Li Xuefeng, He Sisi, Zhou Xikun, Ye Yan, Tan Shirui, Zhang Shuang, Li Rongpeng, Yu Min, Jundt Michael C, Hidebrand Alec, Wang Yongsheng, Li Guoping, Huang Canhua, Wu Min
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, P.R. China.
Department of Biomedical Sciences, University of North Dakota, Grand Forks, North Dakota, United States of America.
PLoS Pathog. 2016 Jan 6;12(1):e1005363. doi: 10.1371/journal.ppat.1005363. eCollection 2016 Jan.
Extracellular bacteria, such as Pseudomonas aeruginosa and Klebsiella pneumoniae, have been reported to induce autophagy; however, the role and machinery of infection-induced autophagy remain elusive. We show that the pleiotropic Src kinase Lyn mediates phagocytosis and autophagosome maturation in alveolar macrophages (AM), which facilitates eventual bacterial eradication. We report that Lyn is required for bacterial infection-induced recruitment of autophagic components to pathogen-containing phagosomes. When we blocked autophagy with 3-methyladenine (3-MA) or by depleting Lyn, we observed less phagocytosis and subsequent bacterial clearance by AM. Both morphological and biological evidence demonstrated that Lyn delivered bacteria to lysosomes through xenophagy. TLR2 initiated the phagocytic process and activated Lyn following infection. Cytoskeletal trafficking proteins, such as Rab5 and Rab7, critically facilitated early phagosome formation, autophagosome maturation, and eventual autophagy-mediated bacterial degradation. These findings reveal that Lyn, TLR2 and Rab modulate autophagy related phagocytosis and augment bactericidal activity, which may offer insight into novel therapeutic strategies to control lung infection.
据报道，胞外细菌，如铜绿假单胞菌和肺炎克雷伯菌，可诱导自噬；然而，感染诱导的自噬的作用和机制仍不清楚。我们发现，多效性Src激酶Lyn介导肺泡巨噬细胞（AM）中的吞噬作用和自噬体成熟，这有助于最终清除细菌。我们报道，Lyn是细菌感染诱导自噬成分募集到含病原体吞噬体所必需的。当我们用3-甲基腺嘌呤（3-MA）或通过消耗Lyn来阻断自噬时，我们观察到AM的吞噬作用和随后的细菌清除减少。形态学和生物学证据均表明，Lyn通过异噬作用将细菌递送至溶酶体。TLR2在感染后启动吞噬过程并激活Lyn。细胞骨架运输蛋白，如Rab5和Rab7，对早期吞噬体形成、自噬体成熟以及最终自噬介导的细菌降解起到关键促进作用。这些发现揭示，Lyn、TLR2和Rab调节与自噬相关的吞噬作用并增强杀菌活性，这可能为控制肺部感染的新治疗策略提供见解。
