IL-17A Promotes Epithelial ADAM9 Expression in Cigarette Smoke-Related COPD

Abstract

Danyang Li,1 Tong Wang,2 Qianli Ma,3 Lu Zhou,1 Yanqing Le,1 Yafei Rao,1 Liang Jin,1 Yuqiang Pei,1 Yaning Cheng,4 Chen Huang,5 Xiaoyan Gai,1 Yongchang Sun1 1Department of Respiratory and Critical Care Medicine, Peking University Third Hospital, Beijing, 100191, People’s Republic of China; 2Department of Thoracic Surgery, Peking University Third Hospital, Beijing, 100191, People’s Republic of China; 3Department of Thoracic Surgery, China-Japan Friendship Hospital, Beijing, 100029, People’s Republic of China; 4School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, People’s Republic of China; 5Center of Basic Medical Research, Peking University Third Hospital, Beijing, 100191, People’s Republic of ChinaCorrespondence: Xiaoyan Gai; Yongchang Sun, Department of Respiratory and Critical Care Medicine, Peking University Third Hospital, No. 49 North Garden Road, Haidian District, Beijing, 100191, People’s Republic of China, Email [email protected]; [email protected]: It has been reported that a disintegrin and metalloproteinase 9 (ADAM9) is involved in the pathogenesis of cigarette smoke (CS)-associated chronic obstructive pulmonary disease (COPD). But how CS exposure leads to upregulation of ADAM9 remains unknown.Methods: Patients who underwent lobectomy for a solitary pulmonary nodule were enrolled and divided into three groups: non-smokers with normal lung function, smokers without COPD and smoker patients with COPD. Immunoreactivity of interleukin (IL)-17A and ADAM9 in small airways and alveolar walls was measured by immunohistochemistry. Wild-type and Il17a−/− C57BL/6 mice were exposed to CS for six months, and ADAM9 expression in the airway epithelia was measured by immunoreactivity. In addition, the protein and mRNA expression levels of IL-17A and ADAM9 were assessed in CS extract (CSE) and/or IL-17A-treated human bronchial epithelial (HBE) cells.Results: The immunoreactivity of ADAM9 was increased in the airway epithelia and alveolar walls of patients with COPD compared to that of the controls. The expression of IL-17A was also upregulated in airway epithelial cells of patients with COPD and correlated positively with the level of ADAM9. The results from the animal model showed that Il17a−/− mice were protected from emphysema induced by CS exposure, together with a reduced level of ADAM9 expression in the airway epithelia, suggesting a possible link between ADAM9 and IL-17A. Consistently, our in vitro cell model showed that CSE stimulated the expression of ADAM9 and IL-17A in HBE cells in a dose- and time-dependent manner. Recombinant IL-17A induced ADAM9 upregulation in HBE cells and had a synergistic effect with CSE, whereas blocking IL-17A inhibited CSE-induced ADAM9 expression. Further analysis revealed that IL-17A induced c-Jun N-terminal kinase (JNK) phosphorylation, thereby increasing ADAM9 expression.Conclusion: Our results revealed a novel role of IL-17A in CS-related COPD, where IL-17A contributes to ADAM9 expression by activating JNK signaling.Keywords: chronic obstructive pulmonary disease, a disintegrin and metalloproteinase 9, interleukin-17A, airway epithelium

Keywords

• chronic obstructive pulmonary disease
• a disintegrin and metalloproteinase 9
• interleukin-17a
• airway epithelium