大气细颗粒物PM2.5通过NLRP3炎症小体激活及细胞焦亡加重脑缺血损伤的机制

Epidemiological studies have demonstrated that ambient fine particulate matter (PM2.5) increases the risk of ischemic stroke and seriously harm for human health. Pyroptosis is a new type of programmed cell death discovered in recent years and closely related to the activation of NLRP3 inflammasome. Our preliminary studies showed that PM2.5 could increase the cerebral infarction volume in rats in a concentration-dependent manner and aggravate the neurological deficit score. Meanwhile, PM2.5 increased the expression of NLRP3 and the secretion of IL-1β in microglial after oxygen and glucose deprivation (OGD) treatment. However, the detailed mechanisms are still unknown. Based on these findings, we intend to investigate the correlation between microglial pyroptosis with stroke using NLRP3 knockout mice. Furthermore, we would explore the effects of PM2.5 on the activation of NLRP3 inflammasome and pyroptosis after cerebral ischemia in vivo and vitro, in order to elucidate the role and mechanism of microglial "NLRP3 inflammasome/Caspase-1 mediated pyroptosis" in ischemic injury after PM2.5 exposure. The completion of this project will not only help to deepen the understanding of the pathogenesis of stroke, but also lay the academic foundation for the development of specific public intervention strategies for PM2.5.

流行病学资料显示，大气细颗粒物PM2.5增加脑卒中发病风险，加重脑缺血损伤，严重危害人类的健康。细胞焦亡是近年来发现的一种新的程序性细胞死亡，与NLRP3炎症小体激活密切相关。我们前期研究发现，PM2.5可呈浓度依赖性增加大鼠脑梗死体积，加重神经功能缺损评分。同时，PM2.5可增加氧糖剥夺（OGD）处理后的小胶质细胞NLRP3的表达，促进IL-1β释放，然而具体作用机制不详。本项目拟在前期研究的基础上，应用NLRP3敲除小鼠研究PM2.5与脑缺血后细胞焦亡的相关性，从整体和细胞水平探索PM2.5对脑缺血后小胶质细胞NLRP3炎症小体激活及细胞焦亡的影响，阐明小胶质细胞“NLRP3炎症小体/Caspase-1介导的细胞焦亡”在PM2.5加重脑缺血损伤中的作用和机制。该研究成果不仅有助于深化对脑卒中发病机制的认识，也为研发针对PM2.5的特异性公共干预策略奠定学术基础。

大气细颗粒物PM2.5增加脑卒中发病风险，加重脑缺血损伤，严重危害人类的健康，然而具体作用机制不详。本项目通过建立PM2.5染毒的脑卒中模型，以“NLRP3炎症小体/Caspase-1介导的细胞焦亡”为切入点，从整体和细胞水平系统研究PM2.5对脑卒中后的行为学、病理生理学及分子生物学机制的影响，阐明PM2.5增加脑缺血损伤可能的机制。体内研究发现，PM2.5可呈浓度依赖性增加MCAO大鼠脑梗死体积，加重神经功能缺损评分，诱导自噬和NLRP3炎症小体激活。体外研究发现，PM2.5可呈浓度和时间依赖性抑制小胶质细胞增殖，促进氧糖剥夺（OGD）处理后小胶质细胞NLRP3炎症小体激活，上调IL-1β、IL-18炎症因子的释放，诱导细胞焦亡，而敲除NLRP3的表达后，可逆转PM2.5的对NLRP3炎症小体和细胞焦亡的作用。同时，我们发现，PM2.5暴露可进一步上调OGD处理后的小胶质细胞内ROS的生成，给予ROS的抑制剂NAS后，可在一定程度上抑制NLRP3炎症小体的激活和细胞焦亡的发生，减轻脑缺血损伤。该研究成果不仅有助于深化对脑卒中发病机制的认识，也在一定程度上为研发针对PM2.5的特异性公共干预策略奠定学术基础。在基金的支持下，发表SCI论文2篇（一作，IF=7.363；共一作，IF=2.173），已接收SCI论文2篇（一作，IF=5.243、5.75），参与发表SCI论文3篇，以通讯作者发表中文核心期刊1篇。