Gasdermin E mediates pyroptotic cell death of neutrophils and macrophages in a zebrafish model of chronic skin inflammation.

Chronic diseases and hematopoietic disorders are associated with dysregulation of the inflammasome. Our group has recently reported the relevance of the inflammasome in the differentiation of hematopoietic stem and progenitor cells. However, the impact of the inflammasome of myeloid cells in the regulation of hematopoiesis is largely unknown. In this study, we used the unique advantages of the zebrafish model to demonstrate that genetic inhibition of macrophage inflammasome resulted in increased number of macrophages in larvae with skin inflammation without affecting erythrocyte and neutrophil counts. Similarly, the inhibition of the neutrophil inflammasome by the same strategy resulted in increased number of neutrophils in larvae with skin inflammation but did not affect erythrocytes and macrophages. Consistently, hyperactivation of the inflammasome in neutrophils in this model promoted neutrophil death, which was recovered by pharmacological inhibition of Gasdermin E. We conclude that the myeloid inflammasome autonomously regulates pyroptotic cell death in chronic inflammation through a Gasdermin E-dependent pathway in zebrafish.