TGF-β uncouples glycolysis and inflammation in macrophages and controls survival during sepsis.

Autor: Gauthier T; Mucosal Immunology Section, National Institutes of Dental and Craniofacial Research (NIDCR), National Institutes of Health, Bethesda, MD 20892, USA., Yao C; National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA., Dowdy T; Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA., Jin W; Mucosal Immunology Section, National Institutes of Dental and Craniofacial Research (NIDCR), National Institutes of Health, Bethesda, MD 20892, USA., Lim YJ; Mucosal Immunology Section, National Institutes of Dental and Craniofacial Research (NIDCR), National Institutes of Health, Bethesda, MD 20892, USA., Patiño LC; Mucosal Immunology Section, National Institutes of Dental and Craniofacial Research (NIDCR), National Institutes of Health, Bethesda, MD 20892, USA., Liu N; Mucosal Immunology Section, National Institutes of Dental and Craniofacial Research (NIDCR), National Institutes of Health, Bethesda, MD 20892, USA., Ohlemacher SI; Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA., Bynum A; Mucosal Immunology Section, National Institutes of Dental and Craniofacial Research (NIDCR), National Institutes of Health, Bethesda, MD 20892, USA., Kazmi R; Mucosal Immunology Section, National Institutes of Dental and Craniofacial Research (NIDCR), National Institutes of Health, Bethesda, MD 20892, USA., Bewley CA; Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA., Mitrovic M; Immune Regulation Unit, National Institutes of Dental and Craniofacial Research (NIDCR), National Institutes of Health, Bethesda, MD 20892, USA., Martin D; Genomics and Computational Biology Core, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892, USA., Morell RJ; Genomics and Computational Biology Core, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892, USA., Eckhaus M; Division of Veterinary Resources, Pathology Service, National Institutes of Health, Bethesda, MD 20892, USA., Larion M; Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA., Tussiwand R; Immune Regulation Unit, National Institutes of Dental and Craniofacial Research (NIDCR), National Institutes of Health, Bethesda, MD 20892, USA., O'Shea JJ; National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA., Chen W; Mucosal Immunology Section, National Institutes of Dental and Craniofacial Research (NIDCR), National Institutes of Health, Bethesda, MD 20892, USA.
Jazyk: angličtina
Zdroj: Science signaling [Sci Signal] 2023 Aug 08; Vol. 16 (797), pp. eade0385. Date of Electronic Publication: 2023 Aug 08.
DOI: 10.1126/scisignal.ade0385
Abstrakt: Changes in metabolism of macrophages are required to sustain macrophage activation in response to different stimuli. We showed that the cytokine TGF-β (transforming growth factor-β) regulates glycolysis in macrophages independently of inflammatory cytokine production and affects survival in mouse models of sepsis. During macrophage activation, TGF-β increased the expression and activity of the glycolytic enzyme PFKL (phosphofructokinase-1 liver type) and promoted glycolysis but suppressed the production of proinflammatory cytokines. The increase in glycolysis was mediated by an mTOR-c-MYC-dependent pathway, whereas the inhibition of cytokine production was due to activation of the transcriptional coactivator SMAD3 and suppression of the activity of the proinflammatory transcription factors AP-1, NF-κB, and STAT1. In mice with LPS-induced endotoxemia and experimentally induced sepsis, the TGF-β-induced enhancement in macrophage glycolysis led to decreased survival, which was associated with increased blood coagulation. Analysis of septic patient cohorts revealed that the expression of PFKL , TGFBRI (which encodes a TGF-β receptor), and F13A1 (which encodes a coagulation factor) in myeloid cells positively correlated with COVID-19 disease. Thus, these results suggest that TGF-β is a critical regulator of macrophage metabolism and could be a therapeutic target in patients with sepsis.
Databáze: MEDLINE