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 serving as the final downstream effector of pyroptosis/interleukin (IL)-1pathway, 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-1, as well as in neutrophil maturation, 2 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 2 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.
Keyphrases
- endothelial cells
- room temperature
- drug induced
- liver failure
- induced pluripotent stem cells
- immune response
- high glucose
- machine learning
- aortic dissection
- type diabetes
- regulatory t cells
- ischemia reperfusion injury
- brain injury
- data analysis
- wild type
- diabetic rats
- replacement therapy
- protein protein
- artificial intelligence
- cell migration