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

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-1 beta 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-1 beta 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-1 beta, 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-1 beta is through suppression of antioxidant responses, which leads to ubiquitylation of IL-1 beta 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.

Automated summary

GM-CSF promotes the ubiquitination and enhanced processing of IL-1 beta through suppression of antioxidant responses, leading to its pro-inflammatory effect.