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The adjuvanticity of \u03b1,\u03b1\u2032-trehalose 6,6\u2032-glycolipids is mediated by signalling through the macrophage inducible C-type lectin (Mincle) and the induction of an inflammatory response. Herein, we present an aryl-functionalised trehalose glycolipid, AF-2, that leads to the release of cytokines and chemokines, including IL-6, MIP-2 and TNF-\u03b1, in a Mincle-dependent manner. Furthermore, plate-coated AF-2 also leads to the Mincle-independent production of IL-1\u03b2, which is unprecedented for this class of glycolipid. Upon investigation into the mode of action of plate-coated AF-2, it was observed that the treatment of WT and Mincle<jats:sup>\u2212\/\u2212<\/jats:sup> bone marrow derived macrophages (BMDM), murine RAW264.7 cells, and human monocytes with AF-2 led to lytic cell death, as evidenced using Sytox Green and lactate dehydrogenase assays, and confocal and scanning electron microscopy. The requirement for functional Gasdermin D and Caspase-1 for IL-1\u03b2 production and cell death by AF-2 confirmed pyroptosis as the mode of action of AF-2. The inhibition of NLRP3 and K<jats:sup>+<\/jats:sup> efflux reduced AF-2 mediated IL-1\u03b2 production and cell death, and allowed us to conclude that AF-2 leads to Capase-1 dependent NLRP3 inflammasome-mediated cell death. The unique mode of action of plate-coated AF-2 was surprising and highlights how the physical presentation of Mincle ligands can lead to dramatically different immunological outcomes.<\/jats:p>","DOI":"10.1007\/s10753-023-01814-5","type":"journal-article","created":{"date-parts":[[2023,5,4]],"date-time":"2023-05-04T12:05:08Z","timestamp":1683201908000},"page":"1365-1380","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Aryl-functionalised \u03b1,\u03b1\u2032-Trehalose 6,6\u2032-Glycolipid Induces Mincle-independent Pyroptotic Cell Death"],"prefix":"10.1007","volume":"46","author":[{"given":"Kristel","family":"Kodar","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emma M.","family":"Dangerfield","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amy J.","family":"Foster","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Devlin","family":"Forsythe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shigenari","family":"Ishizuka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Melanie J.","family":"McConnell","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sho","family":"Yamasaki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mattie S. 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The use of human leukocytes from 20 healthy donor with written informed consent was approved by New Zealand Northern A Health and Disability Ethics Committee (approval number 15\/NTA\/178).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics Statement"}},{"value":"The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of Interest"}}]}}