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In this study, we hypothesized that gasdermin D (GSDMD), a pore-forming protein that serves as the final downstream effector of the pyroptosis\/interleukin-1\u03b2 (IL-1\u03b2) pathway, contributes to TMA and its consequences by amplifying neutrophil maturation and subsequent necrosis. Using a murine model of focal crystalline TMA, we found that Gsdmd deficiency ameliorated immunothrombosis, acute tissue injury, and failure. Gsdmd\u2212\/\u2212 mice exhibited a decrease in mature IL-1\u03b2, as well as in neutrophil maturation, \u03b22-integrin activation, and recruitment to TMA lesions, in which they formed reduced neutrophil extracellular traps in both arteries and interstitial tissue. The GSDMD inhibitor disulfiram dose-dependently suppressed human neutrophil pyroptosis in response to cholesterol crystals. Experiments with GSDMD\u2013deficient, human\u2013induced, pluripotent stem cell\u2013derived neutrophils confirmed the involvement of GSDMD in neutrophil \u03b22-integrin activation, maturation, and pyroptosis. Both prophylactic and therapeutic administration of disulfiram protected the mice from focal TMA, acute tissue injury, and failure. Our data identified GSDMD as a key mediator of focal crystalline TMA and its consequences, including ischemic tissue infarction and organ failure. GSDMD could potentially serve as a therapeutic target for the systemic forms of TMA.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1182\/blood.2023021949","type":"journal-article","created":{"date-parts":[[2024,4,24]],"date-time":"2024-04-24T20:03:02Z","timestamp":1713988982000},"page":"308-322","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":21,"title":["Gasdermin D drives focal crystalline thrombotic microangiopathy by accelerating immunothrombosis and necroinflammation"],"prefix":"10.1182","volume":"144","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8760-8630","authenticated-orcid":false,"given":"Kanako","family":"Watanabe-Kusunoki","sequence":"first","affiliation":[{"name":"1Renal Division, Department of Medicine IV, Ludwig Maximilian University Hospital, Ludwig Maximilian University, Munich, Germany"},{"name":"2Department of Rheumatology, Endocrinology, and Nephrology, Faculty of Medicine and Graduate School of 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