Cortistatin通过影响巨噬细胞中TNFα/NF-κB信号通路抑制特应性皮炎的机制研究

Atopic dermatitis (AD) is a common inflammatory skin disease in clinic, yet much is unknown for the underlying mechanism, and it is lack of effective therapy. It is reported that macrophage plays a critical role in development of AD, which largely relies on TNFα and its mediated activation of NF-κB signaling pathway.Previous studies detected that supression of TNFα/NF-κB signaling pathway in macrophage attenuated onset of AD. As a neuropeptide, Cortistatin（CST）plays a protective role in several inflammatory diseases. CST related receptors are detected on the surface of macrophage. Furthermore, CST is closely associated with TNFα. However, whether CST interplays with TNFα/NF-κB signaling pathway in macrophage, and whether CST is involved in AD remains to be elucidated. In the current study, we plan to investigate the related mechanism as the following two aspects: (1) stimulate macrophage with indicated molecules, and evaluate the function of CST in activation of TNFα/NF-κB signaling pathway as well as inflammatory reaction in macrophage; (2) Establish AD models in wildtype and CST knockout mice, and analyze the role of CST in AD through in vivo experiments. This study may provide new clue for CST in regulating macrophage inflammatory reaction as well as AD development, and shed light on the mechanism and therapeutic target in AD.

特应性皮炎（AD）是临床常见的皮肤炎性疾病，机制仍不明确。数据显示，巨噬细胞在AD进展中发挥重要作用，其中TNFα及其介导的NF-κB信号通路激活意义重大，且抑制巨噬细胞中TNFα/NF-κB信号通路可减轻皮肤炎性反应。Cortistatin（CST）作为一种神经肽，对多种炎性疾病具有抑制作用。已知巨噬细胞表面表达CST的作用受体。另外，有研究表明，CST与TNFα存在关联性。但尚不知晓CST是否通过影响巨噬细胞中TNFα/NF-κB信号通路对AD产生作用。本课题拟从以下两方面进行：（1）应用相关分子刺激巨噬细胞，从体外检测CST对巨噬细胞TNFα/NF-κB信号通路活性及细胞内炎性反应的影响；（2）建立野生型及CST基因敲除鼠AD模型，通过相应实验观察CST在体内对AD发生发展的影响。通过本课题研究，为进一步阐明AD发生机制及寻找治疗靶点提供新的线索。

以炎症细胞浸润，血管生成和表皮增生为特征的银屑病与免疫介导的炎症反应密切相关，此病发病机制尚未完全明确，临床上与治疗相关的各种阻断药物层出不穷，但仍无法改变疾病顽固易复发、治疗成本高的种种弊端。我们的研究发现神经多肽Cortistatin（CST）能够通过直接与巨噬细胞表面的TNFα受体（TNFR）结合，影响巨噬细胞极化，继而影响Th、Treg等细胞的分化，拮抗银屑病样皮炎。本课题通过体外实验及动物模型，首次发现了CST新的结合受体，阐明了CST-TNFα/TNFR-NFκB信号通路轴的作用机制，且证明了巨噬细胞在银屑病样皮炎中的作用不容小觑，为银屑病发病机制的研究及开发一种效优价廉的治疗方法提供了新的思路。