GM‐CSF suppresses antioxidant signaling and drives IL‐1β secretion through NRF2 downregulation. (13th June 2022)

• Record Type: Journal Article
• Authors: Di Carlo, Sara; Häcker, Georg; Gentle, Ian E
• Is Part Of: EMBO reports. Volume 23:Number 8(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-06-13
• Subjects: GM‐CSF -- IL‐1β -- inflammasome -- NRF2 -- TNF; Molecular biology -- Periodicals; Molecular Biology -- Periodicals; Molecular biology; Periodicals; 572.8
• DOI: 10.15252/embr.202154226
• Languages: English
• ISSNs: 1469-221X

Abstract

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. Synopsis: GM‐CSF is a potent cytokine involved in inflammatory pathologies that promotes IL‐1β secretion by blocking antioxidant responses, leading to IL‐1β ubiquitylation. IL‐1β is then processed and secreted from living cells in a NLRP3‐ and gasdermin D‐dependent way. GM‐SF induces IL‐1β secretion from monocytic macrophages. GM‐SF suppresses NRF2 upregulation, causing ROS‐dependent IL‐1β secretion. ROS drives gasdermin D‐dependent IL‐1β K63 ubiquitylation. Ubiquitylation of IL‐1β promotes processing and secretion. Abstract : GM‐CSF is a potent cytokine involved in inflammatory pathologies that promotes IL‐1β secretion by blocking antioxidant responses, leading to IL‐1β ubiquitylation. IL‐1β is then processed and secreted from living cells in a NLRP3‐ and gasdermin D‐dependent way.