| First Author | Gauthier T | Year | 2023 |
| Journal | Sci Signal | Volume | 16 |
| Issue | 797 | Pages | eade0385 |
| PubMed ID | 37552767 | Mgi Jnum | J:363468 |
| Mgi Id | MGI:7780292 | Doi | 10.1126/scisignal.ade0385 |
| Citation | Gauthier T, et al. (2023) TGF-beta uncouples glycolysis and inflammation in macrophages and controls survival during sepsis. Sci Signal 16(797):eade0385 |
| abstractText | Changes in metabolism of macrophages are required to sustain macrophage activation in response to different stimuli. We showed that the cytokine TGF-beta (transforming growth factor-beta) regulates glycolysis in macrophages independently of inflammatory cytokine production and affects survival in mouse models of sepsis. During macrophage activation, TGF-beta 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-kappaB, and STAT1. In mice with LPS-induced endotoxemia and experimentally induced sepsis, the TGF-beta-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-beta receptor), and F13A1 (which encodes a coagulation factor) in myeloid cells positively correlated with COVID-19 disease. Thus, these results suggest that TGF-beta is a critical regulator of macrophage metabolism and could be a therapeutic target in patients with sepsis. |
