干扰素诱导蛋白16介导的免疫微环境紊乱在银屑病中的作用

The immune mechanism of psoriasis is very complicated. It has been found that both the innate immunity system, such as keratinocytes, neutrophils, dendritic cells, and the adaptive immune system, such as T cells, are involved in the occurrence and development of psoriasis. Interferon-inducible protein 16 (IFI16) is an innate immune system sensor, which plays an important role in forming activated inflammasome and triggering immune response. We found that IFI16 was highly expressed in psoriatic epidermal keratinocytes, and knocking down p204—the mouse ortholog of IFI16—improved epidermal hyperplasia in a mouse model of imiquimod-induced psoriasis. However, its function and the underlying mechanism were still unknown. On the basis of our previous findings, this project will further investigate the expression of IFI16 in keratinocytes of psoriasis and what the under mechanism is, explore the function of IFI16 on keratinocyte activation and the IFI16-mediated psoriatic immune disorder, and confirm the function of IFI16 in the development of psoriasis. Therefore, all these research will be helpful to further understand the role of IFI16 in the pathogenesis of psoriasis and its mechanism, which will be hopeful to find a new therapy strategy for psoriasis.

银屑病的免疫机制非常复杂，包括角质形成细胞、树突状细胞等在内的固有免疫机制和以T细胞为代表的适应性免疫机制以不同的方式参与其中并相互作用，介导疾病的发生与发展。干扰素诱导蛋白16（IFI16）是机体感受内源及外源危险信号的重要分子，在启动炎症小体、激活固有免疫反应中发挥重要作用。我们的研究发现IFI16在银屑病皮损处角质形成细胞高表达，抑制其表达可明显减轻银屑病表型，但其发挥的具体作用及机制尚不清楚。本项目在前期工作的基础上，利用细胞、分生、动物模型等手段，系统研究IFI16在银屑病角质形成细胞的表达及调控机制，揭示IFI16对角质形成细胞的活化作用及由其构成的免疫环路和免疫微环境紊乱，最终明确其在银屑病发生发展中的作用和意义。项目的实施将能够明确IFI16介导的免疫紊乱在银屑病发病机制中的作用，并为银屑病治疗提供新的思路。

银屑病发病机制非常复杂，目前还没有完全阐明。IFI16是感知外源及内源性危险信号的重要分子，在启动机体固有免疫反应中发挥重要的免疫调节作用。本课题组和其他研究者在对银屑病的研究中均发现，相比于正常表皮，银屑病患者表皮角质形成细胞IFI16表达明显升高，但其是否在银屑病的发病机制中起到重要的作用以及其分子机制尚不清楚。本项目系统地观察了IFI16在银屑病中的表达与定位情况，明确IFI16在银屑病皮损角质形成细胞中显著高表达；体外研究发现银屑病相关细胞因子IFN-γ、TNF-α、IL-17A、IL22可以通过STAT3信号通路正向调控角质形成细胞中IFI16的表达与转位，并通过与TBK1分子相互作用促进角质形成细胞中NF-κB信号转导通路的活化，继而影响角质形成细胞CXCL10和CCL20的产生和分泌及其对免疫细胞的趋化活性，促进银屑病的发生与发展。进一步利用银屑病小鼠模型研究发现，采用siRNA抑制小鼠IFI16同源分子p204表达可以明显改减轻小鼠银屑病样皮肤炎症，提示靶向IFI16对于银屑病的治疗作用。本项目研究丰富了银屑病发病机制理论，也为今后探索新的治疗策略奠定了基础。