TBK1调控巨噬细胞生物学功能及其在儿童炎症性肠病发生发展中的作用机制研究

Inflammatory bowel diseases (IBD) in children can cause growth retardation and have a high risk of cancer. We have previously found that the inflammatory responses mediated by macrophages play an important role in the development of children’s IBD. In our work, we have proved that the macrophages can specifically recruitment to the inflammatory sites of colon and regulate the inflammatory responses during colitis (Liu T, et al. Sci Rep, 2015). We also found that TBK1 (Tank binding kinase-1) is highly expressed in the macrophages which located in lamina propria. Interestingly, when we conditionally knockout TBK1 in macrophages, the recruitment of macrophages in inflammatory sites of colitis mice increased significantly, however the underlying mechanism remains unclear. In this project, we intend to study the mechanism of TBK1 in regulating the biological function of macrophage. Additionally, we will detect the state of TBK1 gene in children with clinical samples and unveil its role in the development of children’s IBD. Therefore this project may provide us new strategy for the precise treatment of IBD in children.

儿童炎症性肠病（Inflammatory bowel diseases, IBD）会引起生长发育障碍并具有较高的癌变风险。申请者前期的工作证实巨噬细胞介导的炎性反应在儿童IBD的发生发展过程中作用关键。在幼龄小鼠溃疡性结肠炎模型中，我们发现巨噬细胞能够特异性的募集到结直肠炎症部位并参与调控肠道炎症反应（Liu T, et al. Sci Rep, 2015）。进一步的实验发现TBK1(Tank binding kinase-1)在结直肠固有层巨噬细胞中高表达，并且在条件性敲除巨噬细胞TBK1基因后，结直肠部位的巨噬细胞募集明显增多，提示TBK1在调控巨噬细胞功能中有关键作用，但其具体机制尚不清楚。在本项目中，我们拟研究TBK1对巨噬细胞生物学功能的调控机理并检测儿童IBD患者临床样本的TBK1基因状态，阐明TBK1在儿童IBD发病过程中的作用，以期为儿童IBD患者的精准治疗提供新的思路。

巨噬细胞在慢性炎症性疾病如炎症性肠病和非酒精性脂肪性肝炎的发病机制中起着至关重要的作用，但调控巨噬细胞促炎功能的分子机制目前尚不完全清楚。在该项研究工作中，我们发现蛋白激酶TBK1是巨噬细胞中关键的抗炎因子，能够在不同的疾病模型中发挥抗炎作用，保护组织免受炎症损伤。研究发现条件性敲除巨噬细胞TBK1（TBK1-MKO）会促进葡聚糖硫酸钠（DSS）诱导的幼龄小鼠炎症性肠病的发生发展，这一现象与组织M1巨噬细胞浸润以及炎症细胞因子表达增加有关。另外，TBK1-MKO小鼠在老年时会自发发生脂肪肥大和代谢紊乱。当给予高脂饮食时，TBK1-MKO小鼠肝脏炎症加剧并出现明显的胰岛素抵抗，最终表现出非酒精性脂肪性肝炎的临床症状。从机制上讲，TBK1在巨噬细胞中的作用是抑制NF-kB和MAP激酶信号通路，从而抑制炎症细胞因子的分泌，特别是IL-1beta的分泌。阻断IL-1受体1 (IL-1R1)可有效缓解TBK1-MKO小鼠的炎症症状。综上这些结果证实了TBK1是巨噬细胞中一种关键的抗炎因子，也是治疗炎症性疾病的潜在治疗靶点。在本项目的支持下，申请人以第一作者/通讯作者身份（含并列）在Proceedings of the National Academy of Sciences of the United States of America（见附件PNAS接收函，IF=11.205）， Clinical and Experimental Rheumatology和BMC infectious diseases等期刊发表研究论文8篇，获得专利2项，协助指导了一名博士研究生和一名硕士研究生毕业。