Function and Targeting of CCR6/CCL20 in Autoimmune Psoriasiform Skin Disease

描述(申请人提供)：Th17相关细胞和信号通路显然在多种自身免疫过程的发展中非常重要，包括类风湿性关节炎、多发性硬化症和牛皮癣。IL23是Th17介导的炎症的典型驱动因素，我们和其他人已经证明，在小鼠皮肤中重复注射重组IL23会导致牛皮癣样皮炎，这种皮炎在短短5天内就会模仿人类牛皮癣的许多特征。在已知的~20种趋化因子受体中，CC趋化因子受体-6(CCR6)对Th17诱导的免疫活性尤为重要，因为它既是表达Th17表型的T细胞的标志，也是多种自身免疫性疾病模型的关键参与者，包括自身免疫性脑炎、胶原性关节炎和银屑病。我们之前已经证明，CCR6缺陷小鼠在注射IL23后未能在皮肤中发生牛皮癣样皮炎。目前的模型表明，由树突状细胞(DC)产生的IL23支持真皮CC趋化因子受体-6(CCR6)表达的Th17细胞，然后Th17细胞产生IL22作为主要的下游效应因子，通过STAT3介导的机制在人体皮肤刺激表皮增生。正反馈是由表皮和真皮产生的CCR6配体CCL20提供的，可能会招募更多的CCR6+T细胞或CCR6+抗原提呈细胞进入发炎的银屑病皮肤。虽然来自人类的研究数据刚刚开始表明γδT细胞与银屑病和其他自身免疫性疾病有关，但我们公布的数据表明，一种新的CCR6+Vγ3-T细胞受体(Vγδ3-T cell Receptor，Tcr)低(Gdl)T细胞群，不同于常驻的树突状表皮γδT细胞，在暴露于IL23的小鼠表皮中聚集，是小鼠表皮产生IL22和IL17的主要来源。我们推测，1)皮肤中的CCR6+GDLT细胞可能是运送IL22和其他细胞因子的关键先天免疫细胞，这些细胞因子在银屑病等疾病中调节皮肤的表皮增生和炎症；2)CCR6或CCL20的拮抗剂将在包括银屑病在内的几种Th17介导的自身免疫过程中成为有效的治疗剂，因为它们影响CCR6表达细胞的运输和/或功能。基于这一假设，我们试图更好地确定CCR6和γδT细胞在IL23和咪喹莫特诱导的银屑病小鼠皮炎模型中的作用，并使用新的计算方法来识别拮抗CCR6或其配体CCL20功能的小分子先导化合物。我们的结果将在SCID-HU牛皮癣皮肤异种移植模型中得到验证。

DESCRIPTION (provided by applicant): Th17-associated cells and signaling pathways are clearly important in the development of multiple autoimmune processes, including rheumatoid arthritis, multiple sclerosis, and psoriasis. IL23 is a prototypical driver of Th17-mediated inflammation, and we and others have shown that repeated injections of recombinant IL23 in mouse skin result in a psoriasiform dermatitis that mimics many of the features of human psoriasis in as little as 5 days. Among the ~20 known chemokine receptors, CC chemokine receptor-6 (CCR6) is particularly important for Th17-directed immune activity since it is both a marker for T cells that express the Th17 phenotype and a critical participant in several mouse models of autoimmune disease, including autoimmune encephalitis, collagen-induced arthritis, and psoriasis. We have previously shown that CCR6-deficient mice fail to develop psoriasiform dermatitis in skin following IL23 injection. Current models suggest that IL23 produced by dendritic cells (DCs) act to sustain dermal CC chemokine receptor-6 (CCR6)-expressing Th17 cells which then produce IL22 as a major downstream effector that stimulates epidermal hyperplasia through STAT3- mediated mechanisms in human skin. Positive feedback is provided by epidermal and dermal production of CCL20, the CCR6 ligand, potentially recruiting more CCR6+ T cells or CCR6+ antigen-presenting cells into inflamed psoriatic skin. While data from human studies are just beginning to implicate γδT cells in psoriasis and other autoimmune disease, our published data demonstrate that a novel population of CCR6+, Vγ3- T cell receptor (TCR) γδ low (GDL) T cells, distinct from resident dendritic epidermal γδ T cells (DETC), accumulates in murine epidermis following exposure to IL23 and is a major producer of IL22 and IL17 in murine epidermis. We hypothesize that 1) CCR6+ GDL T cells in skin may be critical innate immune cells for the delivery of IL22 and other cytokines that regulate epidermal hyperplasia and inflammation in skin in conditions such as psoriasis and 2) that antagonists of CCR6 or CCL20 would be effective therapeutic agents in several Th17- mediated autoimmune processes, including psoriasis, because of their effects on the trafficking and/or function of CCR6-expressing cells. Based on this hypothesis, we seek to better define the roles of CCR6 and γδ T cells in an IL23- and imiquimod-induced models of psoriasisform dermatitis in mice and to use novel computational methods to identify small molecule lead compounds that antagonize the function of either CCR6 or its ligand, CCL20. Our results will be validated with a SCID-hu psoriasis skin xenotransplant model.