IL-17A促进小胶质细胞自噬在脑出血炎症损伤中的正反馈调节机制研究

Our previous studies indicated that cerebral hemorrhage metabolites induced TH17/IL-17A expression, and promoted autophagy mediated microglial inflammatory reaction. However, the relevant regulation relation is not clear. Combined with IL-17A could be activated by PI3K to make the GSK3β phosphorylation inactivation, so as to promote autophagy, we hypothesized that cerebral hemorrhage might induce microglia activation, and recruit TH17 to secret IL-17A. In addition, IL-17A-PI3K-GSK3β signaling cascade involved in Bcl-2 combined with Beclin-1, and initiate the autophagy pathway to positive feedback regulate microglia inflammatory reaction. In this study, we would utilize IP, WB and laser confocal technique to explore the effect of GSK3β and Bcl-2/Beclin-1, and the effects on microglia autophagy and inflammation through up or down regulation of IL-17A in vivo and in vitro. This study will provide a new perspective of autophagy pathway involved in IL-17A positive regulatory feedback between microglia and TH17 , and the mode of "IL-17A- autophagy-inflammation".The study will also present a theoretical basis and therapeutic strategy for the treatment of intracerebral hemorrhage.

我们前期研究表明，脑出血后的代谢产物可以诱导TH17/IL-17A表达上调，并促进小胶质细胞的自噬介导炎症反应，但相关调控关系尚不清楚。结合IL-17A可以通过激活PI3K使GSK3β磷酸化失活，从而促进自噬的理论依据，我们推测脑出血可能诱导小胶质细胞活化，并募集TH17分泌IL-17A，IL-17A-PI3K-GSK3β信号级联反应参与Bcl-2与Beclin-1结合，并启动自噬途径正反馈调节小胶质细胞的炎症反应。本实验拟在脑出血的细胞和动物模型上，运用IP、WB、激光共聚焦等技术，通过上调或下调IL-17A，观察GSK3β与Bcl-2/Beclin-1的调控作用，以及对小胶质细胞自噬和炎症的影响。本研究将从全新的角度和思路阐明IL-17A通过自噬途径参与“小胶质细胞-TH17”之间的正反馈调节，深入探讨“IL-17A-自噬-炎症”的作用模式，并为脑出血的治疗提供新的理论依据和治疗策略。

脑出血后的代谢产物可以诱导TH17/IL-17A表达上调，并促进小胶质细胞的自噬介导炎症反应，但相关调控关系尚不清楚。结合IL-17A可以通过激活PI3K使GSK3β磷酸化失活，从而促进自噬的理论依据，我们推测脑出血可能诱导小胶质细胞活化，并募集TH17分泌IL-17A，IL-17A-PI3K-GSK3β信号级联反应参与Bcl-2与Beclin-1结合，并启动自噬途径正反馈调节小胶质细胞的炎症反应。本实验在脑出血的细胞和动物模型上，运用IP、WB、激光共聚焦等技术，通过上调或下调IL-17A，观察GSK3β与Bcl-2/Beclin-1的调控作用，以及对小胶质细胞自噬和炎症的影响。研究结果表明：脑出血代谢产物诱导小胶质细胞活化，并募集TH17 分泌IL-17A ，激活小胶质细胞的PI3K ，GSK3β 被磷酸化失活，抑制Bcl-2 Ser70 位磷酸化和Bcl-2 的泛素化降解，促进Bcl-2 与Beclin-l 的结合，进一步诱导小胶质细胞自噬介导的炎症反应，从而形成了 “小胶质细胞-TH17 ”之间的正反馈调节，最终加速了脑出血的炎症损伤。本研究将从全新的角度和思路阐明IL-17A通过自噬途径参与“小胶质细胞-TH17”之间的正反馈调节，深入探讨“IL-17A-自噬-炎症”的作用模式，并为脑出血的治疗提供新的理论依据和治疗策略。