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During macrophage activation, TGF-\u03b2 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\u2013c-MYC\u2013dependent 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-\u03baB, and STAT1. In mice with LPS-induced endotoxemia and experimentally induced sepsis, the TGF-\u03b2\u2013induced 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\n            <jats:italic>PFKL<\/jats:italic>\n            ,\n            <jats:italic>TGFBRI<\/jats:italic>\n            (which encodes a TGF-\u03b2 receptor), and\n            <jats:italic>F13A1<\/jats:italic>\n            (which encodes a coagulation factor) in myeloid cells positively correlated with COVID-19 disease. Thus, these results suggest that TGF-\u03b2 is a critical regulator of macrophage metabolism and could be a therapeutic target in patients with sepsis.\n          <\/jats:p>","DOI":"10.1126\/scisignal.ade0385","type":"journal-article","created":{"date-parts":[[2023,8,8]],"date-time":"2023-08-08T17:58:06Z","timestamp":1691517486000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":110,"title":["TGF-\u03b2 uncouples glycolysis and inflammation in macrophages and controls survival during sepsis"],"prefix":"10.1126","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-3417-2481","authenticated-orcid":true,"given":"Thierry","family":"Gauthier","sequence":"first","affiliation":[{"name":"Mucosal Immunology Section, National Institutes of Dental and Craniofacial Research (NIDCR), National Institutes of Health, Bethesda, MD 20892, 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