Unique role for ATG5 in neutrophil-mediated immunopathology during M. tuberculosis infection.
Unique role for ATG5 in neutrophil-mediated immunopathology during M. tuberculosis infection.
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DOI：
10.1038/nature16451
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发表时间：
2015-12-24
期刊：
影响因子：
64.8
通讯作者：
Stallings CL
中科院分区：
文献类型：
--
作者：
Kimmey JM;Huynh JP;Weiss LA;Park S;Kambal A;Debnath J;Virgin HW;Stallings CL
结核分枝杆菌（Mtb）是全球主要的健康威胁，在巨噬细胞（MΦ）中部分通过抑制吞噬体-溶酶体融合进行复制，直到IFN-γ激活MΦ将结核分枝杆菌运送到溶酶体。IFN-γ如何引发这种作用尚不清楚，但许多研究表明其与巨噬作用有关，巨噬作用是细胞质内容物被隔离到自噬体中并以溶酶体降解为目标的细胞过程。自噬的参与已经根据培养MΦ或树突状细胞（DC）的研究进行了定义，其中Mtb与自噬（ATG）因子ATG5， ATG12, ATG16L1, p62, NDP52， Beclin1和LC3共定位，自噬刺激增加了细菌的杀伤，抑制自噬可以增加细菌的存活率。值得注意的是，这些研究揭示了对结核分枝杆菌复制的适度影响（例如1.5至3倍的变化）。相比之下，Atg5fl/fl-LysM-Cre小鼠在单核细胞来源的细胞和中性粒细胞（多态单核细胞，PMN）中缺乏ATG5，在30天内死于Mtb，这是一种极其严重的表型，类似于缺乏IFN-γ信号的小鼠。重要的是，ATG5是唯一一个在体内Mtb感染过程中被研究的ATG因子，并且ATG5的自噬独立功能已经被描述。因此，我们使用遗传学方法来阐明多个ATG基因在体内抵抗结核分枝杆菌感染中的作用和自噬的要求。我们发现，与预期相反，自噬能力与结核分枝杆菌感染的结果无关。相反，ATG5通过预防pmn介导的免疫病理在Mtb保护中发挥独特作用。此外，虽然结核分枝杆菌感染期间肺泡MΦ中没有ATG5，但PMN中ATG5的缺失会使小鼠对结核分枝杆菌敏感。这些发现改变了我们对ATG5在结核杆菌感染过程中的作用的理解，揭示了ATG5活性的新结果，并阐明了调节结核病病理和结核杆菌复制所需的先天免疫早期事件。
Mycobacterium tuberculosis (Mtb), a major global health threat, replicates in macrophages (MΦ) in part by inhibiting phagosome-lysosome fusion, until IFN-γ activates the MΦ to traffic Mtb to the lysosome. How IFN-γ elicits this effect is unknown, but many studies suggest a role for macroautophagy (autophagy herein), a cellular process by which cytoplasmic contents are sequestered into an autophagosome and targeted for lysosomal degradation. The involvement of autophagy has been defined based on studies in cultured MΦ or dendritic cells (DC) where Mtb colocalizes with autophagy (ATG) factors ATG5, ATG12, ATG16L1, p62, NDP52, Beclin1 and LC3, stimulation of autophagy increases bacterial killing, and inhibition of autophagy allows for increased bacterial survival. Notably, these studies reveal modest (e.g. 1.5- to 3-fold change) effects on Mtb replication. In contrast, Atg5fl/fl-LysM-Cre mice lacking ATG5 in monocyte-derived cells and neutrophils (polymorphic mononuclear cells, PMN) succumb to Mtb within 30 days, an extremely severe phenotype similar to mice lacking IFN-γ signaling. Importantly, ATG5 is the only ATG factor that has been studied during Mtb infection in vivo and autophagy-independent functions of ATG5 have been described. For this reason, we used a genetic approach to elucidate the role for multiple ATG genes and the requirement for autophagy in resistance to Mtb infection in vivo. We have discovered that, contrary to expectation, autophagic capacity does not correlate with the outcome of Mtb infection. Instead, ATG5 plays a unique role in protection against Mtb by preventing PMN-mediated immunopathology. Furthermore, while ATG5 is dispensable in alveolar MΦ during Mtb infection, loss of Atg5 in PMN can sensitize mice to Mtb. These findings shift our understanding of the role of ATG5 during Mtb infection, reveal a new outcome of ATG5 activity, and shed light on early events in innate immunity that are required to regulate tuberculosis disease pathology and Mtb replication.