Lyn Delivers Bacteria to Lysosomes for Eradication through TLR2-Initiated Autophagy Related Phagocytosis.
Lyn Delivers Bacteria to Lysosomes for Eradication through TLR2-Initiated Autophagy Related Phagocytosis.
复制标题
Lyn 将细菌输送至溶酶体，通过 TLR2 启动的自噬相关吞噬作用将细菌消灭。
DOI：
10.1371/journal.ppat.1005363
复制
发表时间：
2016-01
期刊：
影响因子：
6.7
通讯作者：
Wu M
中科院分区：
文献类型：
--
作者：
Li X;He S;Zhou X;Ye Y;Tan S;Zhang S;Li R;Yu M;Jundt MC;Hidebrand A;Wang Y;Li G;Huang C;Wu M
细胞外细菌，如铜绿假单胞菌和肺炎克雷伯菌，已被报道诱导自噬;然而，感染诱导的自噬的作用和机制仍然难以捉摸。我们发现，多效性Src激酶林恩介导的吞噬作用和自噬体成熟的肺泡巨噬细胞（AM），这有利于最终的细菌根除。我们报告说，林恩是需要细菌感染诱导的招聘自噬成分的病原体含有吞噬体。当我们用3-甲基腺嘌呤（3-MA）或耗尽林恩阻断自噬时，我们观察到AM的吞噬作用和随后的细菌清除作用减少。形态学和生物学证据均表明，林恩通过异噬作用将细菌运送到溶酶体。TLR 2启动吞噬过程并在感染后激活林恩。细胞骨架运输蛋白，如Rab 5和Rab 7，关键促进早期吞噬体形成，自噬体成熟，并最终自噬介导的细菌降解。这些发现揭示了林恩、TLR 2和Rab调节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。建立消除细菌感染所需的宿主防御和免疫反应的机制基础至关重要。这一系列的研究将增加细菌发病机制的知识，并发现新的见解，可以提高新疗法的设计和有效性。我们证明，TLR-2是诱导林恩活性在宿主防御Pa感染通过援助自噬体成熟所需的，并可能连接自噬吞噬作用的TLR-2-林恩依赖的方式。因此，这些结果可能有助于进一步减轻革兰氏阴性菌引起的人类急性肺损伤/成人呼吸窘迫综合征（ALI/ARDS）。
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. It is vital to establish the mechanistic basis for initiation of host defenses and immune responses that are required to eliminate bacterial infection. This line of inquiry will increase knowledge of bacterial pathogenesis and uncover new insights that can enhance design and effectiveness of novel therapeutics. We demonstrate that TLR-2 is required for inducing Lyn activity in host defense against Pa infection through assistance in autophagosome maturation, and may link autophagy to phagocytosis in a TLR-2-Lyn-dependent manner. Thus, these results may further help to alleviate human acute lung injury/adult respiratory distress syndrome (ALI/ARDS) caused by Gram-negative bacteria.