RIPK3 activation promotes DAXX ‐dependent neuronal necroptosis after intracerebral hemorrhage in mice

作者：Qingqing Bai, Shuoyang Wang, Dongmei Rao, Zhiming Zhou, Jianfei Wang, Qi Wang, Qin Yu, Zhaohu Chu, Shoucai Zhao, Dijing Yu, Yang Xu · 发表于：CNS Neuroscience & Therapeutics · 年份：2023 · DOI：10.1111/cns.14397 · 被引用次数：19 · 研究领域：Intracerebral and Subarachnoid Hemorrhage Research、Cell death mechanisms and regulation、S100 Proteins and Annexins

BACKGROUND: Necroptosis induced by receptor-interacting protein kinase 3 (RIPK3) is engaged in intracerebral hemorrhage (ICH) pathology. In this study, we explored the impact of RIPK3 activation on neuronal necroptosis and the mechanism of the death domain-associated protein (DAXX)-mediated nuclear necroptosis pathway after ICH. METHODS: Potential molecules linked to the progression of ICH were discovered using RNA sequencing. The level of DAXX was assessed by quantitative real-time PCR, ELISA, and western blotting. DAXX localization was determined by immunofluorescence and immunoprecipitation assays. The RIPK3 inhibitor GSK872 and DAXX knockdown with shRNA-DAXX were used to examine the nuclear necroptosis pathway associated with ICH. Neurobehavioral deficit assessments were performed. RESULTS: DAXX was increased in patients and mice after ICH. In an ICH mouse model, shRNA-DAXX reduced brain water content and alleviated neurologic impairments. GSK872 administration reduced the expression of DAXX. shRNA-DAXX inhibited the expression of p-MLKL. Immunofluorescence and immunoprecipitation assays showed that RIPK3 and AIF translocated into the nucleus and then bound with nuclear DAXX. CONCLUSIONS: RIPK3 revitalization promoted neuronal necroptosis in ICH mice, partially through the DAXX signaling pathway. RIPK3 and AIF interacted with nuclear DAXX to aggravate ICH injury.