应激在银屑病发病中的作用及机制研究

Infection and stress are clinically common factors to induce or exacerbate psoriasis. Both of them can significantly increase dermal IL-17 which is the the key factor involved in the development of psoriasis, and stress can increase IL-17 in peripheral blood too. Now the pathway how infection induces IL-17 production has been rather clear, but there is little knowledge about how stress induces the production of IL-17 and then the development of psoriasis. It is reported that PRL, a endocrine hormone, rises in peripheral blood and skin lesions of psoriasitic patients after psychological stress or delivery. And the cutaneous sensory neurons expressing TRPV1+Nav1.8+ nociceptors are necessary in mediating psoriasiform skin inflammation in mice being exposed to imiquimod. This program aims at proving that stress and infection are two ways of inducing psoriasis, which is the activation of IL-23/IL-17 axis and production of IL-17 The difference of the two ways is that PRL and cutaneous neuronal receptors are involved in the stress-activated IL-23/IL-17 axis and production of IL-17. The understanding of how PRL and cutaneous neurons drive psoriasis under environmental stress will build the foundation for the development of new systemic or topical agents to psoriasis.

感染与应激是临床上诱发或加重银屑病的原因，两者都会引起皮肤关键致病性细胞因子IL-17明显增多，后者还会出现外周血IL-17的升高。感染导致IL-17产生的机制已较明确，但应激引起IL-17产生、银屑病发生或进展的机制所知甚少。有报道泌乳素（PRL）在银屑病患者心理应激与分娩后血清中水平升高，皮损处高表达；只有在皮肤局部感觉神经元（TRPV1+Nav1.8+伤害性受体）的存在下咪喹莫特（IMQ）涂抹鼠后才会出现银屑病样皮损。该项目拟证实应激与感染在导致银屑病发生、发展中的机制殊途同归，都是通过活化IL-23/IL-17轴、IL-17产生引起；两者的“殊途”之处是应激在活化IL-23/IL-17轴的过程中有神经内分泌激素PRL的参与，在皮肤局部神经受体参与下IL-17发挥致病作用。在了解PRL、皮肤局部神经元在环境应激条件下导致银屑病发生机制的基础上为研发系统或外用治疗制剂奠定基础。

银屑病是一种皮肤科常见的慢性炎症性疾病。在特定遗传背景下，环境因素是诱发或加重银屑病的主要因素。环境因素主要有“感染”和“应激”，前者主要是指上呼吸道感染和局部皮肤感染；后者常见有睡眠剥夺、低温应激、紧张、焦虑等。目前关于“感染”的研究已表明，感染激活IL-23/IL-17轴引起皮肤炎症后发病，但应激尤其是睡眠剥夺和低温这两种临床上常见的银屑病诱发因素，其引起银屑病发病或加重的相关研究很少。本研究通过睡眠剥夺联合咪喹莫特（IMQ）进行小鼠建模后发现，睡眠剥夺后小鼠皮肤及淋巴结中炎症活化明显，且催乳素（PRL）和银屑病具有相关性，尤其是皮损局部产生的PRL。此外，相同睡眠剥夺强度联合等量IMQ剂量下，早期应激是关键，较后期应激明显增强皮肤及淋巴结中γδT细胞和IL-17A的表达。在低温应激方面，本研究通过低温应激联合IMQ进行小鼠建模后发现，寒冷应激加重银屑病。