Alveolar Macrophages Prevent Lethal Influenza Pneumonia By Inhibiting Infection Of Type-1 Alveolar Epithelial Cells.
Alveolar Macrophages Prevent Lethal Influenza Pneumonia By Inhibiting Infection Of Type-1 Alveolar Epithelial Cells.
复制标题
肺泡巨噬细胞通过抑制1型肺泡上皮细胞的感染来预防致命的流感肺炎。
DOI：
10.1371/journal.ppat.1006140
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发表时间：
2017-01
期刊：
影响因子：
6.7
通讯作者：
Braciale TJ
中科院分区：
文献类型：
--
作者：
Cardani A;Boulton A;Kim TS;Braciale TJ
甲型流感病毒(IAV)是人类的一种主要病原体，可导致严重的发病率和死亡率。为了探讨肺泡巨噬细胞(ALVM、Φ、S)在调节IAV感染严重程度中的作用，我们采用了髓系细胞中核心结合因子β基因有条件地中断的小鼠模型。这些小鼠表现出ALVMΦS的选择性缺陷。感染IAV后，这些ALVMΦ缺陷小鼠出现严重的弥漫性肺泡损伤、致死性呼吸困难和随后的死亡。这些小鼠的致死性损伤是由于它们的1型肺泡上皮细胞(T1AECs)感染增加，随后获得性免疫T细胞反应消除了感染的T1AECs。进一步分析表明，AlvMΦ介导的半胱氨酰白三烯(CysLT)途径基因在体内和体外均受到抑制。抑制T1AECs细胞中的cysLT途径酶降低了T1AECs对IAV感染的敏感性，提示AlvMΦ介导的抑制该途径参与了T1AECs对IAV感染的抵抗力。此外，抑制半胱氨酸氨基转移酶途径酶，以及阻断半胱氨酰白三烯受体，可降低其T1AECs对Φ感染的易感性，并保护这些小鼠免受致死性感染。这些结果提示ALVMΦS可能利用一种未知的机制来保护T1AECs免受IAV感染，从而减轻感染的严重程度。这些发现进一步表明，CysLT途径和CysLT代谢物受体是治疗严重IAV感染的潜在靶点。致命性流感感染的一个主要特征是病毒性肺炎。流感病毒性肺炎是由肺泡上皮细胞直接感染引起的，继而引起广泛的肺泡炎和损伤。临床表现为弥漫性肺泡损伤导致急性呼吸窘迫综合征。由于肺泡巨噬细胞位于肺泡内，它们是抵御肺泡入侵病原体(如流感)的第一道防线。为了探索肺泡巨噬细胞在致死性流感肺炎发生发展中的作用，我们建立了一种新的肺泡巨噬细胞选择性缺陷的小鼠模型。由于肺泡巨噬细胞缺乏，这些小鼠在流感感染后出现严重的弥漫性肺泡损伤和致命的呼吸损害。致死性损伤是由于1型肺泡上皮细胞感染增加，这些感染细胞被效应性T细胞清除。进一步的分析表明，为了使1型细胞对流感感染具有抵抗力，肺泡巨噬细胞抑制了1型细胞中白三烯D4的产生和自分泌信号。这些结果表明，肺泡巨噬细胞在保护1型肺泡上皮细胞免受IAV感染，从而保护感染的严重程度方面发挥了以前未被认识的作用。
The Influenza A virus (IAV) is a major human pathogen that produces significant morbidity and mortality. To explore the contribution of alveolar macrophages (AlvMΦs) in regulating the severity of IAV infection we employed a murine model in which the Core Binding Factor Beta gene is conditionally disrupted in myeloid cells. These mice exhibit a selective deficiency in AlvMΦs. Following IAV infection these AlvMΦ deficient mice developed severe diffuse alveolar damage, lethal respiratory compromise, and consequent lethality. Lethal injury in these mice resulted from increased infection of their Type-1 Alveolar Epithelial Cells (T1AECs) and the subsequent elimination of the infected T1AECs by the adaptive immune T cell response. Further analysis indicated AlvMΦ-mediated suppression of the cysteinyl leukotriene (cysLT) pathway genes in T1AECs in vivo and in vitro. Inhibition of the cysLT pathway enzymes in a T1AECs cell line reduced the susceptibility of T1AECs to IAV infection, suggesting that AlvMΦ-mediated suppression of this pathway contributes to the resistance of T1AECs to IAV infection. Furthermore, inhibition of the cysLT pathway enzymes, as well as blockade of the cysteinyl leukotriene receptors in the AlvMΦ deficient mice reduced the susceptibility of their T1AECs to IAV infection and protected these mice from lethal infection. These results suggest that AlvMΦs may utilize a previously unappreciated mechanism to protect T1AECs against IAV infection, and thereby reduce the severity of infection. The findings further suggest that the cysLT pathway and the receptors for cysLT metabolites represent potential therapeutic targets in severe IAV infection. A primary feature of lethal influenza infection is viral pneumonia. Influenza viral pneumonia is caused by the direct infection of alveolar epithelial cells, which subsequently causes extensive alveolar inflammation and injury. Clinically this pathology manifests as diffuse alveolar damage leading to acute respiratory distress syndrome. As alveolar macrophages are positioned in the alveoli, they are the ideally localized to be a first-line of defense against alveolar invading pathogens, such as influenza. To explore the contribution of alveolar macrophages to the development of lethal influenza pneumonia, we generated a novel mouse model with a selective deficiency in alveolar macrophages. As a result of the alveolar macrophage deficiency, these mice developed severe diffuse alveolar damage and lethal respiratory compromise after influenza infection. Lethal injury resulted from increased infection of type-1 alveolar epithelial cells, and the elimination of these infected cells by effector T cells. Further analysis indicated that in order to render type 1 cells resistant to influenza infection, alveolar macrophages suppress leukotrieneD4 production and autocrine-signaling in type 1 cells. These results suggest that alveolar macrophages play a previously unappreciated role in protecting type 1 alveolar epithelial cells against IAV infection, and thus the severity of infection.