脑缺血再灌注中BMSCs调控IL-17/Act1介导的损伤作用研究

It is well known that inflammatory cells and cytokines have been involved in cerebral ischemia reperfusion injury. Cell biotherapy has attracted great attention due to its unique effect. IL-17 is an important pro-inflammatory cytokine which aggravates immune injury. Our previous studies demonstrated that the rate of Th17 cells raised in peripheral blood and the expression of IL-17 elevated after stroke. We also found that BMSCs could produce various cytokines, including IL-27 which can affect IL-17 secretion. In addition, BMSCs treatment could attenuate immune injury and improve neurological function by modulating IL-23/IL-17 axis. However, it is still unclear whether IL-27 secreted by BMSCs can modulate the IL-17 expression in cerebral infarction. Also the mechanism of immunolesion induced by IL-17 needs further researches. It is reported that the binding of Act1 to IL-17R followed by the recruitment of TRAF6 and TAK1 can active the NF-κB signal pathway. We aim to resolve the following questions: 1. To complement the mechanism of IL-17 in cerebral ischemia reperfusion. 2. To probe the immunomediative mechanism of BMSCs. Figuring out these questions will provide a new insight into the therapy of cerebral infarction.

缺血再灌注损伤中炎症细胞及细胞因子的参与已得到大家共识，细胞生物治疗因其独特的效果受到高度重视。IL-17是重要的促炎因子，我们前期研究发现，脑缺血后IL-17在外周血及梗死灶周表达增多,参与了免疫损伤过程，并且Th17细胞比率增高；骨髓基质干细胞（BMSCs）分泌多种细胞因子，其中IL-27可抑制PBMC IL-17的表达，BMSCs注射脑缺血模型能够下调IL-23/IL-17轴，减轻脑缺血损伤，改善神经功能。但是，在脑缺血中BMSCs是否通过IL-27调控IL-17阳性细胞及分泌？且IL-17是如何减轻脑缺血免疫损伤的机制也尚未阐明。研究发现IL-17R与Act1结合后诱导下游TRAF6及TAK1聚集，激活NF-κB等信号；结合前期工作项目拟解决以下问题： 1、完善IL-17在脑缺血再灌注中的损伤机制；2、探讨BMSCs的免疫调控作用；这些问题的解决将为临床脑缺血治疗提供新思路。

缺血再灌注损伤中炎症细胞及细胞因子的参与已经得到大家的广泛认同，细胞生物治疗及针对一系列因子的靶向治疗已经逐渐兴起，IL-17是重要的促炎因子，我们前期研究发现，脑缺血后IL-17在外周血及梗死灶周围表达增多，参与免疫损伤，且IL-23可调控IL-17表达，研究发现IL-17R与Act1结合后诱导下游TRAF6及TAK1聚集，激活NF-κB等信号，但是IL-17如何减轻脑缺血免疫损伤的机制仍尚未阐明，Act1的作用机理尚未理清。本研究以各种脑缺血在体离体模型为基础,围绕着IL-23/IL-17轴及Act1的免疫调节作用这一系列新的免疫学研究热点，结合靶向治疗研究热点微小RNA (microRNA)，运用基因干扰、细胞培养、神经功能测定、分子生物学及病理学等多种实验技术，得出研究结果证明：IL-23/IL-17轴在脑梗死发病过程中发挥炎性损伤作用，其作用机制可能在于抑制神经元凋亡，减轻血脑屏障的破坏及脑组织水肿的形成。MiR-298经由靶向调控Act1及其下游细胞凋亡及自噬信号通路在体内及体外实验中加重脑缺血再灌注损伤。MiR-215经由IL-17RA/Act1调控脑缺血再灌注损伤，该研究为临床脑梗死免疫治疗及靶向治疗积累了基础研究证据，同时为今后脑保护制剂的研究打下基础，对今后临床改善患者预后具有积极意义。