Airway Epithelium-derived IL17A In Chronic Obstructive Pulmonary Disease

BACKGROUND:Chronic obstructive pulmonary disease(COPD)is a common chronic airway inflammatory disease with irreversible and progressive airflow limitation.The lung function of patients is progressively decreased and the treatment effect of glucocorticoids is not beneficial sometimes in COPD.IL17A is positively associated with neutrophils,airflow limitation,and disease severity in COPD.And the steroid-inactivated COPD is closely related to Th17 cytokine.It is currently believed that in addition to Th17 cells,innate immune cells and structural cells can also secrete IL17A.Some researchers resumes that the latter could initiate innate immunity to promptly eliminate pathogens in the early stage and induce the development,differentiation and chemotaxis of Th17.Studies have shown that exposure to cigarette smoke could significantly induce IL17A secretion in the airway epithelium,but it has not been clarified whether airway epithelium-derived IL17A plays a key regulatory role in COPD.OBJECTIVE:This study is to investigate the key regulatory role of airway epithelium-derived IL17A in COPD and explore its possible mechanisms.METHODS:IL17A,IL17R was knocked down by siRNA(small interfering),such as IL17AsiRNA and IL17RsiRNA in human bronchial epithelial cell(HBE),whose inflammation,mucus,apotosis and related signaling pathways were detected with intervention of Cigarette smoke extract(CSE)to clarify the key regulatory roles and specific molecular mechanisms of airway epithelium-derived IL17A.Moreover,to further clarify its regulatory roles in overall model,a doxycycline-induced airway epithelium-specific knockout of IL17A transgenic mice(CC10-rtTA/(tet0)7-Cre/IL17Aflox/flox)was used to construct COPD models,whose differential white cells in bronchoalveolar lavage fluid(BALF),H&E and PAS staining,real-time PCR or western blot were made to detect lung inflammation and JNK/AP1 signaling pathway.RESULTS:(1)Cigarette smoke could induce IL17A production in the airway epithelium.(2)In vitro results showed that knockdown of IL17A in HBE significantly down-regulated CSE-induced IL6,Muc5ac expression and apoptosis.Knockdown of IL17R and cJun in HBE also obtained the same down-regulation of CSE-induced IL6 and Muc5ac,and besides knockdown of IL17R could decreased the expression of JNK/AP1 signaling pathway.(3)In vivo results showed that the ratio and number of neutrophils in BALF,expression of CXCL1,CXCL2 and the inflammatory infiltration around airway in lung tissue were decreased in airway epithelium-specific knockout of IL17A mice compared with the control group in a COPD model.CONCLUSION:IL17A is secreted and binds to its own IL17RA-IL17RC receptor in HBE with the stimulation of CSE,which then activates the JNK/AP1 signaling pathway to regulate inflammation and mucus through an autocrine/paracrine pathway.In addition,that source of IL17A can also promote apoptosis of HBE to further aggravate inflammation.In vivo,airway epithelium-specific knockout of IL17A can alleviate airway inflammation in a COPD model.Our study provides new ideas and evidences for basic study and a new direction for the clinical treatment in COPD.