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Autophagic protein ATG5 controls antiviral immunity via glycolytic reprogramming of dendritic cells against respiratory syncytial virus infection
Autophagy ( IF 13.3 ) Pub Date : 2020-08-28 , DOI: 10.1080/15548627.2020.1812218
Dong Sun Oh 1 , Jang Hyun Park 1 , Hi Eun Jung 1 , Hyun-Jin Kim 1 , Heung Kyu Lee 1, 2
Affiliation  

ABSTRACT

Respiratory syncytial virus (RSV) is a leading cause of respiratory tract infections in infants. Macroautophagy/autophagy is a catalytic metabolic process required for cellular homeostasis. Although intracellular metabolism is important for immune responses in dendritic cells, the link between autophagy and immunometabolism remains unknown. Here, we show that the autophagy-related protein ATG5 regulates immunometabolism. Atg5-deficient mouse dendritic cells showed increased CD8A+ T-cell response and increased secretion of proinflammatory cytokines upon RSV infection. Transcriptome analysis showed that Atg5 deficiency alters the expression of metabolism-related genes. Atg5-deficient dendritic cells also showed increased activation of glycolysis and the AKT-MTOR-RPS6KB1 pathway and decreased mitochondrial activity, all of which are cellular signatures for metabolic activation. These cells also showed elevated CD8A+ T-cell priming and surface major histocompatibility complex (MHC) class I expression. Our results suggested that ATG5 regulated host immune responses by modulating dendritic cell metabolism. These findings may help develop potential antiviral therapies that alter host immunity by regulating autophagy and immunometabolism.

Abbreviations : 2-DG: 2-deoxyglucose; AAK1: AP2 associated kinase 1; AKT: AKT serine/threonine kinase; AM: alveolar macrophage; ATG: autophagy; ATP: adenosine triphosphate; BAL: bronchoalveolar lavage; BMDC: bone marrow dendritic cell; CSF2/GM-CSF: colony-stimulating factor 2 (granulocyte-macrophage); CTL: cytotoxic T lymphocyte; ELISA: enzyme-linked immunosorbent assay; GFP: green fluorescent protein; GSEA: gene-set enrichment analysis; H-2Db: H-2 class I histocompatibility antigen, D-B alpha chain; H-2Kb: MHC class I H2-K-b; HIF1A: hypoxia-inducible factor 1 alpha; IFNG: interferon-gamma; IL: interleukin; ITGAX: integrin alpha X; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MHC: major histocompatibility complex; MTORC1: mammalian target of rapamycin kinase complex 1; PBS: phosphate-buffered saline; PFU: plaque-forming unit; RLR: retinoic acid-inducible-I-like receptor; ROS: reactive oxygen species; RPMI: Roswell Park Memorial Institute; RPS6KB1/S6K: ribosomal protein S6 kinase, polypeptide 1; RSV: respiratory syncytial virus; Th: T helper; TLR: toll-like receptor; Treg: regulatory T cells; UMAP: uniform manifold approximation and projection.



中文翻译:

自噬蛋白 ATG5 通过树突状细胞的糖酵解重编程来控制抗病毒免疫,以抵抗呼吸道合胞病毒感染

摘要

呼吸道合胞病毒 (RSV) 是婴儿呼吸道感染的主要原因。巨自噬/自噬是细胞稳态所需的催化代谢过程。尽管细胞内代谢对树突状细胞的免疫反应很重要,但自噬和免疫代谢之间的联系仍然未知。在这里,我们表明自噬相关蛋白 ATG5 调节免疫代谢。Atg5缺陷型小鼠树突状细胞在 RSV 感染后表现出 CD8A + T 细胞反应增加和促炎细胞因子分泌增加。转录组分析表明,Atg5缺乏会改变代谢相关基因的表达。Atg5- 缺乏的树突状细胞还显示糖酵解和 AKT-MTOR-RPS6KB1 通路的激活增加以及线粒体活性降低,所有这些都是代谢激活的细胞特征。这些细胞还表现出升高的 CD8A + T 细胞启动和表面主要组织相容性复合物 (MHC) I 类表达。我们的研究结果表明,ATG5 通过调节树突状细胞代谢来调节宿主免疫反应。这些发现可能有助于开发潜在的抗病毒疗法,通过调节自噬和免疫代谢来改变宿主免疫。

缩写:2-DG:2-脱氧葡萄糖;AAK1:AP2 相关激酶 1;AKT:AKT丝氨酸/苏氨酸激酶;AM:肺泡巨噬细胞;ATG:自噬;ATP:三磷酸腺苷;BAL:支气管肺泡灌洗液;BMDC:骨髓树突状细胞;CSF2/GM-CSF:集落刺激因子 2(粒细胞-巨噬细胞);CTL:细胞毒性T淋巴细胞;ELISA:酶联免疫吸附试验;GFP:绿色荧光蛋白;GSEA:基因集富集分析;H-2D b:H-2 I 类组织相容性抗原,DB α 链;H-2K b: MHC I类H2-Kb;HIF1A:缺氧诱导因子 1 α;IFNG:干扰素-γ;IL:白细胞介素;ITGAX:整合素α X;MAP1LC3/LC3:微管相关蛋白 1 轻链 3;MAP1LC3B/LC3B:微管相关蛋白1轻链3β;MHC:主要组织相容性复合体;MTORC1:雷帕霉素激酶复合物 1 的哺乳动物靶标;PBS:磷酸盐缓冲液;PFU:斑块形成单元;RLR:视黄酸诱导型 I 样受体;ROS:活性氧;RPMI:罗斯威尔公园纪念研究所;RPS6KB1/S6K:核糖体蛋白 S6 激酶,多肽 1;RSV:呼吸道合胞病毒;Th:T 帮手;TLR:toll样受体;Treg:调节性 T 细胞;UMAP:统一流形逼近和投影。

更新日期:2020-08-28
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