Overlapping Roles for Interleukin-36 Cytokines in Protective Host Defense against Murine Legionella pneumophila Pneumonia
Overlapping Roles for Interleukin-36 Cytokines in Protective Host Defense against Murine Legionella pneumophila Pneumonia
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DOI：
10.1128/iai.00583-18
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发表时间：
2018-10
影响因子：
3.1
通讯作者：
Yuta Nanjo;M. Newstead;T. Aoyagi;Xianying Zeng;Kazuhisa Takahashi;F. Yu;K. Tateda;T. Standiford
中科院分区：
文献类型：
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作者：
Yuta Nanjo;M. Newstead;T. Aoyagi;Xianying Zeng;Kazuhisa Takahashi;F. Yu;K. Tateda;T. Standiford
嗜肺军团菌引起危及生命的肺炎，最终导致急性肺损伤。先天性和适应性细胞因子在宿主防御L.嗜肺菌感染。摘要嗜肺军团菌引起危及生命的肺炎，最终导致急性肺损伤。先天性和适应性细胞因子在宿主防御L.嗜肺菌感染。白细胞介素-36（IL-36）细胞因子是最近描述的较大的IL-1细胞因子家族的成员，已知其发挥有效的炎症作用。本研究旨在阐明IL-36细胞因子在实验性肺炎中的作用。嗜肺菌肠内愈合（i.t.）管理L. pneumophila诱导肺中IL-36α和IL-36γ mRNA和蛋白产生的上调。与L.嗜肺菌感染的野生型（WT）小鼠，i.t.管理L. pneumophila感染IL-36受体缺陷（IL-36 R −/−）小鼠导致死亡率增加，肺部细菌清除延迟，L.嗜肺菌播散至肺外器官和葡萄糖稳态受损。IL-36 R −/−小鼠肺部细菌清除受损与炎症细胞积聚显著减少以及促炎细胞因子和趋化因子产生减少相关。与WT小鼠的巨噬细胞相比，在从感染的IL-36 R −/−小鼠分离的肺泡巨噬细胞中观察到离体共刺激分子表达减少和M1极化受损。而L. IL-36α-或IL-36γ-缺陷小鼠中嗜肺细胞因子诱导的死亡率与WT动物中的死亡率没有差异，IL-36α−/−小鼠中抗体介导的IL-36γ中和导致的死亡率与IL-36 R −/−小鼠中观察到的死亡率相似，表明这些细胞因子在实验性小鼠L.嗜肺性肺炎
Legionella pneumophila causes life-threatening pneumonia culminating in acute lung injury. Innate and adaptive cytokines play an important role in host defense against L. pneumophila infection. ABSTRACT Legionella pneumophila causes life-threatening pneumonia culminating in acute lung injury. Innate and adaptive cytokines play an important role in host defense against L. pneumophila infection. Interleukin-36 (IL-36) cytokines are recently described members of the larger IL-1 cytokine family known to exert potent inflammatory effects. In this study, we elucidated the role for IL-36 cytokines in experimental pneumonia caused by L. pneumophila. Intratracheal (i.t.) administration of L. pneumophila induced the upregulation of both IL-36α and IL-36γ mRNA and protein production in the lung. Compared to the findings for L. pneumophila-infected wild-type (WT) mice, the i.t. administration of L. pneumophila to IL-36 receptor-deficient (IL-36R−/−) mice resulted in increased mortality, a delay in lung bacterial clearance, increased L. pneumophila dissemination to extrapulmonary organs, and impaired glucose homeostasis. Impaired lung bacterial clearance in IL-36R−/− mice was associated with a significantly reduced accumulation of inflammatory cells and the decreased production of proinflammatory cytokines and chemokines. Ex vivo, reduced expression of costimulatory molecules and impaired M1 polarization were observed in alveolar macrophages isolated from infected IL-36R−/− mice compared to macrophages from WT mice. While L. pneumophila-induced mortality in IL-36α- or IL-36γ-deficient mice was not different from that in WT animals, antibody-mediated neutralization of IL-36γ in IL-36α−/− mice resulted in mortality similar to that observed in IL-36R−/− mice, indicating redundant and overlapping roles for these cytokines in experimental murine L. pneumophila pneumonia.