E3泛素酶FBXW7正向调控白细胞介素23影响银屑病发生发展的机制研究

银屑病是常见炎性皮肤病，其炎性微环境中树突状细胞亚群异常活化在其病理机制中扮演关键角色，DC通过分泌白细胞介素23，启动IL-23/IL-17/IL-22轴，致角化细胞过度增殖，但其调控网络及分子机制远未清楚。我们前期研究表明DC中敲除E3泛素连接酶FBXW7可显著减轻小鼠银屑病的发生，且IL-23的水平显著下降，将在此基础上，利用FBXW7条件性基因敲除小鼠的银屑病模型和临床银屑病组织样本，深入研究FBXW7分子在皮肤炎性微环境中对不同树突状细胞亚群的活化、功能、触发的炎症因子轴的调控作用及其分子机制，拟进一步证实其通过介导组蛋白赖氨酸甲基转移酶SUV39H2的泛素化降解而调控IL-23启动子区的H3K9me3水平，从而调控DC触发的IL-23/IL-17/IL-22细胞因子网络，影响银屑病发生发展。研究结果可望为揭示银屑病的免疫学机制提供新的认识，并为开发治疗药物提供新的思路。

Psoriasis is a common chronic inflammatory skin disease, the abnormal activation and accumulation of dermal dendritic cell subsets in the inflammatory microenvironment play key roles in the pathogenesis of Psoriasis, through the induction of interleukin 23 to initiate the IL-23/IL-17/IL-22 axis, thus causes excessive proliferation of keratinocytes, however its regulatory network and molecular mechanisms are far from clear. E3 ubiquitin ligase mediated ubiquitination plays very important roles in the regulation of the activation and function of dendritic cells in adaptive and innate immune response. In our previous work, we found that the expression of FBXW7, 9, 11 was significantly upregulated in skin, ear tissues and dendritic cells in mouse psoriasis model. FBXW7 deficiency in dendritic cells suppressed the inflammation in mouse psoriasis model. Based on previous findings, in this project we will focus on the functions of FBXW7 in the regulation of different subsets of dendritic cells in psoriatic skin inflammatory microenvironment. We will investigate the correlation of FBXW7 expression pattern and inflammation status of the skin with use of skin tissue samples of patients with Psoriasis. By using FBXW7 gene knockout mice to establish the model of psoriasis, we will perform in-depth study of molecular mechanisms of FBXW7 in different subsets of dendritic cells, how they orchestrate and crosstalk in IL-23/IL-17/IL-22 cytokine axis and other important inflammatory cytokine network. We aim to further confirm that FBXW7 regulates the H3K9me3 level in IL-23 promoter region by mediating the ubiquitination and degradation of histone lysine methyltransferase SUV39H2, thereby positively regulates IL-23/IL-17/IL-22 axis and affects the development of psoriasis. The results will be helpful to provide the basis and the potential targets for the development of more specific therapeutic drugs or immunotherapy for Psoriasis.