biostudies-literatureUnknown23(8)Di Carlo SGM-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 antioxiEMBO reportse54226https://www.ebi.ac.uk/biostudies/studies/S-EPMC9346485biostudies-literatureGM-CSF suppresses antioxidant signaling and drives IL-1β secretion through NRF2 downregulation.PMC9346485Hacker GDi Carlo SGentle IEfalseGM-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-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 antioxi2022-01-01T00:00:00Z2022 Aug2025-04-18T15:36:18.953Z2025-02-19T03:58:05.347ZS-EPMC93464853569508010.15252/embr.202154226