白介素-37通过分泌与入核双重途径调控银屑病免疫病理的分子机制研究

Psoriasis is a common chronic, relapsing, auto-inflammatory skin disease characterized by demarcated, red and scaly plaques, which results in great morbidity for severely affected patients. The pro-inflammatory microenvironment comprises complex cross-talk between professional immune and resident cutaneous cell lineages, leading to the initiation and maintenance of psoriasis. Interleukin-37 (IL-37), a newly identified member of IL-1 cytokine family, is a fundamental inhibitor of innate immunity and adaptive response. However, the molecular mechanism of IL-37 has remained elusive. The applicant reported IL-37 ameliorated the inflammatory process in psoriasis by suppressing pro-inflammatory cytokine production (The Journal of Immunology, 2014, 192: 1815–1823). The data we obtained demonstrates that IL-37 could be as a dual-function cytokine (both with extracellular and intracellular mode). The applicant proposed here several main contents in this study: the relationship between the expression pattern of IL-37 and the development of psoriatic inflammation, the immunological effect of IL-37 in psoriatic mice model, and the novel signal pathway of IL-37 both as secretory cytokine and transcriptional molecule. The applicant, interested in immunology and life science, hope that this research could reveal new pathogenesis of psoriasis and provide some new ideas for intracellular mechanism study of the multifaceted cytokines, such as IL-37, in autoimmune diseases.

银屑病是多基因遗传背景下的自身免疫性皮肤疾病，皮肤固有细胞与免疫细胞之间异常激活的级联放大交互作用是导致银屑病皮损的关键因素。IL-37是新发现的IL-1 细胞因子家族成员，具有强烈的免疫抑制作用，但具体分子机制尚不明确。申请者在J Immunol期刊报道了IL-37减缓银屑病发病进程的实验研究，具有良好的研究背景。本课题前期研究表明IL-37可能通过经典的分泌途径和非经典的入核途径影响银屑病免疫病理，在此研究基础上，申请者继续利用临床银屑病标本和IL-37转基因小鼠，归纳IL-37分子表达模式与银屑病发生发展的相关性，深入阐述IL-37对银屑病的免疫调控功能，创新性地探索IL-37分泌、入核途径调控银屑病病理免疫的分子机制，重点阐明IL-37的非经典转录调控功能。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思路，还为探索传统细胞因子的非经典作用途径提供良好借鉴。

IL-37是新发现的IL-1 细胞因子家族成员，具有强烈的免疫抑制作用，但具体分子机制尚不明确。本课题前期研究表明IL-37影响银屑病免疫病理，在此研究基础上，我们利用临床银屑病标本和IL-37转基因小鼠，归纳出IL-37分子表达模式与银屑病发生发展的相关性，深入阐述IL-37对银屑病的免疫调控功能，绘制成免疫调控图谱。同时，我们研究了IL-37调控炎症相关的肿瘤生成机器细胞免疫学机制，发现该分子促进了AOM/DSS诱导的小鼠结肠炎相关结直肠癌CAC的发生。我们从促进转化的肠上皮细胞的增殖和肿瘤免疫调控两方面探讨IL-37促进CAC发生的生物学机制，发现与IL-37诱导结肠上皮细胞基因突变或增殖无关；真正的原因是IL-37诱导了低炎症应答的免疫环境，抑制了杀伤性T细胞的抗肿瘤免疫应答。我们继续探明IL-37诱导肿瘤逃逸分子机制，发现IL-37通过启动SIGIRR阻断IL-1受体家族信号通路和mTOR信号通路介导CD8+ T的耗竭，并且这一作用不依赖于TGF-beta/Smad3信号通路。本课题的实施不仅为银屑病等自身免疫性疾病和肿瘤免疫治疗的基础研究提供新思路，还为探索免疫检查点新疆域提供良好借鉴。在本项目的资助下，我们已发表SCI研究论文1篇，国际会议收录摘要1篇。完成1名博士后工作培训和2名研究生的培养。