Epithelium-derived IL17A Promotes Cigarette Smoke-induced Inflammation and Mucus Hyperproduction.

2021 
Airway epithelium is a central modulator of innate and adaptive immunity in the lung. Interleukin (IL)17A expression was found to be increased in airway epithelium; however, the role of epithelial-derived IL17A in chronic obstructive pulmonary disease (COPD) remains unclear. In this study, we aim to determine whether epithelial-derived IL17A regulates inflammation and mucus hyperproduction in COPD using a cultured human bronchial epithelial (HBE) cell line in vitro and airway epithelium IL17A-specific knockout mouse in vivo. Increased IL17A expression was observed in mouse airway epithelium upon cigarette smoke (CS) exposure or in a COPD mouse model that was induced by CS and elastin. CS extract (CSE) also triggered IL17A expression in HBE cells. Blocking IL17A or IL17RA effectively attenuated CSE-induced MUC5AC and the inflammatory cytokines IL6, tumor necrosis factor (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 and p-JNK, which were also reduced by IL17RA-siRNA, and JUN-siRNA attenuated CSE-induced IL6 and MUC5AC. In vivo, selective knockout of IL17A in airway epithelium markedly reduced the neutrophilic infiltration in Bronchoalveolar Lavage Fluid (BALF), peribronchial inflammation, pro-inflammatory mediators (CXCL1 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.
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