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Histone deacetylases 3 (HDAC3) modulates the acetylation state of histone and non‐histone proteins and could be a powerful regulator of the inflammatory process in stroke. Inflammasome activation is a ubiquitous but poorly understood consequence of acute ischemic stroke. Here, we investigated the potential contributions of HDAC3 to inflammasome activation in primary cultured microglia and experimental stroke models. In this study, we documented that HDAC3 expression was increased in microglia of mouse experimental stroke model. Intraperitoneal injection of RGFP966 (a selective inhibitor of HDAC3) decreased infarct size and alleviated neurological deficits after the onset of middle cerebral artery occlusion (MCAO). In vitro data indicated that LPS stimulation evoked a time‐dependent increase of HDAC3 and absent in melanoma 2 (AIM2) inflammasome in primary cultured microglia. Interestingly, AIM2 was subjected to spatiotemporal regulation by RGFP966. The ability of RGFP966 to inhibit the AIM2 inflammasome was confirmed in an experimental mouse model of stroke. As expected, AIM2 knockout mice also demonstrated significant resistance to ischemia injury compared with their wild‐type littermates. RGFP966 failed to exhibit extra protective effects in AIM2−/− stroke mice. Furthermore, we found that RGFP966 enhanced STAT1 acetylation and subsequently attenuated STAT1 phosphorylation, which may at least partially contributed to the negative regulation of AIM2 by RGFP966. Together, we initially found that RGFP966 alleviated the inflammatory response and protected against ischemic stroke by regulating the AIM2 inflammasome. [ABSTRACT FROM AUTHOR]

Due to the limitation of human studies with respect to individual difference or the accessibility of fresh tissue samples, how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection results in pathological complications in lung, the main site of infection, is still incompletely understood. Therefore, physiologically relevant animal models under realistic SARS-CoV-2 infection conditions would be helpful to our understanding of dysregulated inflammation response in lung in the context of targeted therapeutics. Here, we characterized the single-cell landscape in lung and spleen upon SARS-CoV-2 infection in an acute severe disease mouse model that replicates human symptoms, including severe lung pathology and lymphopenia. We showed a reduction of lymphocyte populations and an increase of neutrophils in lung and then demonstrated the key role of neutrophil-mediated lung immunopathology in both mice and humans. Under severe conditions, neutrophils recruited by a chemokine-driven positive feedback produced elevated "fatal signature" proinflammatory genes and pathways related to neutrophil activation or releasing of granular content. In addition, we identified a new Cd177 high cluster that is undergoing respiratory burst and Stfa high cluster cells that may dampen antigen presentation upon infection. We also revealed the devastating effect of overactivated neutrophil by showing the highly enriched neutrophil extracellular traps in lung and a dampened B-cell function in either lung or spleen that may be attributed to arginine consumption by neutrophil. The current study helped our understanding of SARS-CoV-2-induced pneumonia and warranted the concept of neutrophil-targeting therapeutics in COVID-19 treatment. IMPORTANCE We demonstrated the single-cell landscape in lung and spleen upon SARS-CoV-2 infection in an acute severe disease mouse model that replicated human symptoms, including severe lung pathology and lymphopenia. Our comprehensive study revealed the key role of neutrophil-mediated lung immunopathology in SARS-CoV-2-induced severe pneumonia, which not only helped our understanding of COVID-19 but also warranted the concept of neutrophil targeting therapeutics in COVID-19 treatment.