CGRP对银屑病朗格汉斯细胞的分子调节机制研究

Psoriasis is an autoimmune-mediated inflammatory skin disease and neuro-immune regulation plays an important role in the pathogenesis of psoriasis. However, the mechanism of interaction between nerve fibers and Langerhans cells (LC) is not clear. Nerve fibers in skin have close contact with LC which expressing IL-23 to stimulate γδT cells to induce IL-17 and IL-22 secretion. The latters participate the recruitment of inflammatory cytokines driving and aggravating psoriatic skin inflammation. Study discovers PDK1 is required for LC development and LC in Rsk1/2-/- mice is significantly reduced. Our previous studies have found there is increased secretion of CGRP in psoriasis lesions and CGRP+ nerve fibers have close contact with LC. Based on the preliminary research, we speculate CGRP excreted by nerve fibers regulates PDK1-Rsk signal pathway of LC expressing IL-23 and stimulates γδT cells to induce IL-17 and IL-22 secretion. Therefore, this study from the aspects of clinical, cytological and animal experimentsinvestigate the effect of CGRP on the regulation of PDK1-Rsk pathway in LC and stimulation of γδT cells. Eventually elucidating the neuro-immunemolecular regulative mechanism of CGRP on cutaneous Langerhans cells in psoriasis.

银屑病是自身免疫性炎症性皮肤病，神经免疫调节在其发病中起着重要作用，但神经纤维与LC的相互作用机制尚未明确。皮肤神经末梢纤维与朗格汉斯细胞(LC)密切接触，通过分泌神经肽活化LC使其表达IL-23增加，继而促进γδT细胞分泌IL-17和IL-22、募集炎症细胞、促进和加重银屑病炎症反应。研究发现PDK1缺陷鼠不表达LC，并且Rsk1/2-/-小鼠的LC明显减少。我们前期研究发现银屑病皮损中CGRP分泌增加，CGRP阳性的神经纤维与LC密切接触。在此基础上，我们推测银屑病皮损中神经末梢分泌的CGRP通过PDK1-Rsk信号通路调控LC的成熟、活化及分泌细胞因子，进而激活下游γδT细胞，表达IL-17、IL-22。为此本研究从临床、细胞学及动物实验方面，探讨CGRP对银屑病皮肤朗格汉斯细胞PDK1-Rsk通路的调控，及对γδT细胞功能的影响，从而阐明CGRP在银屑病神经免疫调节中的分子机制。

强烈的精神刺激和压力往往诱发或加重银屑病。相反，有神经损伤和神经系统功能障碍的患者银屑病得到缓解。神经系统在银屑病的炎症过程中起着重要作用，神经肽被认为是疾病维持的局部介质。为了研究其分子机制，我们首先分析了降钙素基因相关肽（CGRP）处理的单细胞培养体系：朗格汉斯细胞和γδ-T细胞。结果发现CGRP通过PDK1-Rsk信号通路诱导朗格汉斯细胞中IL-23mRNA和蛋白表达，而CGRP对γδ-T细胞分泌IL-17A和IL-22无影响。然后，我们用CGRP处理LCs/γδ-T细胞共培养模型。结果发现CGRP通过LCs的旁分泌作用上调共培养模型中IL-17A和IL-22的表达。IL-17A和IL-22是银屑病的关键细胞因子。这些结果提供了神经因素影响银屑病发展的潜在机制。