GM-CSF suppresses antioxidant signaling and drives IL-1β secretion through NRF2 downregulation

EMBO Rep. 2022 Aug 3;23(8):e54226. doi: 10.15252/embr.202154226. Epub 2022 Jun 13.

Abstract

GM-CSF is a potent inflammatory cytokine regulating myeloid cell differentiation, hematopoiesis, and various other functions. It is functionally associated with a number of inflammatory pathologies including rheumatoid arthritis and inflammatory bowel disease. GM-CSF has been found to promote NLRP3-dependent IL-1β secretion, which may have a significant role in driving inflammatory pathologies. However, the molecular mechanisms remain unknown. Here, we show that GM-CSF induces IL-1β secretion through a ROS-dependent pathway. TNF is required for reactive oxygen species (ROS) generation that strikingly does not promote NLRP3 activation, but instead drives ubiquitylation of IL-1β, promoting its cleavage through basal NRLP3 activity. GM-CSF regulates this pathway through suppression of antioxidant responses via preventing upregulation of NRF2. Thus, the pro-inflammatory effect of GM-CSF on IL-1β is through suppression of antioxidant responses, which leads to ubiquitylation of IL-1β and enhanced processing. This study highlights the role of metabolic regulation of inflammatory signaling and reveals a novel mechanism for GM-CSF to promote inflammation.

Keywords: GM-CSF; IL-1β; NRF2; TNF; inflammasome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antioxidants / pharmacology
  • Cells, Cultured
  • Down-Regulation
  • Granulocyte-Macrophage Colony-Stimulating Factor* / genetics
  • Granulocyte-Macrophage Colony-Stimulating Factor* / metabolism
  • Granulocyte-Macrophage Colony-Stimulating Factor* / pharmacology
  • Inflammasomes / metabolism
  • Interleukin-1beta / genetics
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism
  • NLR Family, Pyrin Domain-Containing 3 Protein* / genetics
  • Reactive Oxygen Species / metabolism

Substances

  • Antioxidants
  • Inflammasomes
  • Interleukin-1beta
  • NF-E2-Related Factor 2
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Reactive Oxygen Species
  • Granulocyte-Macrophage Colony-Stimulating Factor