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 in vitro and an airway epithelium IL17A–specific knockout mouse in vivo. 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. In vivo, 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.

气道上皮是肺中先天免疫和适应性免疫的中枢调节剂。发现气道上皮中 IL17A 表达增加；然而，上皮来源的 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，我们的目的是确定通过使用培养的人支气管上皮（HBE）细胞系上皮衍生IL17A是否调节在COPD炎症和粘液hyperproduction体外和一个气道上皮特定IL17A-敲除小鼠体内. 在暴露于香烟烟雾 (CS) 后的小鼠气道上皮或通过使用 CS 和 Eln（弹性蛋白）诱导的 COPD 小鼠模型中观察到 IL17A 表达增加。CS 提取物 (CSE) 也触发了 HBE 细胞中的 IL17A 表达。阻断 IL17A 或 IL17RA（IL17 受体 A）可有效减弱 CSE 诱导的 MUC5AC 和 HBE 细胞中的炎性细胞因子 IL6、TNF-α 和 IL1β，表明 IL17A 以自分泌方式介导 CSE 诱导的炎症和粘蛋白的产生。CSE 激活 p-JUN（磷酸-JUN）和 p-JNK（磷酸-c-Jun N-末端激酶），它们也被 IL17RA siRNA 减少，而 JUN siRNA 减弱了 CSE 诱导的 IL6 和 MUC5AC。体内在 COPD 小鼠模型中，气道上皮中 IL17A 的选择性敲除显着减少了 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）和粘液产生。我们展示了气道上皮衍生的 IL17A 的一种新功能，它可以以自分泌方式局部作用以放大炎症并增加 COPD 发病机制中的粘液产生。