Homeostatic Control of Innate Lung Inflammation by Vici Syndrome Gene Epg5 and Additional Autophagy Genes Promotes Influenza Pathogenesis.
Homeostatic Control of Innate Lung Inflammation by Vici Syndrome Gene Epg5 and Additional Autophagy Genes Promotes Influenza Pathogenesis.
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DOI：
10.1016/j.chom.2015.12.011
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发表时间：
2016-01-13
影响因子：
30.3
通讯作者：
Virgin HW
中科院分区：
文献类型：
--
作者：
Lu Q;Yokoyama CC;Williams JW;Baldridge MT;Jin X;DesRochers B;Bricker T;Wilen CB;Bagaitkar J;Loginicheva E;Sergushichev A;Kreamalmeyer D;Keller BC;Zhao Y;Kambal A;Green DR;Martinez J;Dinauer MC;Holtzman MJ;Crouch EC;Beatty W;Boon AC;Zhang H;Randolph GJ;Artyomov MN;Virgin HW
自噬基因EPG5的突变与多系统人类疾病维西综合征有关，该综合征的部分特征是肺部异常，包括复发性感染。我们发现Epg5缺陷小鼠表现出升高的基线先天免疫细胞和基于精氨酸的肺部炎症，并且对致命的流感病毒感染具有抗性。肺转录组学、骨髓移植实验和细胞细胞因子表达的分析表明，Epg5通过其在巨噬细胞中的功能在肺生理学中发挥作用。髓样细胞中其他自噬基因（包括Atg14、FIP200、Atg5和Atg7）的缺失也导致基底肺炎症和流感抗性升高。这表明Epg5和其他Atg基因在巨噬细胞中起作用，以限制肺中的先天免疫炎症。肺部炎症的这种正常稳态抑制的破坏导致对流感的抵抗力增加，这表明限制基底组织炎症的正常稳态机制支持某些感染性疾病。
Mutations in the autophagy gene EPG5 are linked to the multisystem human disease Vici syndrome, which is characterized in part by pulmonary abnormalities, including recurrent infections. We found that Epg5-deficient mice exhibited elevated baseline innate immune cellular and cytokine-based lung inflammation and were resistant to lethal influenza virus infection. Lung transcriptomics, bone marrow transplantation experiments, and analysis of cellular cytokine expression indicated that Epg5 plays a role in lung physiology through its function in macrophages. Deletion of other autophagy genes including Atg14, FIP200, Atg5, and Atg7 in myeloid cells also led to elevated basal lung inflammation and influenza resistance. This suggests that Epg5 and other Atg genes function in macrophages to limit innate immune inflammation in the lung. Disruption of this normal homeostatic dampening of lung inflammation results in increased resistance to influenza, suggesting that normal homeostatic mechanisms that limit basal tissue inflammation support some infectious diseases.