Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
J Exp Med. 2010 Mar 15;207(3):535-52. doi: 10.1084/jem.20092121. Epub 2010 Feb 22.
Idiopathic pulmonary fibrosis (IPF) is a destructive inflammatory disease with limited therapeutic options. To better understand the inflammatory responses that precede and concur with collagen deposition, we used three models of pulmonary fibrosis and identify a critical mechanistic role for IL-17A. After exposure to bleomycin (BLM), but not Schistosoma mansoni eggs, IL-17A produced by CD4(+) and gammadelta(+) T cells induced significant neutrophilia and pulmonary fibrosis. Studies conducted with C57BL/6 il17a(-/-) mice confirmed an essential role for IL-17A. Mechanistically, using ifngamma(-/-), il10(-/-), il10(-/-)il12p40(-/-), and il10(-/-)il17a(-/-) mice and TGF-beta blockade, we demonstrate that IL-17A-driven fibrosis is suppressed by IL-10 and facilitated by IFN-gamma and IL-12/23p40. BLM-induced IL-17A production was also TGF-beta dependent, and recombinant IL-17A-mediated fibrosis required TGF-beta, suggesting cooperative roles for IL-17A and TGF-beta in the development of fibrosis. Finally, we show that fibrosis induced by IL-1beta, which mimics BLM-induced fibrosis, is also highly dependent on IL-17A. IL-17A and IL-1beta were also increased in the bronchoalveolar lavage fluid of patients with IPF. Together, these studies identify a critical role for IL-17A in fibrosis, illustrating the potential utility of targeting IL-17A in the treatment of drug and inflammation-induced fibrosis.
特发性肺纤维化(IPF)是一种具有有限治疗选择的破坏性炎症性疾病。为了更好地了解胶原沉积之前和同时发生的炎症反应,我们使用了三种肺纤维化模型,并确定了 IL-17A 的关键机制作用。在暴露于博莱霉素(BLM)后,但不是曼氏血吸虫卵后,CD4(+)和γδ(+)T 细胞产生的 IL-17A 诱导了显著的中性粒细胞增多和肺纤维化。用 C57BL/6 il17a(-/-)小鼠进行的研究证实了 IL-17A 的重要作用。从机制上讲,使用 ifngamma(-/-)、il10(-/-)、il10(-/-)il12p40(-/-)和 il10(-/-)il17a(-/-)小鼠和 TGF-β 阻断,我们证明了 IL-17A 驱动的纤维化受到 IL-10 的抑制,受到 IFN-γ和 IL-12/23p40 的促进。BLM 诱导的 IL-17A 产生也依赖于 TGF-β,重组 IL-17A 介导的纤维化需要 TGF-β,这表明 IL-17A 和 TGF-β 在纤维化的发展中具有协同作用。最后,我们表明,IL-1β诱导的纤维化(模拟 BLM 诱导的纤维化)也高度依赖于 IL-17A。在 IPF 患者的支气管肺泡灌洗液中也增加了 IL-17A 和 IL-1β。总之,这些研究确定了 IL-17A 在纤维化中的关键作用,说明了靶向 IL-17A 在治疗药物和炎症诱导的纤维化中的潜在效用。