Blocking IL-17A Promotes the Resolution of Pulmonary Inflammation and Fibrosis Via TGF-β1-Dependent and -Independent Mechanisms
Blocking IL-17A Promotes the Resolution of Pulmonary Inflammation and Fibrosis Via TGF-β1-Dependent and -Independent Mechanisms
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DOI：
10.4049/jimmunol.1004081
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发表时间：
2011-09-15
影响因子：
4.4
通讯作者：
Hu, Zhuo-Wei
中科院分区：
文献类型：
--
作者：
Mi, Su;Li, Zhe;Hu, Zhuo-Wei
肺纤维化是人类多种无法治愈的慢性肺部疾病的病理基础。 IL-17A 是一种由产生 IL-17 的细胞分泌的糖蛋白，最近被证明是一种参与慢性炎症和自身免疫性疾病的促炎细胞因子。在这项研究中，我们报道IL-17A以TGF-β1依赖性方式增加胶原蛋白的合成和分泌，并促进肺泡上皮细胞的上皮-间质转化。使用体内纤维化模型，我们发现纤维化肺组织中 IL-17A 表达升高，并且 IL-17A 相关信号通路被激活。体内 IL-17A 的中和促进了博来霉素诱导的急性炎症的消退，减轻了肺纤维化并增加了生存率。此外，IL-17A 拮抗作用可抑制二氧化硅诱导的慢性炎症和肺纤维化。靶向IL-17A导致纤维化肺组织中的抑制性免疫反应向Th1型免疫反应转变，并有效诱导自噬，从而促进胶原蛋白的自噬降解和自噬相关的细胞死亡。此外，发现 IL-17A 可以减弱饥饿诱导的自噬，自噬调节剂以不依赖 TGF-β1 的方式调节肺泡上皮细胞中的胶原蛋白降解。给予自噬抑制剂 3-甲基苯丙胺可逆转 IL-17A 拮抗剂在肺纤维化中的治疗效果。我们的研究表明IL-17A以TGF-β1依赖性和非依赖性方式参与肺纤维化的发生和进展，并且IL-17A信号通路的组成部分是治疗纤维增殖性肺疾病的潜在治疗靶点。免疫学杂志，2011，187：3003-3014。
Pulmonary fibrosis is the pathologic basis for a variety of incurable human chronic lung diseases. IL-17A, a glycoprotein secreted from IL-17-producing cells, has recently been shown to be a proinflammatory cytokine involved in chronic inflammation and autoimmune disease. In this study, we report that IL-17A increased the synthesis and secretion of collagen and promoted the epithelial-mesenchymal transition in alveolar epithelial cells in a TGF-beta 1-dependent manner. Using in vivo fibrotic models, we found IL-17A expression to be elevated and IL-17A-associated signaling pathways to be activated in fibrotic lung tissues. Neutralization of IL-17A in vivo promoted the resolution of bleomycin-induced acute inflammation, attenuated pulmonary fibrosis, and increased survival. Additionally, IL-17A antagonism inhibited silica-induced chronic inflammation and pulmonary fibrosis. Targeting IL-17A resulted in a shift of the suppressive immune response in fibrotic lung tissue toward a Th1-type immune response, and it effectively induced autophagy, which promoted the autophagic degradation of collagen and autophagy-associated cell death. Moreover, IL-17A was found to attenuate the starvation-induced autophagy, and autophagy modulators regulated collagen degradation in the alveolar epithelial cells in a TGF-beta 1-independent manner. Administration of 3-methylamphetamine, an autophagy inhibitor, reversed the therapeutic efficacy of IL-17A antagonism in pulmonary fibrosis. Our studies indicate that IL-17A participates in the development and progression of pulmonary fibrosis in both TGF-beta 1-dependent and -independent manners and that the components of the IL-17A signaling pathway are potential therapeutic targets for the treatment of fibroproliferative lung diseases. The Journal of Immunology, 2011, 187: 3003-3014.