GATA3调控IL-33—ILC2信号轴在变应性鼻炎发生发展中的作用及机制研究

The traditional Th1/Th2 immune imbalance theory can not fully explain the pathogenesis of allergic rhinitis. Recently, it has been found that the group 2 innate lymphoid cell (ILC2) plays an important role in the development of allergic diseases.However, the role of allergic rhinitis is poorly understood and controversial. We found that the expression of GATA3 and IL-33 was significantly up-regulated in allergic rhinitis, which was related to the severity of the disease,and the expression of ILC2 was significantly increased.At present, the mechanism of GATA3 regulation of IL-33-ILC2 in allergic rhinitis has not been reported. Accordingly, we put forward the hypothesis that the IL-33-ILC2 signal axis can be regulated by siRNA GATA3 interference to control the development of allergic rhinitis.This study is to clear the role of ILC2 in allergic rhinitis from multiple levels of molecules, cells, tissues and animal levels,then to explore the mechanism of IL-33-ILC2, to clarify the regulation of GATA3 on IL-33-ILC2, and to reveal the mechanism of GATA3 effect on allergic rhinitis by regulating IL-33-ILC2. In this study, we will explore the pathogenesis of allergic rhinitis from the perspective of ILC2, and further enrich the pathogenesis of allergic rhinitis.

传统的Th1/Th2免疫平衡失调理论不能完全解释变应性鼻炎的发病机制。新近研究发现固有2型淋巴细胞（ILC2）在变应性疾病的发生发展中发挥着重要作用，但在变应性鼻炎中的作用知之不多并存在争议。我们前期研究发现GATA3和IL-33在变应性鼻炎的表达明显上调，与疾病的严重程度有关；固有2型淋巴细胞的表达也明显增高。目前关于变应性鼻炎中GATA3调控IL-33-ILC2的机制尚未见报道。据此我们提出假说：通过siRNA干扰GATA3来调控IL-33-ILC2信号轴来可控制变应性鼻炎的发生。本课题拟从分子、细胞、组织以及动物水平等多层次明确ILC2在变应性鼻炎的作用，探讨IL-33-ILC2的作用机制，明确GATA3对IL-33-ILC2调控，揭示GATA3通过调控IL-33-ILC2影响变应性鼻炎的作用机制。本研究将从ILC2这个新炎症细胞角度来探讨变应性鼻炎的发生机制，进一步丰富其发病机制。

变应性鼻炎的发病机制复杂，致病因素的多样性，传统的Th1/Th2免疫平衡失调理论不能完全解释变应性鼻炎的发病机制。研究发现固有2型淋巴细胞（ILC2）在变应性鼻炎的发生发展中发挥着重要作用，ILC2在IL-33刺激下迁移和活化，分泌Ⅱ型应答相关的细胞因子，在过敏性炎症为代表的Ⅱ型免疫应答的发生发展中发挥着重要作用。GATA3是调控Th2细胞分化的关键特异的转录因子，也是ILC2分化的关键转录因子。本研究将ILC2和IL-33作为研究对象，利用小鼠构建变应性鼻炎动物模型，通过siRNA干扰GATA3调控IL-33-ILC2信号轴,观察变应性鼻炎动物模型症状的变化，从分子、细胞、组织以及动物水平等多层次探讨GATA3对IL-33-ILC2调控后IL-5、IL-13等细胞因子的变化及嗜酸性粒细胞数量的改变，从而揭示GATA3通过调控IL-33-ILC2影响变应性鼻炎的作用机制。研究结果如下：①利用IL-33成功构建了变应性鼻炎的小鼠模型；②变应性鼻炎中ILC2和Th2型细胞因子(IL-4、IL-5、IL-9和IL-13)的比例呈正相关，在鼻粘膜和外周血中均增高；③GATA3是miR-155的下游靶点，Circ_0067835通过下调miR-155的表达从而影响Th2型细胞因子水平的表达，最终影响变应性鼻炎的发病。上述研究结果证实在中ILC2参与了变应性鼻炎的发病机制，GATA3可以调控ILC2的功能，其调控机制是Circ_0067835通过下调miR-155的表达降低了GATA3的表达，从而导致ILC2分泌的Th2型细胞因子减少，导致变应性鼻炎的症状减轻。本研究从ILC2这个新炎症细胞角度来探讨变应性鼻炎的发生机制，进一步丰富其发病机制为防治变应性鼻炎提供新的思路。