Mindin与CD11b/CD18配受体轴在肠炎模型及炎症性肠病发生中的功能与机制

The abnormal immune response in intestinal mucosa is a key factor of immunopathogenesis in inflammatory bowel disease (IBD). The extracellular matrixprotein Mindin has been previously demonstrated to have important functional roles both in the innate and adaptive immune responses. Our preliminary results identified that CD11b/CD18 is membrane receptor of Mindin and binds with functional αM-I domain of CD11b/CD18. Further determined the ligand–receptor axis can induce the migration, adhesion and phagocytosis of macrophages and involved mechanism. However, role of function and mechanism of Mindin-CD11b/CD18 axis during colitis model and IBD immunopathogenesis are poorly understood. Thus, in this study, we will further silence the CD11b/CD18 using siRNA on Mindin deficient mice. Then, establish the acute and chronic colitis model to analyze the phenotype of inflammation, isolate the immune cells from circulating blood and intestinal lamina propria, stimulates them with recombinant Mindin protein to perform functional rescue experiments and detect the cytokine profile. We will perform the similar analysis on isolated samples from patients and healthy controls to further confirm them. We aimed to elucidate the function and mechanism of Mindin-CD11b/CD18 axis during intestinal immune responses of colitis and provide a novel molecular target for therapy of IBD.

肠黏膜异常免疫应答是炎症性肠病（IBD）发生的关键因素之一。细胞外基质蛋白Mindin在不同免疫应答中发挥着重要作用，本课题组前期已鉴定CD11b/CD18为Mindin的细胞膜受体，且Mindin结合其αM-I功能区域；并已揭示配/受体相互作用下诱导巨噬细胞的趋化迁移、黏附、吞噬功能及其机制，但Mindin-CD11b/CD18轴在肠道炎症过程尤其是IBD发生中的功能与机制尚未解明。因此本课题将：已构建的Mindin基因敲除小鼠上，利用体内siRNA干扰技术，建立干扰CD11b/CD18的模式动物，并构建急慢性肠炎模型，分析炎症评分等表型差异，从外周血及肠黏膜分离免疫细胞，体外予以Mindin重组蛋白的刺激等功能恢复实验和细胞因子表达谱检测；从IBD患者临床样本上得以验证。从而阐明Mindin与CD11b/CD18轴在肠炎、黏膜异常免疫应答中的作用与机制，为IBD的治疗提供新的分子靶点。

Mindin是一种结构高度保守的细胞外基质蛋白，在先天性免疫系统中具有重要的作用。Mindin可与CD18结合作用于免疫细胞。我们明确了小鼠结肠ILC3分泌mindin，通过构建体外炎症模型的实验方法来研究mindin-CD18在炎症反应中的作用，明确了mindin和CD18敲除加重了小鼠急性肠道炎症。我们初步探明mindin-/-和CD18-/-小鼠可通过提高结肠巨噬细胞和CX3CR1-炎症巨噬细胞的数量来加重DSS诱导的肠炎，为我们后续深入研究mindin和CD18在肠炎中的作用机制提供了一个研究方向。