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

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.

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。

银屑病，是一种由遗传、免疫及感染等多因素诱发的慢性炎症性皮肤疾病，发病以青壮年为主，病程较长，易复发，有的病例几乎终生不愈，对患者的身体健康和精神状况造成极大影响。目前认为IL-23-IL17轴是关键的免疫学发病机制之一。树突状细胞（dendritic cells, DCs）作为固有免疫细胞和专职抗原提呈细胞，是炎症和免疫应答的始动环节，处于最核心和关键的地位。树突状细胞可通过分泌IL-23，启动IL-23/IL-17/IL-22细胞因子轴，导致角质形成细胞过度增殖。然而，其复杂的调控网络和精细的调节机制远未深入阐明。.. E3泛素酶FBXW7在巨噬细胞和树突状细胞介导的抗病毒天然免疫中发挥重要作用，但其在皮肤炎症性疾病中的作用还未有报道。本项目利用FBXW7条件性基因敲除小鼠和临床银屑病组织样本，深入研究了FBXW7分子在皮肤炎性微环境树突状细胞中的调控作用及其分子机制，为银屑病诊治提供新的思路和潜在靶点。.. 本研究中，我们发现树突状细胞FBXW7选择性缺失小鼠在咪喹莫特诱导的银屑病模型中，皮肤炎症减轻，银屑病表型减弱。多种TLRs配体刺激下，FBXW7缺失导致DCs中IL-23的产生显著减少。在分子机制研究中，我们发现FBXW7与组蛋白H3K9三甲基化甲基转移酶SUV39H2相互结合。FBXW7介导SUV39H2的泛素化降解，从而减少H3K9m3在Il23a启动子上的富集，促进Il23的转录表达。同时，Suv39h2敲除小鼠表现出IL-23-IL-17轴的过度激活和皮肤炎症加剧。本研究首次发现FBXW7可通过降解DCs中SUV39H2来表观调控IL-23的表达，从而加重银屑病样炎症，并提示靶向树突状细胞中FBXW7 在开发银屑病药物中可能具有潜在的应用前景。相关研究结果已在Molecular Cell、Journal Of Clinical Investigation、Cellular & Molecular Immunology等SCI收录期刊发表标注本项目资助号的论文7篇，参加3次国内外学术会议交流，培养博士研究生3 名，硕士研究生2名。