肿瘤坏死因子-α在分枝杆菌肉芽肿免疫中的研究进展

Advances in understanding the role of tumor necrosis factor-α in the immune response to mycobacterial granulomas

摘要:

肿瘤坏死因子-α（TNF-α）通过TNFR1/TNFR2受体介导的核转录因子κB、丝裂原活化蛋白激酶及凋亡信号通路，在肺感染性肉芽肿免疫中呈现“保护-损伤”双重效应。TNF-α通过调控巨噬细胞极化及T细胞免疫应答，在分枝杆菌肉芽肿免疫中发挥核心防御功能，通过维持肉芽肿结构完整性限制病原体播散及增强吞噬杀伤能力清除病原体。TNF-α缺失或过量则引发肉芽肿坏死、纤维化及病原播散，凸显其精准调控在免疫保护中的必要性。临床使用抗TNF治疗可显著增加结核再激活、真菌及非结核分枝杆菌感染风险，单克隆抗体类药物风险尤甚。未来需解析肉芽肿微环境中TNF-α的动态互作网络，开发精准干预TNF-α信号策略，优化抗感染疗效并减少副作用，为分枝杆菌肺病的治疗提供新思路。

Abstract:

Tumor necrosis factor-α (TNF-α) exerts a dual “protective-pathogenic” effect in pulmonary infectious granuloma immunity through TNFR1/TNFR2-mediated NF-κB, MAPK, and apoptotic signaling pathways. By regulating macrophage polarization and T-cell immune responses, TNF-α plays a central defensive role in mycobacterial granuloma immunity, maintaining granuloma structural integrity to limit pathogen dissemination and enhancing phagocytic killing capacity for pathogen clearance. Both deficiency and excessive production of TNF-α can lead to granuloma necrosis, fibrosis, and pathogen spread, underscoring the necessity of precise regulation for immune protection. Clinically, anti-TNF therapy significantly increases the risk of tuberculosis reactivation, as well as fungal and nontuberculous mycobacterial infections, with monoclonal antibody therapies posing particularly high risks. Future research should focus on delineating the dynamic interaction network of TNF-α within the granuloma microenvironment and developing precision-targeted TNF-α interventions to optimize anti-infective efficacy while minimizing adverse effects, offering new strategies for the treatment of mycobacterial pulmonary diseases.