Influenza virus causes lung immunopathology through down-regulating PPARγ activity in macrophages.
Influenza virus causes lung immunopathology through down-regulating PPARγ activity in macrophages.
复制标题
DOI：
10.3389/fimmu.2022.958801
复制
发表时间：
2022
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
--
作者：
致命的流感病毒感染通常会激活过多的炎症信号，导致多器官衰竭和死亡，也称为细胞因子风暴。 PPARγ（过氧化物酶体增殖物激活受体γ）激动剂是众所周知的细胞因子风暴调节候选药物。本研究发现，流感感染降低了来自不同供体的人肺泡巨噬细胞（AM）中的 PPARγ 表达并降低了 PPARγ 转录活性。使用 PPARγ 激动剂曲格列酮治疗可改善病毒诱导的促炎细胞因子分泌，但不会干扰人类 AM 中 IFN 诱导的抗病毒途径。相比之下，PPARγ拮抗剂和人类AMs中PPARγ的敲除进一步增强了病毒刺激的促炎反应。在流感感染的小鼠模型中，流感病毒剂量依赖性地降低 PPARγ 转录活性并降低 PPARγ 表达。此外，PPARγ激动剂曲格列酮显着降低高剂量流感感染引起的肺部病理。此外，流感感染降低了所有小鼠巨噬细胞（包括 AM、间质巨噬细胞和骨髓源性巨噬细胞）中 PPARγ 的表达，但肺泡上皮细胞中的 PPARγ 表达却没有降低。我们的研究结果表明，流感病毒特异性靶向巨噬细胞中的 PPARγ 通路，对肺部造成急性损伤。
Fatal influenza (flu) virus infection often activates excessive inflammatory signals, leading to multi-organ failure and death, also referred to as cytokine storm. PPARγ (Peroxisome proliferator-activated receptor gamma) agonists are well-known candidates for cytokine storm modulation. The present study identified that influenza infection reduced PPARγ expression and decreased PPARγ transcription activity in human alveolar macrophages (AMs) from different donors. Treatment with PPARγ agonist Troglitazone ameliorated virus-induced proinflammatory cytokine secretion but did not interfere with the IFN-induced antiviral pathway in human AMs. In contrast, PPARγ antagonist and knockdown of PPARγ in human AMs further enhanced virus-stimulated proinflammatory response. In a mouse model of influenza infection, flu virus dose-dependently reduced PPARγ transcriptional activity and decreased expression of PPARγ. Moreover, PPARγ agonist troglitazone significantly reduced high doses of influenza infection-induced lung pathology. In addition, flu infection reduced PPARγ expression in all mouse macrophages, including AMs, interstitial macrophages, and bone-marrow-derived macrophages but not in alveolar epithelial cells. Our results indicate that the influenza virus specifically targets the PPARγ pathway in macrophages to cause acute injury to the lung.