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It is functionally associated with a number of inflammatory pathologies including rheumatoid arthritis and inflammatory bowel disease. GM\u2010CSF has been found to promote NLRP3\u2010dependent IL\u20101\u03b2 secretion, which may have a significant role in driving inflammatory pathologies. However, the molecular mechanisms remain unknown. Here, we show that GM\u2010CSF induces IL\u20101\u03b2 secretion through a ROS\u2010dependent pathway. TNF is required for reactive oxygen species (ROS) generation that strikingly does not promote NLRP3 activation, but instead drives ubiquitylation of IL\u20101\u03b2, promoting its cleavage through basal NRLP3 activity. GM\u2010CSF regulates this pathway through suppression of antioxidant responses via preventing upregulation of NRF2. Thus, the pro\u2010inflammatory effect of GM\u2010CSF on IL\u20101\u03b2 is through suppression of antioxidant responses, which leads to ubiquitylation of IL\u20101\u03b2 and enhanced processing. This study highlights the role of metabolic regulation of inflammatory signaling and reveals a novel mechanism for GM\u2010CSF to promote inflammation.<\/jats:p>","DOI":"10.15252\/embr.202154226","type":"journal-article","created":{"date-parts":[[2022,6,13]],"date-time":"2022-06-13T05:35:26Z","timestamp":1655098526000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["GM\u2010CSF suppresses antioxidant signaling and drives IL\u20101\u03b2 secretion through NRF2 downregulation"],"prefix":"10.1038","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2148-5372","authenticated-orcid":false,"given":"Sara","family":"Di Carlo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1058-5746","authenticated-orcid":false,"given":"Georg","family":"H\u00e4cker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6707-7809","authenticated-orcid":false,"given":"Ian E","family":"Gentle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,6,13]]},"reference":[{"key":"BFEMBR202154226_CR1","doi-asserted-by":"crossref","first-page":"9745","DOI":"10.1073\/pnas.0308558101","volume":"101","author":"C Andrei","year":"2004","unstructured":"Andrei C, Margiocco P, Poggi A, Lotti LV, Torrisi MR, Rubartelli A (2004) Phospholipases C and A2 control lysosome\u2010mediated IL\u20101 beta secretion: implications for inflammatory processes. 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