Th22型免疫反应在血管紧张素II介导的高血压中的作用和机制研究

CD4+T淋巴细胞(TCs)和高血压进程密切相关。Th22是CD4+TCs第四个亚群，IL-22是其功能性细胞因子。我们前期研究发现AngII灌注增加小鼠Th22和IL-22表达，IL-22可以放大AngII介导的炎症反应并升高血压。在预实验中，我们发现敲除Th22的转录因子AHR显著减少Th22和IL-22表达，并且缓解AngII介导的高血压；主动脉P38磷酸化和OPN表达显著加少，而SM22α表达增多。因此，我们提出：AngII灌注上调AHR表达和促进Th22分化，后者分泌IL-22结合SMCs表面IL-22受体，进而激活P38通路放大炎症，引起SMCs表型转化和升高血压。本项目拟通过：1）敲除Th22转录因子AHR，2）Th22过继转输，3）阻断IL-22/IL-22R1信号，4）阻断P38通路证实上述猜测。本项目的顺利进行，有望为临床高血压的防治提供新的理论基础和干预靶点。

CD4+T lymphocytes (TCs) were demonstrated to be closely with the progression of hypertension. T helper cells (Th22) is the fourth subgroup of CD4+TCs, and interleukin-22 (IL-22) is the functional cytokine of Th22. Our previous study found that angiotensin II (AngII) perfusion increased the expression of Th22 and IL-22 in mice, and recombinant IL-22 treatment aggravated AngII-induced inflammatory response and raised blood pressure, while neutralizing IL-22 had the opposite effects. In the preliminary experiment, we found that knockout of AHR, the transcription factor of Th22, significantly decreased both Th22 and IL-22 expression and lower blood pressure in Ang II-infused mice. In addition, knockout of AHR also reduced aortic P38 phosphorylation and OPN expression, while increased the SM22α expression. Therefore, we propose that AngII perfusion up-regulates the expression of AHR and promotes the differentiation of Th22, which secretes a large amount of IL-22, binds to the IL-10R2-IL-22-22R1 on the surface of vascular smooth muscle cells, then activates the P38 signaling pathway, leads to the phenotypic transformation of SMCs and amplifies the inflammatory response, thereby promoting the elevation of blood pressure and vascular injury. This project is intended to confirm the above conjecture by: 1) knockout of Th22 transcription factor AHR, 2) adoptive transfer of Th22, 3) blocking of IL-22/IL-22R1 signaling, and 4) blocking of P38 pathway. The successful implementation of this project is expected to provide a new theoretical basis and new target for the prevention of clinical hypertension.