Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA.
Am J Pathol. 2011 Dec;179(6):2779-87. doi: 10.1016/j.ajpath.2011.08.019. Epub 2011 Oct 5.
Hypersensitivity pneumonitis (HP), an inflammatory lung disease, develops after repeated exposure to inhaled particulate antigen and is characterized by a vigorous T helper type 1-mediated immune response, resulting in the release of IL-12 and interferon (IFN)-γ. These T helper type 1 cytokines may participate in the pathogenesis of HP. Stachybotrys chartarum (SC) is a dimorphic fungus implicated in a number of respiratory illnesses, including HP. Here, we have developed a murine model of SC-induced HP that reproduces pathology observed in human HP and hypothesized that toll receptor-like 9 (TLR9)-mediated dendritic cell responses are required for the generation of granulomatous inflammation induced by inhaled SC. Mice sensitized and challenged with 10(6) SC spores develop granulomatous inflammation with multinucleate giant cells, accompanied by increased accumulation of neutrophils and CD4(+) and CD8(+) T cells. SC sensitization and challenge resulted in robust pulmonary expression of tumor necrosis factor-α, IL-12, and IFN-γ. SC-mediated granulomatous inflammation required IFN-γ and was TLR9 dependent, because TLR9(-/-) mice displayed reduced peribronchial inflammation, decreased accumulation and/or activation of polymorphonuclear (PMN) and CD4(+) and CD8(+) T cells, and reduced lung expression of type 1 cytokines and chemokines. T-cell production of IFN-γ was IL-12 dependent. Our studies suggest that TLR9 is critical for dendritic cell-mediated development of a type 1 granulomatous inflammation in the lung in response to SC.
过敏性肺炎（HP）是一种炎症性肺部疾病，在反复吸入颗粒性抗原后发生，其特征是强烈的 Th1 型辅助性免疫应答，导致白细胞介素 12（IL-12）和干扰素（IFN）-γ的释放。这些 Th1 型细胞因子可能参与 HP 的发病机制。串珠镰刀菌（SC）是一种双相真菌，与多种呼吸道疾病有关，包括 HP。在这里，我们建立了一个 SC 诱导的 HP 小鼠模型，该模型再现了人类 HP 中观察到的病理学特征，并假设 Toll 样受体 9（TLR9）介导的树突状细胞反应对于吸入 SC 诱导的肉芽肿炎症的发生是必需的。用 10（6）个 SC 孢子致敏和激发的小鼠会发展为具有多核巨细胞的肉芽肿性炎症，同时伴有中性粒细胞和 CD4（+）和 CD8（+）T 细胞的大量积聚。SC 致敏和激发导致肿瘤坏死因子-α、IL-12 和 IFN-γ在肺部的强烈表达。SC 介导的肉芽肿性炎症需要 IFN-γ，并且依赖于 TLR9，因为 TLR9（-/-）小鼠表现出支气管周围炎症减少，多形核（PMN）和 CD4（+）和 CD8（+）T 细胞的积聚和/或激活减少，以及 1 型细胞因子和趋化因子在肺部的表达减少。T 细胞产生 IFN-γ依赖于 IL-12。我们的研究表明，TLR9 对于树突状细胞介导的对 SC 的肺部 1 型肉芽肿性炎症的发展至关重要。
