STAT5/TET2调控单核细胞FCER1G基因DNA去甲基化分子机制及其在AD发病中的作用

Our previous study has proved that pathologic DNA hypomethylation of FCER1G leads to overexpression of FcRγ and FcεR1 on monocytes of patients with atopic deramtitis(AD), which plays an important role in the pathogenesis of AD, but the mechanism of FcεR1 hypomethylation is still unknown. Our preliminary results found that proinflammatory cytokines GM-CSF and TSLP activated pSTAT5 recruiting DNA demethylase TET2 binding with FCER1G promoter, then upregulated FcRγ and its related receptors FcεR1 and Dectin-2 in monocyte. So we propose the novel hypothsis：GM-CSF and TSLP should cause demethylation of FCER1G promoter through activating pSTAT5 recruiting TET2 binding with FCER1G promoter in monocyte, result in upregulation of FcRγ and its related receptors FcεR1 and Dectin-2 ,then promote Th2 immunity and allergy, which ultimately leads to the onset of AD. In this study, this hypothsis should be comfirmed through investigating molecular mechanisms of STAT5/TET2 regulating FCER1G DNA demethylation and effect of Dectin-2/FcRγ on Th2 immunity and allergy in AD.

我们前期研究证实AD（特应性皮炎）患者单核细胞FCER1G基因病理性低甲基化促使FcRγ蛋白及FcεR1过度表达在AD发病中扮演重要作用，但引起FCER1G基因病理性低甲基化的机制不清。我们的预实验结果发现前炎症细胞因子GM-CSF和TSLP可通过激活pSTAT5募集DNA去甲基化酶TET2结合至FCER1G启动子序列上，导致FcRγ及相关受体Dectin-2、FcεR1表达增加；因此我们提出GM-CSF和TSLP通过活化pSTAT5募集TET2引起单核细胞FCER1G启动子 DNA去甲基化，促进FcRγ及其相关受体FcεR1和Dectin-2表达，诱导TH2免疫反应及过敏反应的发生，导致AD发病这一全新假说。本项目将通过研究STAT5/TET2调控FECR1G DNA去甲基化的分子机制及Dectin-2/FcRγ对AD患者Th2免疫反应和过敏反应的影响来证实这一假说。

我们前期研究证实AD（特应性皮炎）患者单核细胞FCER1G 基因病理性低甲基化促使FcRγ 蛋白及Fcε R1 过度表达在AD 发病中扮演重要作用，但引起FCER1G 基因病理性低甲基化的机制不清。本研究发现前炎症细胞因子TSLP 促进人CD14+单核细胞FcRγ 及相关受体Fcε R1、Dectin-2、CD16 表达增加，也发现与正常对照相比，AD患者CD14+单核细胞Dectin-2异常过表达；进一步研究证实TSLP促进单核细胞FCER1G调控序列DNA低甲基化，用免疫共沉淀与CHIP-PCR技术证实其DNA去甲基化机制是通过激活pSTAT5 募集DNA 去甲基化酶TET2 结合至FCER1G 启动子序列上，导致FCER1G调控序列DNA去甲基化；同时本研究发现TSLP促进DCs诱导Th2过敏反应新机制，TSLP诱导MoDCs是一种特殊的DCs（TSLP-DCs），既是成熟分化的DCs又维持Dectin-2等识别受体高表达，使其兼有未成熟DCs过敏原摄取提呈功能又有成熟DCs诱导Th分化的功能，进一步研究体外试验证实TSLP-DCs通过Dectin-2诱导OVA特异性Th2/Th17免疫反应。