity. Furthermore, maintaining mitochondrial integrity and functionality following isolation poses a significant challenge. In a pioneering approach, our research team developed a method for encapsulating mitochondria within erythrocytes, termed Mitochondria-Loading Erythrocytes (MiLE), which ensures extended mitochondrial functionality and controlled transfer. Within an inflammatory microenvironment, MiLE supplies both mitochondria and O2 to macrophages. By undergoing metabolic reprogramming, MiLE alleviates lipopolysaccharide-induced osteoclast differentiation and promotes macrophage polarization from M1 to M2 phenotype, ultimately ameliorating inflammatory bone destruction.
    Keywords:  Inflammatory bone loss; Mitochondria-loading erythrocytes; Mitochondrial transfer
    DOI:  https://doi.org/10.1016/j.actbio.2025.02.024
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