The nod-like receptor family pyrin domain containing 3(NLRP3)inflammasome plays a crucial role in the prognosis of subarachnoid hemorrhage(SAH).WNK1 kinase negatively regulates NLRP3 in various inflammatory conditions...The nod-like receptor family pyrin domain containing 3(NLRP3)inflammasome plays a crucial role in the prognosis of subarachnoid hemorrhage(SAH).WNK1 kinase negatively regulates NLRP3 in various inflammatory conditions,but its role in early brain injury(EBI)after SAH remains unclear.In this study,we used an in vivo SAH model in rats/mice and AAV-WNK1 intraventricular injection to investigate its neuroprotective mechanisms.WNK1 expression was significantly reduced in SAH patient blood and SAH model brain tissue,correlating negatively with microglial activation.AAV-WNK1 alleviated brain edema,neuronal necrosis,behavioral deficits,and inflammation by inhibiting NLRP3 inflammasome activation.In hemin-stimulated BV-2 cells,WNK1 overexpression reduced NLRP3 activation and inflammatory cytokines.Chloride counteracted WNK1’s inhibitory effects,and WNK1 suppressed P2X7R-induced NLRP3 activation.Mechanistically,WNK1 functioned via the OXSR1/STK39 pathway.These findings highlight WNK1 as a key regulator of intracellular chloride balance and neuroinflammation,presenting a potential therapeutic target for SAH treatment.展开更多
基金supported by Grants from the Basic Research Program of Jiangsu(BK20240492)Lianyungang Science and Technology Plan Project(JCYJ2304)+2 种基金Lianyungang Aging Health Research Project(L202301)Doctoral Research Start-up Fund of the First Peopel’Hospital of Lianyungang City(BS202314)The funders had no role in study design,data collection and analysis,decision to publish,or preparation of the manuscript.
文摘The nod-like receptor family pyrin domain containing 3(NLRP3)inflammasome plays a crucial role in the prognosis of subarachnoid hemorrhage(SAH).WNK1 kinase negatively regulates NLRP3 in various inflammatory conditions,but its role in early brain injury(EBI)after SAH remains unclear.In this study,we used an in vivo SAH model in rats/mice and AAV-WNK1 intraventricular injection to investigate its neuroprotective mechanisms.WNK1 expression was significantly reduced in SAH patient blood and SAH model brain tissue,correlating negatively with microglial activation.AAV-WNK1 alleviated brain edema,neuronal necrosis,behavioral deficits,and inflammation by inhibiting NLRP3 inflammasome activation.In hemin-stimulated BV-2 cells,WNK1 overexpression reduced NLRP3 activation and inflammatory cytokines.Chloride counteracted WNK1’s inhibitory effects,and WNK1 suppressed P2X7R-induced NLRP3 activation.Mechanistically,WNK1 functioned via the OXSR1/STK39 pathway.These findings highlight WNK1 as a key regulator of intracellular chloride balance and neuroinflammation,presenting a potential therapeutic target for SAH treatment.
