白介素-30（IL-27p28）介导的DC细胞炎症反应对银屑病发生发展的免疫调节作用及分子机制研究

Psoriasis is an immune-mediated, genetic disease manifesting in the skin. It is mainly a dendritic cell and T-cell-mediated disease with complex feedback loops from antigen-presenting cells, neutrophilic granulocytes, keratinocytes, and the cutaneous nervous system, giving a serious impact on the physical and mental healthand life quality of the patients. IL-30, also calledIL-27p28.Recentstudies have shownthat IL-30 was biologically active in the absence of EBI3, thus, it has been recently recognized as a novel cytokine endowed with its own properties. However, the exact regulatory mechanisms of expressing functions independent of EBI3 and the effect of IL-30 on the pathogenesis of psoriasis remain largely elusive.In our previous study, we found that IL-30 treatment can alleviateexperimental psoriasis.Based on our previous studies, the applicant adopt various search methods, such asbioinformatics, biochips, structuralbiology and structural bioinformatics proposed here the main contents in this project: the relationship between IL-30 and the development of psoriasis, the regulatory mechanisms of IL-30 expressing functions independent of EBI3, the immunological mechanism of IL-30 on the pathogenesis of psoriasis. The applicant has good experiences working in immunology and life science, and always focuses on the combination of clinical and basic research of psoriasis. The implementation of this project will highlight new basic research and provide some new ideas for the development of new clinical diagnosis markers and psoriasis treatment strategies.

银屑病是一种多基因遗传背景下由T细胞、DC细胞和角质形成细胞等共同介导的皮肤特异性疾病，给患者身心健康及生活带来严重影响。IL-30（IL-27p28）在免疫反应中发挥作用方式独特，不仅可以与Ebi3结合形成IL-27参与免疫调节，亦可独立于EBI3作为单体细胞因子IL-30发挥生物学功能，调节DC细胞分化及相关细胞因子的表达，从而抑制机体免疫应答。但IL-30参与免疫调节的具体机制及在银屑病免疫病理调控中的作用目前尚无报道。课题组已有结果表明IL-30与银屑病发生具有密切的相关性，并能有效延缓银屑病小鼠的发病进程，在此研究基础上，申请者利用银屑病患者临床标本，基于IL-30tg小鼠采用生物信息学、细胞因子芯片技术等先进研究手段，深入探讨IL-30在银屑病免疫调控中的作用机制，阐明IL-30作为单独细胞因子发挥免疫调节功能的具体作用机理及意义。希望本课题的实施，能够为银屑病的基础研究提供新

银屑病是由T细胞、DC细胞和角质形成细胞等多种免疫细胞共同介导的一种多基因遗传背景下的皮肤特异性疾病，IL-30可以调节DC细胞分化及相关细胞因子的表达，本课题前期研究表明，IL-30影响银屑病样小鼠发病进程，但作用机制目前尚不明确。本课题利用临床银屑病患者标本、银屑病样病变细胞模型和小鼠模型，研究IL-30与银屑病发生发展的相关性，深入探讨IL-30在银屑病免疫调控中的可能机制。该项目研究中，我们发现IL-30在银屑病患者皮损区表达量明显高于非皮损区和正常皮肤组织，与银屑病发生发展具有密切相关性。IL-30能够有效抑制M5刺激的银屑病样病变HaCaT细胞炎症因子的表达，进一步研究发现，IL-30通过抑制抑制银屑病样小鼠角质形成细胞的分裂及皮损区炎症因子IL-17A、IL-23、IFN-γ、RORγt等的表达，延缓银屑病皮损的进程，深入研究IL-30对银屑病相关免疫调节细胞的影响，结果显示IL-30能够降低cDC细胞CD40、CD86和MHCII的表达，抑制cDC细胞的成熟，并参与cDC介导的T细胞成熟分化调节银屑病的疾病进程。另外，研究者发现银屑病患者皮损区具有不同程度的瘙痒并常伴有细菌感染，目前已有部分纳米抗菌材料用于治疗银屑病患者皮损区的细菌感染。为进一步加深对银屑病皮肤免疫微环境调控机制的理解，对发展新的银屑病治疗策略和方法提供新的研究思路，课题组设计出新型类内源性过氧化物酶的纳米酶材料，该新型纳米酶细菌杀伤力高达97%以上，能够有效降低银屑病皮损区的感染率。本课题的实施，不仅为银屑病等自身免疫性疾病的基础研究提供新的思路，还有望为银屑病患者皮损区的感染治疗提供良好借鉴。通过本项目资助，已发表SCI论文2篇。