基于IL-33-ST2-p38通路调控Foxp3甲基化探讨益气温阳方对变应性鼻炎Treg-免疫耐受机制的影响

Allergic rhinitis (AR) is the most common allergic inflammatory disease. Traditional Chinese medicine treatment of this disease is unique, and emphasizes the overall treatment. Study on the efficacy of compound prescription from Foxp3+Treg- immune tolerance mechanism is a hot spot in the research of Chinese medicine. Foxp3 is the key transcription protein of Treg cells, which is regulated by Foxp3 gene, and methylation modification is one of the most common ways of epigenetic regulation. Recently, it has been found that IL-33-ST2-p38 pathway can influence the methylation of Foxp3 by affecting methylase activity, but the specific mechanism is not clear. Yiqi Wenyang Decoction (YWF) is a common prescription for the lung and spleen deficiency cold syndrome. Previous studies showed that YWF could increase the expression of Foxp3mRNA and Foxp3, increase the number of Foxp3+Treg and induce immune tolerance. And the components of YWF can be confirmed expression down-regulation of p38, so the project plan from two levels in vivo and in vitro experiments to study whether YWF is through IL-33-ST2-p38 pathway in regulation of Foxp3 methylation, thus affecting the immune tolerance mechanism of Foxp3+Treg, and provide a theoretical basis for the study of the mechanism of YWF treatment.

变应性鼻炎（AR）是最常见的变应性炎症疾病。中药复方治疗本病疗效独特，且强调整体治疗。从Foxp3+Treg-免疫耐受机制研究复方的疗效是近来中医疗效研究的热点。Foxp3是Treg细胞关键的转录蛋白，受Foxp3基因的调控，而甲基化修饰又是表观遗传学调控基因最常见的方式之一。近来研究发现IL-33-ST2-p38通路可影响甲基化酶的活性引起Foxp3甲基化改变，但具体机制不明确。益气温阳方（YWF）是针对本病肺脾虚寒证的常用方。课题组前期研究表明：YWF可增加Foxp3mRNA和Foxp3表达,上调Foxp3+Treg数量，诱导免疫耐受。且文献证实YWF的部分成分可以下调p38的表达，所以本项目设想从体内和体外实验两个层次来研究YWF是否通过IL-33-ST2-p38通路调控Foxp3甲基化，从而影响Foxp3+Treg-免疫耐受机制，为YWF治疗AR机制研究提供理论依据。

变应性鼻炎（AR）是最常见的变应性炎症疾病。中药复方治疗本病疗效独特，且强调整体治疗。从Foxp3+Treg-免疫耐受机制研究复方的疗效是近来中医疗效研究的热点。Foxp3是Treg细胞关键的转录蛋白，受Foxp3基因的调控，而甲基化修饰又是表观遗传学调控基因最常见的方式之一。近来研究发现IL-33-ST2-p38通路可影响甲基化酶的活性引起Foxp3甲基化改变，但具体机制不明确。益气温阳方（YWF）是针对本病肺脾虚寒证的常用方。课题组前期研究表明：YWF可增加Foxp3mRNA和Foxp3表达,上调Foxp3+Treg数量，诱导免疫耐受。且文献证实YWF的部分成分可以下调p38的表达。本项目从体内和体外实验两个层次展开研究，表明：益气温阳方治疗后可缓解鼻痒打喷嚏流清涕的症状，病理方面嗜酸性粒细胞为主的炎细胞浸润明显改善；Foxp3+CD4+CD25+Treg细胞数量恢复正常。其作用机制是YWF通过抑制IL-33-ST2-P38通路，下调DNMT(甲基化转移酶)，抑制Foxp3甲基化（常发生于启动子区域的CpG位点，分别为99、126、320、353、361、378、397、456、468、484，其总甲基化率与基因的活性呈负相关），增强Foxp3基因活性，从而增加Foxp3转录因子的表达，促进Treg细胞增多，抑制Th2为主的过强炎症反应，减轻嗜酸性粒细胞为主的炎细胞浸润，从而缓解鼻痒打喷嚏流清涕等症状。