STAT3 serine phosphorylation is required for TLR4 metabolic reprogramming and IL-1β expression

Nat Commun. 2020 Jul 30;11(1):3816. doi: 10.1038/s41467-020-17669-5.

Abstract

Detection of microbial components such as lipopolysaccharide (LPS) by Toll-like receptor 4 (TLR4) on macrophages induces a robust pro-inflammatory response that is dependent on metabolic reprogramming. These innate metabolic changes have been compared to aerobic glycolysis in tumour cells. However, the mechanisms by which TLR4 activation leads to mitochondrial and glycolytic reprogramming are unknown. Here we show that TLR4 activation induces a signalling cascade recruiting TRAF6 and TBK-1, while TBK-1 phosphorylates STAT3 on S727. Using a genetically engineered mouse model incapable of undergoing STAT3 Ser727 phosphorylation, we show ex vivo and in vivo that STAT3 Ser727 phosphorylation is critical for LPS-induced glycolytic reprogramming, production of the central immune response metabolite succinate and inflammatory cytokine production in a model of LPS-induced inflammation. Our study identifies non-canonical STAT3 activation as the crucial signalling intermediary for TLR4-induced glycolysis, macrophage metabolic reprogramming and inflammation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Line
  • Cells, Cultured
  • Gene Expression
  • Glycolysis / drug effects
  • Inflammation / genetics
  • Inflammation / metabolism
  • Interleukin-1beta / genetics
  • Interleukin-1beta / metabolism*
  • Lipopolysaccharides / pharmacology
  • Macrophages / drug effects
  • Macrophages / metabolism*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Phosphorylation
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism*
  • Serine / genetics
  • Serine / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • TNF Receptor-Associated Factor 6 / genetics
  • TNF Receptor-Associated Factor 6 / metabolism
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / metabolism*

Substances

  • Interleukin-1beta
  • Lipopolysaccharides
  • STAT3 Transcription Factor
  • TNF Receptor-Associated Factor 6
  • TRAF6 protein, mouse
  • Toll-Like Receptor 4
  • Serine
  • Tbk1 protein, mouse
  • Protein Serine-Threonine Kinases