上睑下垂
血栓性微血管病
中性粒细胞胞外陷阱
医学
炎症体
炎症
癌症研究
病理
免疫学
疾病
作者
Kanako Watanabe‐Kusunoki,Chenyu Li,Tâmisa Seeko Bandeira Honda,Danyang Zhao,Yoshihiro Kusunoki,John Ku,Hao Long,Martin Klaus,Chao Han,Attila Braun,Elmina Mammadova‐Bach,Andreas Linkermann,Kristof Van Avondt,Mathis Richter,Oliver Soehnlein,Monika I. Linder,Christoph Klein,Stefanie Steiger,Hans‐Joachim Anders
出处
期刊:Blood
[American Society of Hematology]
日期:2024-04-24
被引量:2
标识
DOI:10.1182/blood.2023021949
摘要
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 serving as the final downstream effector of pyroptosis/interleukin (IL)-1β 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-/- mice exhibited a decrease in mature IL-1β, as well as in neutrophil maturation, β2 integrin activation, and recruitment to TMA lesions, where they formed reduced neutrophil extracellular traps both in arteries and interstitial tissue. The GSDMD inhibitor disulfiram dose-dependently suppressed human neutrophil pyroptosis in response to cholesterol crystals. Experiments with GSDMD-deficient human induced pluripotent stem cell-derived neutrophils confirmed the involvement of GSDMD in neutrophil β2 integrin activation, maturation as well as pyroptosis. Both prophylactic and therapeutic administration of disulfiram protected mice from focal TMA, acute tissue injury and failure. Our data identify GSDMD as a key mediator of focal crystalline TMA and its consequences: ischemic tissue infarction and organ failure. GSDMD could potentially serve as a therapeutic target for systemic forms of TMA.
科研通智能强力驱动
Strongly Powered by AbleSci AI