bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2024‒09‒01
fifteen papers selected by
Dylan Ryan, University of Cambridge
  1. Sodium chloride in the tumor microenvironment enhances T cell metabolic fitness and cytotoxicity.
  2. NaCl enhances CD8+ T cell effector functions in cancer immunotherapy.
  3. Immune suppression by human thymus-derived effector Tregs relies on glucose/lactate-fueled fatty acid synthesis.
  4. Activation and antitumor immunity of CD8+ T cells are supported by the glucose transporter GLUT10 and disrupted by lactic acid.
  5. The glycolytic metabolite methylglyoxal covalently inactivates the NLRP3 inflammasome.
  6. Fatty acid metabolism constrains Th9 cell differentiation and antitumor immunity via the modulation of retinoic acid receptor signaling.
  7. Aberrant mitochondrial DNA synthesis in macrophages exacerbates inflammation and atherosclerosis.
  8. Release of mitochondrial dsRNA into the cytosol is a key driver of the inflammatory phenotype of senescent cells.
  9. Lipid synthesis, triggered by PPARγ T166 dephosphorylation, sustains reparative function of macrophages during tissue repair.
  10. Host cell-specific metabolism of linoleic acid controls Toxoplasma gondii growth in cell culture.
  11. Role of Mitofusin 1 in mediating reactive oxygen species in alveolar macrophages during Streptococcuspneumoniae.
  12. Immunometabolism in atherosclerotic disorders.
  13. Macrophage energy metabolism in cardiometabolic disease.
  14. T-Cell Metabolic Reprogramming in Atherosclerosis.
  15. New anti-inflammatory mechanism of glucocorticoids uncovered.
  1. Nat Immunol. 2024 Aug 28.
    Sodium chloride in the tumor microenvironment enhances T cell metabolic fitness and cytotoxicity.
    Dominik Soll, Chang-Feng Chu, Shan Sun, Veronika Lutz, Mahima Arunkumar, Mariam Gachechiladze, Sascha Schäuble, Maha Alissa-Alkhalaf, Trang Nguyen, Michelle-Amirah Khalil, Ignacio Garcia-Ribelles, Michael Mueller, Katrin Buder, Bernhard Michalke, Gianni Panagiotou, Kai Ziegler-Martin, Pascal Benz, Philipp Schatzlmaier, Karsten Hiller, Hannes Stockinger, Maik Luu, Kilian Schober, Carolin Moosmann, Wolfgang W Schamel, Magdalena Huber, Christina E Zielinski.
      The efficacy of antitumor immunity is associated with the metabolic state of cytotoxic T cells, which is sensitive to the tumor microenvironment. Whether ionic signals affect adaptive antitumor immune responses is unclear. In the present study, we show that there is an enrichment of sodium in solid tumors from patients with breast cancer. Sodium chloride (NaCl) enhances the activation state and effector functions of human CD8+ T cells, which is associated with enhanced metabolic fitness. These NaCl-induced effects translate into increased tumor cell killing in vitro and in vivo. Mechanistically, NaCl-induced changes in CD8+ T cells are linked to sodium-induced upregulation of Na+/K+-ATPase activity, followed by membrane hyperpolarization, which magnifies the electromotive force for T cell receptor (TCR)-induced calcium influx and downstream TCR signaling. We therefore propose that NaCl is a positive regulator of acute antitumor immunity that might be modulated for ex vivo conditioning of therapeutic T cells, such as CAR T cells.
    DOI:  https://doi.org/10.1038/s41590-024-01918-6
  2. Nat Immunol. 2024 Aug 28.
    NaCl enhances CD8+ T cell effector functions in cancer immunotherapy.
    Caterina Scirgolea, Rosa Sottile, Marco De Luca, Alberto Susana, Silvia Carnevale, Simone Puccio, Valentina Ferrari, Veronica Lise, Giorgia Contarini, Alice Scarpa, Eloise Scamardella, Simona Feno, Chiara Camisaschi, Gabriele De Simone, Gianluca Basso, Desiree Giuliano, Emilia Maria Cristina Mazza, Luca Gattinoni, Rahul Roychoudhuri, Emanuele Voulaz, Diletta Di Mitri, Matteo Simonelli, Agnese Losurdo, Davide Pozzi, Carlson Tsui, Axel Kallies, Sara Timo, Giuseppe Martano, Elettra Barberis, Marcello Manfredi, Maria Rescigno, Sebastien Jaillon, Enrico Lugli.
      CD8+ T cells control tumors but inevitably become dysfunctional in the tumor microenvironment. Here, we show that sodium chloride (NaCl) counteracts T cell dysfunction to promote cancer regression. NaCl supplementation during CD8+ T cell culture induced effector differentiation, IFN-γ production and cytotoxicity while maintaining the gene networks responsible for stem-like plasticity. Accordingly, adoptive transfer of tumor-specific T cells resulted in superior anti-tumor immunity in a humanized mouse model. In mice, a high-salt diet reduced the growth of experimental tumors in a CD8+ T cell-dependent manner by inhibiting terminal differentiation and enhancing the effector potency of CD8+ T cells. Mechanistically, NaCl enhanced glutamine consumption, which was critical for transcriptional, epigenetic and functional reprogramming. In humans, CD8+ T cells undergoing antigen recognition in tumors and predicting favorable responses to checkpoint blockade immunotherapy resembled those induced by NaCl. Thus, NaCl metabolism is a regulator of CD8+ T cell effector function, with potential implications for cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s41590-024-01923-9
  3. Cell Rep. 2024 Aug 23. pii: S2211-1247(24)01032-5. [Epub ahead of print]43(9): 114681
    Immune suppression by human thymus-derived effector Tregs relies on glucose/lactate-fueled fatty acid synthesis.
    Sander de Kivit, Mark Mensink, Sarantos Kostidis, Rico J E Derks, Esther A Zaal, Marieke Heijink, Lotte J Verleng, Evert de Vries, Ellen Schrama, Niek Blomberg, Celia R Berkers, Martin Giera, Jannie Borst.
      Regulatory T cells (Tregs) suppress pro-inflammatory conventional T cell (Tconv) responses. As lipids impact cell signaling and function, we compare the lipid composition of CD4+ thymus-derived (t)Tregs and Tconvs. Lipidomics reveal constitutive enrichment of neutral lipids in Tconvs and phospholipids in tTregs. TNFR2-co-stimulated effector tTregs and Tconvs are both glycolytic, but only in tTregs are glycolysis and the tricarboxylic acid (TCA) cycle linked to a boost in fatty acid (FA) synthesis (FAS), supported by relevant gene expression. FA chains in tTregs are longer and more unsaturated than in Tconvs. In contrast to Tconvs, tTregs effectively use either lactate or glucose for FAS and rely on this process for proliferation. FASN and SCD1, enzymes responsible for FAS and FA desaturation, prove essential for the ability of tTregs to suppress Tconvs. These data illuminate how effector tTregs can thrive in inflamed or cancerous tissues with limiting glucose but abundant lactate levels.
    Keywords:  (regulatory) T cell; CP: Immunology; CP: Metabolism; costimulation; fatty acids; glycolysis; immune suppression; isotopologue tracing; lactate; lipidomics; mass spectrometry; metabolism
    DOI:  https://doi.org/10.1016/j.celrep.2024.114681
  4. Sci Transl Med. 2024 Aug 28. 16(762): eadk7399
    Activation and antitumor immunity of CD8+ T cells are supported by the glucose transporter GLUT10 and disrupted by lactic acid.
    Ying Liu, Feng Wang, Dongxue Peng, Dan Zhang, Luping Liu, Jun Wei, Jian Yuan, Luyao Zhao, Huimin Jiang, Tingting Zhang, Yunxuan Li, Chenxi Zhao, Shuhua He, Jie Wu, Yechao Yan, Peitao Zhang, Chunyi Guo, Jiaming Zhang, Xia Li, Huan Gao, Ke Li.
      CD8+ T cell activation leads to the rapid proliferation and differentiation of effector T cells (Teffs), which mediate antitumor immunity. Although aerobic glycolysis is preferentially activated in CD8+ Teffs, the mechanisms that regulate CD8+ T cell glucose uptake in the low-glucose and acidic tumor microenvironment (TME) remain poorly understood. Here, we report that the abundance of the glucose transporter GLUT10 is increased during CD8+ T cell activation and antitumor immunity. Specifically, GLUT10 deficiency inhibited glucose uptake, glycolysis, and antitumor efficiency of tumor-infiltrating CD8+ T cells. Supplementation with glucose alone was insufficient to rescue the antitumor function and glucose uptake of CD8+ T cells in the TME. By analyzing tumor environmental metabolites, we found that high concentrations of lactic acid reduced the glucose uptake, activation, and antitumor effects of CD8+ T cells by directly binding to GLUT10's intracellular motif. Disrupting the interaction of lactic acid and GLUT10 by the mimic peptide PG10.3 facilitated CD8+ T cell glucose utilization, proliferation, and antitumor functions. The combination of PG10.3 and GLUT1 inhibition or anti-programmed cell death 1 antibody treatment showed synergistic antitumor effects. Together, our data indicate that GLUT10 is selectively required for glucose uptake of CD8+ T cells and identify that TME accumulated lactic acid inhibits CD8+ T cell effector function by directly binding to GLUT10 and reducing its glucose transport capacity. Last, our study suggests disrupting lactate-GLUT10 binding as a promising therapeutic strategy to enhance CD8+ T cell-mediated antitumor effects.
    DOI:  https://doi.org/10.1126/scitranslmed.adk7399
  5. Cell Rep. 2024 Aug 27. pii: S2211-1247(24)01039-8. [Epub ahead of print]43(9): 114688
    The glycolytic metabolite methylglyoxal covalently inactivates the NLRP3 inflammasome.
    Caroline Stanton, Chavin Buasakdi, Jie Sun, Ian Levitan, Prerona Bora, Sergei Kutseikin, R Luke Wiseman, Michael J Bollong.
      The NLRP3 inflammasome promotes inflammation in disease, yet the full repertoire of mechanisms regulating its activity is not well delineated. Among established regulatory mechanisms, covalent modification of NLRP3 has emerged as a common route for the pharmacological inactivation of this protein. Here, we show that inhibition of the glycolytic enzyme phosphoglycerate kinase 1 (PGK1) results in the accumulation of methylglyoxal, a reactive metabolite whose increased levels decrease NLRP3 assembly and inflammatory signaling in cells. We find that methylglyoxal inactivates NLRP3 via a non-enzymatic, covalent-crosslinking-based mechanism, promoting inter- and intraprotein MICA (methyl imidazole crosslink between cysteine and arginine) posttranslational linkages within NLRP3. This work establishes NLRP3 as capable of sensing a host of electrophilic chemicals, both exogenous small molecules and endogenous reactive metabolites, and suggests a mechanism by which glycolytic flux can moderate the activation status of a central inflammatory signaling pathway.
    Keywords:  CP: Immunology; CP: Metabolism; MICA modification; NLRP3; PGK1; covalent; glycolysis; inflammasome; inflammation; methylglyoxal
    DOI:  https://doi.org/10.1016/j.celrep.2024.114688
  6. Cell Mol Immunol. 2024 Aug 26.
    Fatty acid metabolism constrains Th9 cell differentiation and antitumor immunity via the modulation of retinoic acid receptor signaling.
    Takahiro Nakajima, Toshio Kanno, Yuki Ueda, Keisuke Miyako, Takeru Endo, Souta Yoshida, Satoru Yokoyama, Hikari K Asou, Kazuko Yamada, Kazutaka Ikeda, Yosuke Togashi, Yusuke Endo.
      T helper 9 (Th9) cells are interleukin 9 (IL-9)-producing cells that have diverse functions ranging from antitumor immune responses to allergic inflammation. Th9 cells differentiate from naïve CD4+ T cells in the presence of IL-4 and transforming growth factor-beta (TGF-β); however, our understanding of the molecular basis of their differentiation remains incomplete. Previously, we reported that the differentiation of another subset of TGF-β-driven T helper cells, Th17 cells, is highly dependent on de novo lipid biosynthesis. On the basis of these findings, we hypothesized that lipid metabolism may also be important for Th9 cell differentiation. We therefore investigated the differentiation and function of mouse and human Th9 cells in vitro under conditions of pharmacologically or genetically induced deficiency of the intracellular fatty acid content and in vivo in mice genetically deficient in acetyl-CoA carboxylase 1 (ACC1), an important enzyme for fatty acid biosynthesis. Both the inhibition of de novo fatty acid biosynthesis and the deprivation of environmental lipids augmented differentiation and IL-9 production in mouse and human Th9 cells. Mechanistic studies revealed that the increase in Th9 cell differentiation was mediated by the retinoic acid receptor and the TGF-β-SMAD signaling pathways. Upon adoptive transfer, ACC1-inhibited Th9 cells suppressed tumor growth in murine models of melanoma and adenocarcinoma. Together, our findings highlight a novel role of fatty acid metabolism in controlling the differentiation and in vivo functions of Th9 cells.
    Keywords:  RARα; Th9 cell; anti-tumor effect; fatty acid; immunometabolism; omics analysis
    DOI:  https://doi.org/10.1038/s41423-024-01209-y
  7. Nat Commun. 2024 Aug 26. 15(1): 7337
    Aberrant mitochondrial DNA synthesis in macrophages exacerbates inflammation and atherosclerosis.
    Niranjana Natarajan, Jonathan Florentin, Ebin Johny, Hanxi Xiao, Scott Patrick O'Neil, Liqun Lei, Jixing Shen, Lee Ohayon, Aaron R Johnson, Krithika Rao, Xiaoyun Li, Yanwu Zhao, Yingze Zhang, Sina Tavakoli, Sruti Shiva, Jishnu Das, Partha Dutta.
      There is a large body of evidence that cellular metabolism governs inflammation, and that inflammation contributes to the progression of atherosclerosis. However, whether mitochondrial DNA synthesis affects macrophage function and atherosclerosis pathology is not fully understood. Here we show, by transcriptomic analyzes of plaque macrophages, spatial single cell transcriptomics of atherosclerotic plaques, and functional experiments, that mitochondrial DNA (mtDNA) synthesis in atherosclerotic plaque macrophages are triggered by vascular cell adhesion molecule 1 (VCAM-1) under inflammatory conditions in both humans and mice. Mechanistically, VCAM-1 activates C/EBPα, which binds to the promoters of key mitochondrial biogenesis genes - Cmpk2 and Pgc1a. Increased CMPK2 and PGC-1α expression triggers mtDNA synthesis, which activates STING-mediated inflammation. Consistently, atherosclerosis and inflammation are less severe in Apoe-/- mice lacking Vcam1 in macrophages. Downregulation of macrophage-specific VCAM-1 in vivo leads to decreased expression of LYZ1 and FCOR, involved in STING signalling. Finally, VCAM-1 expression in human carotid plaque macrophages correlates with necrotic core area, mitochondrial volume, and oxidative damage to DNA. Collectively, our study highlights the importance of macrophage VCAM-1 in inflammation and atherogenesis pathology and proposes a self-acerbating pathway involving increased mtDNA synthesis.
    DOI:  https://doi.org/10.1038/s41467-024-51780-1
  8. Nat Commun. 2024 Aug 27. 15(1): 7378
    Release of mitochondrial dsRNA into the cytosol is a key driver of the inflammatory phenotype of senescent cells.
    Vanessa López-Polo, Mate Maus, Emmanouil Zacharioudakis, Miguel Lafarga, Camille Stephan-Otto Attolini, Francisco D M Marques, Marta Kovatcheva, Evripidis Gavathiotis, Manuel Serrano.
      The escape of mitochondrial double-stranded dsRNA (mt-dsRNA) into the cytosol has been recently linked to a number of inflammatory diseases. Here, we report that the release of mt-dsRNA into the cytosol is a general feature of senescent cells and a critical driver of their inflammatory secretome, known as senescence-associated secretory phenotype (SASP). Inhibition of the mitochondrial RNA polymerase, the dsRNA sensors RIGI and MDA5, or the master inflammatory signaling protein MAVS, all result in reduced expression of the SASP, while broadly preserving other hallmarks of senescence. Moreover, senescent cells are hypersensitized to mt-dsRNA-driven inflammation due to their reduced levels of PNPT1 and ADAR1, two proteins critical for mitigating the accumulation of mt-dsRNA and the inflammatory potency of dsRNA, respectively. We find that mitofusin MFN1, but not MFN2, is important for the activation of the mt-dsRNA/MAVS/SASP axis and, accordingly, genetic or pharmacologic MFN1 inhibition attenuates the SASP. Finally, we report that senescent cells within fibrotic and aged tissues present dsRNA foci, and inhibition of mitochondrial RNA polymerase reduces systemic inflammation associated to senescence. In conclusion, we uncover the mt-dsRNA/MAVS/MFN1 axis as a key driver of the SASP and we identify novel therapeutic strategies for senescence-associated diseases.
    DOI:  https://doi.org/10.1038/s41467-024-51363-0
  9. Nat Commun. 2024 Aug 23. 15(1): 7269
    Lipid synthesis, triggered by PPARγ T166 dephosphorylation, sustains reparative function of macrophages during tissue repair.
    Shiman Zuo, Yuxin Wang, Hanjing Bao, Zehui Zhang, Nanfei Yang, Meng Jia, Qing Zhang, Ani Jian, Rong Ji, Lidan Zhang, Yan Lu, Yahong Huang, Pingping Shen.
      Macrophages may acquire a reparative phenotype that supports tissue repair and remodeling in response to tissue injury. However, the metabolic requirements underpinning this process are incompletely understood. Here, we show that posttranslational modification (PTM) of PPARγ regulates lipid synthesis in response to wound microenvironmental cues and that metabolic rewiring orchestrates function of reparative macrophages. In injured tissues, repair signaling leads to decreased macrophage PPARγ threonine 166 (T166) phosphorylation, which results in a partially active PPARγ transcriptional program comprised of increased binding activity to the regulator regions of lipid synthesis-associated genes, thereby increased lipogenesis. The accumulated lipids serve as signaling molecules, triggering STAT3-mediated growth factor expression, and supporting the synthesis of phospholipids for the expansion of the endoplasmic reticulum (ER), which is required for protein secretion. Genetic or pharmacological inhibition of PPARγ T166 phosphorylation promotes the reparative function of macrophages and facilitates tissue regeneration. In summary, our work identifies PPARγ T166-regulated lipid biosynthesis as an essential pathway for meeting the anabolic demands of the activation and function of macrophages and provides a rationale for potential therapeutic targeting of tissue repair.
    DOI:  https://doi.org/10.1038/s41467-024-51736-5
  10. Infect Immun. 2024 Aug 28. e0029924
    Host cell-specific metabolism of linoleic acid controls Toxoplasma gondii growth in cell culture.
    Nicole D Hryckowian, Carlos J Ramírez-Flores, Caitlin Zinda, Sung Chul Park, Martin T Kelty, Laura J Knoll.
      The obligate intracellular parasite Toxoplasma gondii can infect and replicate in any warm-blooded cell tested to date, but much of our knowledge about T. gondii cell biology comes from just one host cell type: human foreskin fibroblasts (HFFs). To expand our knowledge of host-parasite lipid interactions, we studied T. gondii in intestinal epithelial cells, the first site of host-parasite contact following oral infection and the exclusive site of parasite sexual development in feline hosts. We found that highly metabolic Caco-2 cells are permissive to T. gondii growth even when treated with high levels of linoleic acid (LA), a polyunsaturated fatty acid (PUFA) that kills parasites in HFFs. Caco-2 cells appear to sequester LA away from the parasite, preventing membrane disruptions and lipotoxicity that characterize LA-induced parasite death in HFFs. Our work is an important step toward understanding host-parasite interactions in feline intestinal epithelial cells, an understudied but important cell type in the T. gondii life cycle.
    Keywords:  Toxoplasma gondii; enterocytes; linoleic acid; lipid droplet; lipotoxicity; polyunsaturated fatty acid
    DOI:  https://doi.org/10.1128/iai.00299-24
  11. Redox Biol. 2024 Aug 27. pii: S2213-2317(24)00307-0. [Epub ahead of print]76 103329
    Role of Mitofusin 1 in mediating reactive oxygen species in alveolar macrophages during Streptococcuspneumoniae.
    David Thomas, Jianjun Yang, Soo Jung Cho, Heather Stout-Delgado.
      Alveolar macrophages (AM) are key effectors of the immune response and are essential for host responses to S. pneumoniae. Mitochondria are highly dynamic organelles whose function aids in regulating the cell cycle, innate immunity, autophagy, redox signaling, calcium homeostasis, and mitochondrial quality control in AM. In response to cellular stress, mitochondria can engage in stress-induced mitochondrial hyperfusion (SIMH). The current study aimed to investigate the role of Mfn1 on mitochondrial control of reactive oxygen species (ROS) in AMs and the role of Mfn1 deficiency on immune responses to S. pneumoniae. Compared to Mfn1FloxCre- controls, there were distinct histological differences in lung tissue collected from Mfn1Floxed; CreLysM mice, with less injury and inflammation observed in mice with Mfn1 deficient myeloid cells. There was a significant decrease in lipid peroxidation and ROS production in Mfn1 deficient AM that was associated with increased superoxide dismutase (SOD) and antioxidant activity. Our findings demonstrate that Mfn1 deficiency in myeloid cells decreased inflammation and lung tissue injury during S. pneumoniae infection.
    DOI:  https://doi.org/10.1016/j.redox.2024.103329
  12. Nat Cardiovasc Res. 2024 Jun;3(6): 637-650
    Immunometabolism in atherosclerotic disorders.
    Andrew J Fleetwood, Jonathan Noonan, Nicole La Gruta, Axel Kallies, Andrew J Murphy.
      Cardiovascular diseases (CVDs), including atherosclerosis, myocardial infarction and heart failure, are the leading causes of morbidity and mortality worldwide. Emerging evidence suggests a crucial role for immune cell dysfunction and inflammation in the progression of this complex set of diseases. Recent advances demonstrate that immune cells, tightly linked to CVD pathogenesis, are sensitive to environmental signals and respond by engaging immunometabolic networks that shape their behavior. Inflammatory cues and altered nutrient availability within atherosclerotic plaques or following ischemia synergize to elicit metabolic shifts in immune cells that influence the course of disease pathology. Understanding these metabolic adaptations and how they contribute to cellular dysfunction may reveal novel therapeutic approaches for the treatment of CVD. Here we provide a comprehensive summary of the metabolic reprogramming that occurs in immune cells and their progenitors during CVD, offering insights into the potential therapeutic interventions to mitigate disease progression.
    DOI:  https://doi.org/10.1038/s44161-024-00473-5
  13. Mol Cell Biochem. 2024 Aug 29.
    Macrophage energy metabolism in cardiometabolic disease.
    Angela Wong, Qiuyu Sun, Ismail I Latif, Qutuba G Karwi.
      In a rapidly expanding body of literature, the major role of energy metabolism in determining the response and polarization status of macrophages has been examined, and it is currently a very active area of research. The metabolic flux through different metabolic pathways in the macrophage is interconnected and complex and could influence the polarization of macrophages. Earlier studies suggested glucose flux through cytosolic glycolysis is a prerequisite to trigger the pro-inflammatory phenotypes of macrophages while proposing that fatty acid oxidation is essential to support anti-inflammatory responses by macrophages. However, recent studies have shown that this understanding is oversimplified and that the metabolic control of macrophage polarization is highly complex and not fully defined yet. In this review, we systematically reviewed and summarized the literature regarding the role of energy metabolism in controlling macrophage activity and how that might be altered in cardiometabolic diseases, namely heart failure, obesity, and diabetes. We critically appraised the experimental studies and methodologies in the published studies. We also highlighted the challenging concepts in macrophage metabolism and identified several research questions yet to be addressed in future investigations.
    Keywords:  Diabetes; Heart failure; Macrophage; Metabolism; Obesity
    DOI:  https://doi.org/10.1007/s11010-024-05099-6
  14. Biomedicines. 2024 Aug 14. pii: 1844. [Epub ahead of print]12(8):
    T-Cell Metabolic Reprogramming in Atherosclerosis.
    Shuye Chang, Zhaohui Wang, Tianhui An.
      Atherosclerosis is a key pathological basis for cardiovascular diseases, significantly influenced by T-cell-mediated immune responses. T-cells differentiate into various subtypes, such as pro-inflammatory Th1/Th17 and anti-inflammatory Th2/Treg cells. The imbalance between these subtypes is critical for the progression of atherosclerosis (AS). Recent studies indicate that metabolic reprogramming within various microenvironments can shift T-cell differentiation towards pro-inflammatory or anti-inflammatory phenotypes, thus influencing AS progression. This review examines the roles of pro-inflammatory and anti-inflammatory T-cells in atherosclerosis, focusing on how their metabolic reprogramming regulates AS progression and the associated molecular mechanisms of mTOR and AMPK signaling pathways.
    Keywords:  T-cells; atherosclerosis; inflammations; metabolic reprogramming
    DOI:  https://doi.org/10.3390/biomedicines12081844
  15. Trends Endocrinol Metab. 2024 Aug 23. pii: S1043-2760(24)00222-4. [Epub ahead of print]
    New anti-inflammatory mechanism of glucocorticoids uncovered.
    Carolyn L Cummins, Ido Goldstein.
      Glucocorticoids (GCs) are potent anti-inflammatory drugs. A new study by Auger et al. found that GCs increase itaconate, an anti-inflammatory tricarboxylic acid (TCA) cycle intermediate, by promoting movement of cytosolic pyruvate dehydrogenase (PDH) to mitochondria. Itaconate was sufficient for mediating the anti-inflammatory effects of GCs in mice, overriding the notion that nuclear glucocorticoid receptor (GR) is necessary for inflammation inhibition.
    Keywords:  GR; LPS; PDH; itaconate; macrophage
    DOI:  https://doi.org/10.1016/j.tem.2024.08.003
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