脑卒中患者常合并糖尿病（DM），炎症瀑布效应加重卒中后脑损伤。NLRP3炎症小体是否主导DM脑卒中后脑损伤及其调控机制尚未明确。前期研究结合文献表明：异氟烷通过RISK通路减轻炎症反应，降低脑损伤；异氟烷可诱导NLRP3下降；NLRP3敲除后小鼠脑卒中后脑损伤减轻。那么异氟烷是否调控NLRP3而改善脑卒中预后？如何启动？已知异氟烷可激活NF-κB，诱发线粒体自噬，抑制NLRP3炎症小体；而调控TLR4/NF-κB可影响线粒体自噬。预实验发现：DM小鼠TLR4表达增加；异氟烷增加DM小鼠脑卒中后自噬蛋白的表达。据此推测：DM合并脑卒中时，异氟烷通过TLR4调控RISK/NF-κB通路，诱发线粒体自噬，抑制NLRP3炎症小体。本项目拟构建基因敲除小鼠DM脑卒中模型，建立神经元与巨噬细胞共培养体系，通过体内外实验，阐明异氟烷通过TLR4/RISK/NF-κB途径调控NLRP3炎症小体的形成机制。

Stroke is common in diabetes mellitus (DM), and inflammation cascade reaction aggravates brain injury after stroke. It is unknown whether and how NLRP3 inflammasome plays an essential role in cerebral injury after stroke in DM. Our previous study showed that isoflurane alleviated inflammation response after cerebral injury via RISK pathway, as well as reduced the expression of NLRP3 inflammasome. Further study indicated that cerebral infarct volume was decreased in NLRP3 gene knockout mice after stoke. May isoflurane involved in regulating NLRP3 inflammasome formation, hence improve prognosis after stoke in DM? And what’s the mechanism of the regulation? Researches showed that isoflurane could activate NF-κB pathway and inhibit NIRP3 expression via mitochondrial autophagy. Furthermore, mitochondrial autophagy could be regulated by TLR4/NF-κB pathway. In our preliminary experiments, TLR4 was increased in DM mice, and isoflurane could induce the enhancement of autophagy related proteins in a DM stroke model. We therefore hypothesize that isoflurane inhibits NLRP3 inflammasome formation via a RISK/NF-κB pathway, which resulting in TLR regulation for the mitochondrial autophagy. We will establish stroke models in wild-type and NLRP3 or TLR4 genes knock-out DM mice, as well as the neuron-macrophage co-culture system to test our hypothesis via in vitro and in vivo experiments.