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

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. Description TGF-β induces a distinct macrophage phenotype that promotes coagulation and worsens survival during sepsis. Editor’s summary Macrophages can initiate or resolve inflammatory responses. Usually, glycolytic metabolism results in an inflammatory phenotype in immune cells, but Gauthier et al. found that macrophages activated by the cytokine TGF-β had a glycolytic metabolism but were less inflammatory. TGF-β decreased the survival of mice with sepsis, which was associated with increased coagulation, a complication of sepsis that can lead to organ dysfunction. COVID-19 disease correlated with enhanced expression of genes encoding a TGF-β receptor, a glycolytic enzyme, and a coagulation factor in septic patients. Thus, targeting TGF-β may improve survival and reduce coagulation-associated complications in septic patients. —Wei Wong