TET2通过mRNA去甲基化调控巨噬细胞极化在变应性鼻炎中的作用及机制

变应性鼻炎(allergic rhinitis，AR)发病率居高不下，近期研究提示AR发生发展与巨噬细胞极化密切相关，但机制不明。表观遗传调控在巨噬细胞极化中发挥重要作用，而RNA甲基化修饰是重要的表观调控机制。新近发现TET2可催化RNA胞嘧啶的去甲基化而实现基因的表达调控。本项目组前期研究显示AR患者和OVA致敏小鼠的鼻黏膜巨噬细胞均呈明显的M2极化，且M2巨噬细胞mRNA的5-hmC显著下降，同时TET2敲除可促进OVA诱导的巨噬细胞M2极化。据此推测TET2可能通过影响mRNA去甲基化调控巨噬细胞极化而在AR免疫平衡中发挥关键作用。本课题拟建立TET2敲除AR小鼠模型，采用过继免疫和质粒转染等方法，运用RIP-seq、TSA免疫荧光及Dot blot等技术，从临床、动物和细胞水平研究TET2通过mRNA去甲基化调控巨噬细胞极化的作用，并深入探讨其机制，为AR防治提供新靶点。

The prevalence of allergic rhinitis (AR) remains high in recent decades. Studies have suggested that the occurrence and development of AR is closely related to the polarization of macrophages, but the mechanism is not clear. Epigenetics plays an important role in the regulation of macrophage polarization, and RNA methylated modification is one of the major epigenetic regulatory systems. Recent research discovered that TET2 could mediate the demethylation of cytosine of RNA to regulate gene expression. Our preliminary work revealed that the nasal mucosa of AR patients and OVA-induced mice showed obvious M2 macrophage polarization. In addition, the mRNA 5-hmc of M2 macrophage was significantly reduced and TET2 deficiency could promote M2 polarization in OVA-induced macrophages. These findings suggested that TET2 might play a key role in AR immune balance by affecting mRNA demethylation and regulating macrophage polarization. Our research plans to explore the effect and mechanism of TET2-mediated mRNA demethylation in macrophage polarization in AR at clinical, animal and cellular levels, by using TET2 deficient mice to construct AR animal models, and the methods of adoptive immunity, plasmid transfection, RIP-seq, TSA Immunofluorescence and Dot blot, etc. We hope this research would provide a new target for AR treatment by restoring immune balance through epigenetic modification.