抗TNF生物制剂治疗类风湿关节炎对巨噬细胞自噬的影响及机制研究

Tumour necrosis factor-a (TNF-a) plays a pivotal role in the pathogenesis of inflammatory arthritis, such as rheumatoid arthritis (RA). TNF antagonists brought new hopes for treating these diseases but also increased the risk for infection, since TNF-a is also an essential factor involved in the macrophage anti-infection immune responses. Autophagy is an important functional process both in the innate and adaptive immunity. In recent years, studies showed that autophagy played an important role in anti-infection immunity, which might go far beyond its ability to degrade pathogens directly. It is still unknow about how autophagy in macrophage is involved in the elevated risk for infection associated with TNF antagonists. Here, we used macrophage line to study the effects of TNF antagonists on macrophage autophagy and associated mechanisms. The study may provide a new theoretical basis and experimental data which can effectively help to reduce the risk for infection associated with TNF antagonists.

肿瘤坏死因子-α（TNF-α）作为一中心炎症介质,在类风湿关节炎（RA）等炎性关节病的发病及病程进展中起重要作用。TNF拮抗剂是目前炎性关节病治疗领域的一个重要突破。由于TNF-α在巨噬细胞抗感染免疫中起重要作用，因此TNF拮抗剂不可避免导致感染风险增高。巨噬细胞对感染的清除不仅仅是通过对病原体的直接降解，自噬被证实通过多种信号途径在巨噬细胞清除病原体中起重要的作用。TNF拮抗剂如何通过影响巨噬细胞自噬导致感染风险的增高，目前在国际上尚无报道。本项目将以自噬为切入点，根据国际上最新研究进展，探讨不同TNF拮抗剂对巨噬细胞自噬的影响及具体机制，从而为有效规避TNF拮抗剂相关感染风险提供新的干预靶点和治疗策略。

肿瘤坏死因子-α（TNF-α）在类风湿关节炎（RA）等炎性关节疾病发病及病程进展中起重要作用。TNF拮抗剂是目前炎性关节疾病治疗领域的一个重要突破。由于TNF-α在单核巨噬细胞抗感染免疫中起重要作用，因此TNF拮抗剂不可避免导致感染风险增高。自噬被证实通过多种信号途径在巨噬细胞清除病原体中起重要的作用，本研究探索TNF拮抗剂如何通过影响巨噬细胞自噬导致感染风险的增高，同时也采用单细胞测序分析TNF单抗治疗后不同感染状态的RA外周血CD14+单核细胞差异基因的表达，从而为有效规避TNF拮抗剂相关感染风险提供新的干预靶点和治疗策略。同时，本课题也从单核巨噬细胞角度探讨了植物类抗风湿药物抗炎机制，发现姜酮能通过抑制破骨细胞中NF-κB信号途径减轻炎症性骨侵蚀；基于网络药理学与分子对接发现雷公藤的有效成分雷公藤内酯醇对TNF具有最强和最稳定的结合亲和力。