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

Sci Signal. 2023 Aug 8;16(797):eade0385. doi: 10.1126/scisignal.ade0385. Epub 2023 Aug 8.


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.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • COVID-19* / metabolism
  • Cytokines / metabolism
  • Glycolysis
  • Inflammation / metabolism
  • Lipopolysaccharides / toxicity
  • Macrophages / metabolism
  • Mice
  • Sepsis* / metabolism
  • Transforming Growth Factor beta / metabolism


  • Transforming Growth Factor beta
  • Lipopolysaccharides
  • Cytokines