Autophagy prevents early proinflammatory responses and neutrophil recruitment during Mycobacterium tuberculosis infection without affecting pathogen burden in macrophages.
Autophagy prevents early proinflammatory responses and neutrophil recruitment during Mycobacterium tuberculosis infection without affecting pathogen burden in macrophages.
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DOI：
10.1371/journal.pbio.3002159
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发表时间：
2023-06
期刊：
影响因子：
9.8
通讯作者：
中科院分区：
文献类型：
--
作者：
对结核分枝杆菌感染的免疫反应决定了结核病的预后，但我们对哪些免疫因素有助于保护性免疫反应的了解并不完全。在人类和动物模型中，中性粒细胞炎症与结核分枝杆菌感染期间的不良疾病预后有关，因此必须严格调节。ATG5是固有免疫细胞控制中性粒细胞主导的炎症和促进结核分枝杆菌感染期间存活所必需的自噬蛋白；然而，ATG5调控中性粒细胞募集的机制基础尚不清楚。为了探究在结核分枝杆菌感染期间，先天免疫细胞需要ATG5来控制中性粒细胞募集，我们使用不同的小鼠品系，在特定细胞类型中有条件地删除ATG5。我们发现ATG5在CD11c+细胞（肺巨噬细胞和树突状细胞）中是必需的，以控制结核分枝杆菌感染期间促炎细胞因子和趋化因子的产生，否则会促进中性粒细胞募集。ATG5的这种作用依赖于自噬，但不依赖于自噬蛋白调节炎症的自噬、lc3相关吞噬和炎性小体激活。除了在结核分枝杆菌感染期间巨噬细胞产生的促炎细胞因子增加外，先天免疫细胞中ATG5的缺失也导致TH17反应的早期诱导。尽管先前发表的体外细胞培养实验支持自噬在控制巨噬细胞中的结核分枝杆菌复制中的作用，但自噬对炎症反应的影响并不会改变巨噬细胞中的结核分枝杆菌负荷。这些发现揭示了自噬蛋白在肺常驻巨噬细胞和树突状细胞中的新作用，这些细胞需要抑制与结核分枝杆菌感染控制不良相关的炎症反应。对结核分枝杆菌感染的免疫反应决定了结核病的预后。本研究确定了自噬途径在不控制病原体复制的情况下调节肺巨噬细胞对结核分枝杆菌感染的促炎反应中的新作用。
The immune response to Mycobacterium tuberculosis infection determines tuberculosis disease outcomes, yet we have an incomplete understanding of what immune factors contribute to a protective immune response. Neutrophilic inflammation has been associated with poor disease prognosis in humans and in animal models during M. tuberculosis infection and, therefore, must be tightly regulated. ATG5 is an essential autophagy protein that is required in innate immune cells to control neutrophil-dominated inflammation and promote survival during M. tuberculosis infection; however, the mechanistic basis for how ATG5 regulates neutrophil recruitment is unknown. To interrogate what innate immune cells require ATG5 to control neutrophil recruitment during M. tuberculosis infection, we used different mouse strains that conditionally delete Atg5 in specific cell types. We found that ATG5 is required in CD11c+ cells (lung macrophages and dendritic cells) to control the production of proinflammatory cytokines and chemokines during M. tuberculosis infection, which would otherwise promote neutrophil recruitment. This role for ATG5 is autophagy dependent, but independent of mitophagy, LC3-associated phagocytosis, and inflammasome activation, which are the most well-characterized ways that autophagy proteins regulate inflammation. In addition to the increased proinflammatory cytokine production from macrophages during M. tuberculosis infection, loss of ATG5 in innate immune cells also results in an early induction of TH17 responses. Despite prior published in vitro cell culture experiments supporting a role for autophagy in controlling M. tuberculosis replication in macrophages, the effects of autophagy on inflammatory responses occur without changes in M. tuberculosis burden in macrophages. These findings reveal new roles for autophagy proteins in lung resident macrophages and dendritic cells that are required to suppress inflammatory responses that are associated with poor control of M. tuberculosis infection. The immune response to Mycobacterium tuberculosis infection determines tuberculosis disease outcomes. This study identifies new roles for the autophagy pathway in regulating proinflammatory responses of lung macrophages to M. tuberculosis infection, without controlling pathogen replication.
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影响因子：
7.3
作者：
Carvalho ACC;Amorim G;Melo MGM;Silveira AKA;Vargas PHL;Moreira ASR;Rocha MS;Souza AB;Arriaga MB;Araújo-Pereira M;Figueiredo MC;Durovni B;Lapa-E-Silva JR;Cavalcante S;Rolla VC;Sterling TR;Cordeiro-Santos M;Andrade BB;Silva EC;Kritski AL;RePORT Brazil consortium
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RePORT Brazil consortium
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Rucker, Edmund B., III
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