Gasdermin D inhibition ameliorates neutrophil mediated brain damage in acute ischemic stroke

Acute ischemic stroke (AIS) induces high level of neutrophils, which correlates inversely with patient survival. Pyroptosis induced by gasdermin D (GSDMD) has been shown to have an important role in the pathophysiology of several inflammatory disorders. The role of GSDMD in the high level of neutrophils after AIS is unknown. Using a middle cerebral artery occlusion (MCAO) mouse model, we identified activation of pyroptosis signal, including expression of caspase-1/11, GSDMD, and interleukin-1 beta/18 (IL-1 beta/18), in the brain and spleen at early ischemic injury. Knockout of GSDMD in mice reduced infarct size, improved neurological function, and increased survival after MCAO. GSDMD deficiency decreased the overall degree of inflammation and the proportion of neutrophils in the brain after MCAO. Quantitative studies of neutrophils at several time intervals and organs demonstrated that early inflammatory leucocyte production and supplement (1 day after MCAO) was GSDMD-dependent. A series of bone marrow transplantation experiments, neutrophil depletion experiments, and RNA sequencing results demonstrated that neutrophil specific GSDMD is essential for the production and supply of neutrophil in bone marrow to blood. Moreover, pharmacological suppression of GSDMD decreased pathological abnormalities, infarct volume, and ameliorated neurological function. These results provided a new viewpoint on the immunological modulation of neutrophils after MCAO and suggest that suppression of GSDMD may relieve the neuroinflammatory load, thereby providing a potential treatment strategy for stroke.

Automated summary

Acute ischemic stroke (AIS) leads to elevated levels of neutrophils, which negatively affects patient survival. The study discovered that gasdermin D (GSDMD)-induced pyroptosis plays a crucial role in the pathophysiology of AIS. Knockout of GSDMD in mice demonstrated reductions in infarct size, improved neurological function, and increased survival rates after AIS. Additionally, pharmacological suppression of GSDMD showed positive effects on reducing pathological abnormalities and infarct volume, as well as improving neurological function. These findings provide new insights into the immunological modulation of neutrophils after AIS and suggest GSDMD suppression as a potential treatment strategy for stroke.