Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, and.
Department of Respiration, Shantou Central Hospital, Affiliated Shantou Hospital of Sun Yat-sen University, Shantou, Guangdong, China.
Am J Respir Cell Mol Biol. 2021 Dec;65(6):581-592. doi: 10.1165/rcmb.2020-0424OC.
The airway epithelium is a central modulator of innate and adaptive immunity in the lung. IL17A expression was found to be increased in the airway epithelium; however, the role of epithelium-derived IL17A in chronic obstructive pulmonary disease (COPD) remains unclear. In this study, we aimed to determine whether epithelium-derived IL17A regulates inflammation and mucus hyperproduction in COPD by using a cultured human bronchial epithelial (HBE) cell line and an airway epithelium IL17A-specific knockout mouse . Increased IL17A expression was observed in the mouse airway epithelium upon cigarette smoke (CS) exposure or in a mouse model of COPD that was induced by using CS and Eln (elastin). CS extract (CSE) also triggered IL17A expression in HBE cells. Blocking IL17A or IL17RA (IL17 receptor A) effectively attenuated CSE-induced MUC5AC and the inflammatory cytokines IL6, TNF-α, and IL1β in HBE cells, suggesting that IL17A mediates CSE-induced inflammation and mucin production in an autocrine manner. CSE activated p-JUN (phospho-JUN) and p-JNK (phospho-c-Jun N-terminal kinase), which were also reduced by IL17RA siRNA, and JUN siRNA attenuated CSE-induced IL6 and MUC5AC. , selective knockout of IL17A in the airway epithelium markedly reduced the neutrophilic infiltration in BAL fluid, peribronchial inflammation, proinflammatory mediators (CXCL1 [CXC ligand 1] and CXCL2), and mucus production in a COPD mouse model. We showed a novel function of airway epithelium-derived IL17A, which can act locally in an autocrine manner to amplify inflammation and increase mucus production in COPD pathogenesis.
气道上皮细胞是肺部固有和适应性免疫的核心调节者。研究发现，IL17A 在气道上皮细胞中的表达增加；然而，上皮细胞衍生的 IL17A 在慢性阻塞性肺疾病（COPD）中的作用仍不清楚。在这项研究中，我们旨在通过使用培养的人支气管上皮（HBE）细胞系和气道上皮细胞 IL17A 特异性敲除小鼠来确定上皮细胞衍生的 IL17A 是否通过调节 COPD 中的炎症和黏液高分泌。在香烟烟雾（CS）暴露或使用 CS 和 Eln（弹性蛋白）诱导的 COPD 小鼠模型中，观察到小鼠气道上皮细胞中 IL17A 表达增加。CS 提取物（CSE）也能触发 HBE 细胞中 IL17A 的表达。阻断 IL17A 或 IL17RA（IL17 受体 A）可有效减轻 CSE 诱导的 HBE 细胞中 MUC5AC 和炎症细胞因子 IL6、TNF-α 和 IL1β 的表达，表明 IL17A 以自分泌方式介导 CSE 诱导的炎症和黏蛋白产生。CSE 激活了 p-JUN（磷酸化-JUN）和 p-JNK（磷酸化-c-Jun N 端激酶），而 IL17RA siRNA 也降低了这两种激酶的表达，JUN siRNA 则减弱了 CSE 诱导的 IL6 和 MUC5AC。气道上皮细胞中 IL17A 的选择性敲除显著减少了 BAL 液中的中性粒细胞浸润、支气管周围炎症、促炎介质（CXCL1[CXC 配体 1]和 CXCL2）和 COPD 小鼠模型中的黏液产生。我们展示了气道上皮细胞衍生的 IL17A 的一个新功能，它可以在 COPD 发病机制中以自分泌方式局部作用，放大炎症并增加黏液产生。
