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The phospholipid, platelet-activating factor (PAF), exerts multiple physiological functions by binding to a G protein\u2013coupled seven-transmembrane receptor (PAFR). PAF is associated with a number of inflammatory disorders, yet the molecular mechanism underlying its proinflammatory function remains to be fully elucidated. We show that multiple PAF isoforms and PAF-like lipids can activate the inflammasome, resulting in IL-1\u03b2 and IL-18 maturation. This is dependent on NLRP3, ASC, caspase-1, and NEK7, but not on NLRC4, NLRP1, NLRP6, AIM2, caspase-11, or GSDMD. Inflammasome activation by PAF also requires potassium efflux and calcium influx but not lysosomal cathepsin or mitochondrial reactive oxygen species. PAF exacerbates peritonitis partly through inflammasome activation, but PAFR is dispensable for PAF-induced inflammasome activation in vivo or in vitro. These findings reveal that PAF represents a damage-associated signal that activates the canonical inflammasome independently of PAFR and provides an explanation for the ineffectiveness of PAFR antagonist in blocking PAF-mediated inflammation in the clinic.<\/jats:p>","DOI":"10.1084\/jem.20190111","type":"journal-article","created":{"date-parts":[[2019,9,26]],"date-time":"2019-09-26T19:29:21Z","timestamp":1569526161000},"page":"2838-2853","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":52,"title":["Platelet-activating factor (PAF) mediates NLRP3-NEK7 inflammasome induction independently of PAFR"],"prefix":"10.1084","volume":"216","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9051-7534","authenticated-orcid":true,"given":"Meng","family":"Deng","sequence":"first","affiliation":[{"name":"Oral and Craniofacial Biomedicine PhD Program, University of North Carolina at Chapel Hill, Chapel Hill, NC 1"},{"name":"Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2737-2723","authenticated-orcid":true,"given":"Haitao","family":"Guo","sequence":"additional","affiliation":[{"name":"Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 2"},{"name":"Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason W.","family":"Tam","sequence":"additional","affiliation":[{"name":"Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 2"},{"name":"Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brandon M.","family":"Johnson","sequence":"additional","affiliation":[{"name":"Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 2"},{"name":"Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W. 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