补体C5a/C5aR通路促pDCs分化和功能形成介导银屑病的机制研究

Psoriasis is a chronic inflammatory disease of the skin，which is involved in a various factors including genetics and immune system, and there is not an effective treatment strategy for patients with psoriasis. Imiquimod (IMQ)-induced psoriasis dermatitic mice is a now widely accepted animal model in the study about the pathogenesis of psoriasis. In the previous studies, by using this successfully established mice psoriasis model, it was found that, complement C5a receptor (C5aR) gene deficiency significantly attenuated IMQ -induced scaly skin inflammation in mice. Moreover, compared with the wild type mice, both IMQ-induced plasmacytoid dendritic cells (pDCs) infiltration in local skin and the ability of bone marrow cells differentiating into pDCs was remarkably reduced in C5aR KO mice. According to the literatures, pDCs play a critical role during the pathogenesis of psoriasis. We therefore hypothesize that complement C5a/C5aR pathway mediates psoriasis development via the potentiating of pDCs differentiation and functions formation. In the present study, we will define the role of C5a/C5aR pathway in the pathogenesis of psoriasis by combination in vitro with in vivo mice experiments, and then further explore the underlying molecular mechanisms involved in C5a/C5aR pathway regulation in pDCs differentiation and function. Anticipative results will help us further clarify the precise pathogenesis of psoriasis, which may ultimately indicate effective treatment strategies for clinical patients with psoriasis.

银屑病(psoriasis)是一种慢性炎症性皮肤病，涉及遗传和免疫等多种因素，确切的病理机制尚不明确。咪喹莫特(Imiquimod,IMQ)诱导的银屑病皮炎小鼠是研究银屑病最常见的动物模型。利用此模型，在前期研究中我们首次发现,补体C5aR基因缺失可显著衰减小鼠银屑病病情。进一步的研究表明，与C5aR+/+小鼠相比，C5aR-/-小鼠中pDCs (plasmacytoid dendritic cells)的分化和功能均明显受损。新近的文献证实pDCs是导致银屑病免疫病理的关键细胞类型。据此推测：C5a/C5aR通路可能通过促pDCs分化与功能形成来介导银屑病的发生。本研究拟通过体内外实验明确补体C5a/C5aR通路在银屑病免疫病理中的作用；探讨该通路对pDCs分化及功能形成的调控机制。预期结果不但有助于银屑病发病机制的阐明，并且可为临床银屑病有效治疗策略的发展提供重要的理论依据。

银屑病是一种慢性炎症性皮肤病，涉及遗传和免疫等多种因素，确切的病理机制尚不明确。咪喹莫特(Imiquimod,IMQ)涂抹和IL-23皮内注射诱导的银屑病皮炎小鼠是研究银屑病最常见的动物模型。利用此俩模型，我们发现银屑病损皮肤局部补体C5aR1表达增加，C5aR1基因缺陷显著减轻银屑病皮肤炎症，而C5aR拮抗剂阻断C5aR1信号通路后可显著减轻IMQ诱导的银屑病皮肤炎症。基于pDCs是导致银屑病免疫病理的关键细胞类型，我们进一步研究了它们之间的关联，结果发现C5aR1缺乏可显著减少银屑病病灶的pDCs浸润及其功能，体外实验证明C5a可加速骨髓细胞向pDCs的分化以及迁移能力。而且，C5aR1缺乏可显著减少γδ-T细胞IL-17A的产生，并且证实C5a/C5aR1通过PI3K/Akt信号通路促进了IL-17A的产生，C5aR1拮抗剂可降低银屑病样皮炎的发生和T细胞反应，阻断C5aR1可进一步减弱IMQ诱导的IL-17缺陷小鼠的银屑病样皮肤炎症。有趣的是，作为补体C5活化的上游分子，补体 C3缺乏可加重IMQ诱导的银屑病样皮肤炎症；与野生型小鼠相比，C3缺陷小鼠具有相似的IMQ诱导的IL-17A应答，但IFN- gamma应答更强，细胞凋亡增加；Z-VAD-FMK预处理可减轻IMQ诱导的银屑病样皮肤炎症和细胞凋亡，提示补体是一个复杂的网络系统，其内在的关联需进一步阐明。总之，以上结果提示C5a/C5aR1信号通路通过促pDC细胞分化和功能形成，以及上调皮肤炎症γδ-T细胞IL-17A的表达在银屑病的发病机制中发挥关键作用，阻断C5a/C5aR1/IL-17A轴有望成为治疗银屑病的一种有前途的策略。