Gasdermin D drives focal crystalline thrombotic microangiopathy by accelerating immunothrombosis and necroinflammation

Watanabe-Kusunoki, Kanako; Li, Chenyu; Honda, Tamisa Seeko Bandeira; Zhao, Danyang; Kusunoki, Yoshihiro; Ku, John; Long, Hao; Klaus, Martin; Han, Chao; Braun, Attila; Mammadova-Bach, Elmina; Linkermann, Andreas; Van Avondt, Kristof; Richter, Mathis; Soehnlein, Oliver; Linder, Monika I.; Klein, Christoph; Steiger, Stefanie; Anders, Hans-Joachim

Gasdermin D drives focal crystalline thrombotic microangiopathy by accelerating immunothrombosis and necroinflammation

Watanabe-Kusunoki, Kanako; Li, Chenyu; Honda, Tamisa Seeko Bandeira et al.

Blood, 2024, 144(3), 308-322

Permalink : https://hdl.handle.net/2115/95820

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論文情報

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アクセス権	open access
URI	https://hdl.handle.net/2115/95820
タイトル	Gasdermin D drives focal crystalline thrombotic microangiopathy by accelerating immunothrombosis and necroinflammation
著者	Watanabe-Kusunoki, Kanako ; Li, Chenyu ; Honda, Tamisa Seeko Bandeira ; Zhao, Danyang ; Kusunoki, Yoshihiro ; Ku, John ; Long, Hao ; Klaus, Martin ; Han, Chao ; Braun, Attila ; Mammadova-Bach, Elmina ; Linkermann, Andreas ; Van Avondt, Kristof ; Richter, Mathis ; Soehnlein, Oliver ; Linder, Monika I. ; Klein, Christoph ; Steiger, Stefanie ; Anders, Hans-Joachim
著者名 Watanabe-Kusunoki, Kanako
著者名 Li, Chenyu
著者名 Honda, Tamisa Seeko Bandeira
著者名 Zhao, Danyang
著者名 Kusunoki, Yoshihiro
著者名 Ku, John
著者名 Long, Hao
著者名 Klaus, Martin
著者名 Han, Chao
著者名 Braun, Attila
著者名 Mammadova-Bach, Elmina
著者名 Linkermann, Andreas
著者名 Van Avondt, Kristof
著者名 Richter, Mathis
著者名 Soehnlein, Oliver
著者名 Linder, Monika I.
著者名 Klein, Christoph
著者名 Steiger, Stefanie
著者名 Anders, Hans-Joachim
言語	英語
発行日	2024-07-18
出版者	American Society of Hematology
収録物名	Blood
巻(号)	144(3)
ページ	308-322
抄録	Thrombotic microangiopathy (TMA) is characterized by immunothrombosis and life- threatening organ failure but the precise underlying mechanism driving its pathogenesis remains elusive. In this study, we hypothesized that gasdermin D (GSDMD), a pore-forming protein that serves as the fi nal downstream effector of the pyroptosis/ interleukin-1 beta beta (IL-1 beta) beta ) 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 fi ciency ameliorated immunothrombosis, acute tissue injury, and failure. Gsdmd-/- - / - mice exhibited a decrease in mature IL-1 beta, beta, as well as in neutrophil maturation, beta 2-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 fi ram dose-dependently suppressed human neutrophil pyroptosis in response to cholesterol crystals. Experiments with GSDMD - de fi cient, human- - induced, pluripotent stem cell-derived - derived neutrophils confirmed fi rmed the involvement of GSDMD in neutrophil beta 2-integrin activation, maturation, and pyroptosis. Both prophylactic and therapeutic administration of disulfiram fi ram protected the mice from focal TMA, acute tissue injury, and failure. Our data identified fi ed 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.
資源タイプ	学術雑誌論文
出版タイプ	Version of Record
PISSN	0006-4971
関連情報 (isIdenticalTo)	出版社版DOI https://doi.org/10.1182/blood.2023021949