Gasdermin D drives focal crystalline thrombotic microangiopathy by accelerating immunothrombosis and necroinflammation.
Kanako Watanabe-KusunokiChenyu LiTâmisa Seeko Bandeira HondaDanyang ZhaoYoshihiro KusunokiJohn KuHao LongMartin KlausChao HanAttila BraunElmina Mammadova-BachAndreas LinkermannKristof Van AvondtMathis RichterOliver SoehnleinMonika I LinderChristoph KleinStefanie SteigerHans-Johachim AndersPublished in: Blood (2024)
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 final downstream effector of the pyroptosis/interleukin-1β (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, 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-deficient, human-induced, pluripotent stem cell-derived neutrophils confirmed the involvement of GSDMD in neutrophil β2-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.
Keyphrases
- endothelial cells
- room temperature
- liver failure
- drug induced
- nlrp inflammasome
- respiratory failure
- high fat diet induced
- high glucose
- machine learning
- deep learning
- small molecule
- regulatory t cells
- metabolic syndrome
- big data
- adipose tissue
- pluripotent stem cells
- type diabetes
- acute respiratory distress syndrome
- subarachnoid hemorrhage
- artificial intelligence
- cell adhesion
- cerebral ischemia
- binding protein