Tao Liu1, Yu Tao Zhou2, Li Qiu Wang1, Li Yue Li2, Qing Bao2, Shuo Tian1, Mei Xin Chen1, He Xin Chen2, Jun Cui3, Chun Wei Li4. 1. State Key Laboratory of Oncology in South China, MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, China. 2. Department of Otolaryngology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangzhou Key Laboratory of Otorhinolaryngology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. 3. State Key Laboratory of Oncology in South China, MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, China. Electronic address: cuij5@mail.sysu.edu.cn. 4. Department of Otolaryngology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangzhou Key Laboratory of Otorhinolaryngology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. Electronic address: hi_chunwei@aliyun.com.
Abstract
BACKGROUND: The airway epithelium maintains mucosal homeostasis and effectively responds to pathogens. The roles of the epithelial NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome in human rhinovirus (hRV) infection and its effects mediating epithelial functional changes remain poorly understood. OBJECTIVE: We investigated the mechanisms and cellular functions mediated by the epithelial NLRP3 inflammasome on hRV infection. METHODS: Using models of primary human nasal epithelial progenitor cells and differentiated human nasal epithelial cells (hNECs) infected by hRV, we functionally examined key factors for NLRP3 inflammasome activation, cell death, and mucus production. Furthermore, NLRP3 and IL-1β in human epithelium from nasal mucosal inflammation induced by hRV were evaluated. RESULTS: The inflammasome-mediated IL-1β secretion and pyroptosis in human nasal epithelial progenitor cells and hNECs on hRV infection were dependent on the DDX33/DDX58-NLRP3-caspase-1-GSDMD axis. In differentiated hNECs hRV could also promote major airway epithelial mucin (MUC5AC) production through this axis. Our results further confirmed that the NLRP3 inflammasome signaling pathway was responsible for suppressing hRV replication in airway epithelium. Finally, hRV infection in chronically inflamed nasal mucosa was associated with epithelial mucus hyperproduction, whereas NLRP3 and IL-1β expression levels were significantly increased in hRV-infected epithelium with goblet cell hyperplasia compared with normal epithelium without viral infection. CONCLUSION: The current study showed that the NLRP3 inflammasome signaling axis could functionally mediate hRV-induced inflammation, pyroptosis, and mucus production in airway epithelium, which might be an essential mechanism associated with hRV-induced airway remodeling.
BACKGROUND: The airway epithelium maintains mucosal homeostasis and effectively responds to pathogens. The roles of the epithelial NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome in humanrhinovirus (hRV) infection and its effects mediating epithelial functional changes remain poorly understood. OBJECTIVE: We investigated the mechanisms and cellular functions mediated by the epithelial NLRP3 inflammasome on hRV infection. METHODS: Using models of primary human nasal epithelial progenitor cells and differentiated human nasal epithelial cells (hNECs) infected by hRV, we functionally examined key factors for NLRP3 inflammasome activation, cell death, and mucus production. Furthermore, NLRP3 and IL-1β in human epithelium from nasal mucosal inflammation induced by hRV were evaluated. RESULTS: The inflammasome-mediated IL-1β secretion and pyroptosis in human nasal epithelial progenitor cells and hNECs on hRV infection were dependent on the DDX33/DDX58-NLRP3-caspase-1-GSDMD axis. In differentiated hNECs hRV could also promote major airway epithelial mucin (MUC5AC) production through this axis. Our results further confirmed that the NLRP3 inflammasome signaling pathway was responsible for suppressing hRV replication in airway epithelium. Finally, hRV infection in chronically inflamed nasal mucosa was associated with epithelial mucus hyperproduction, whereas NLRP3 and IL-1β expression levels were significantly increased in hRV-infected epithelium with goblet cell hyperplasia compared with normal epithelium without viral infection. CONCLUSION: The current study showed that the NLRP3 inflammasome signaling axis could functionally mediate hRV-induced inflammation, pyroptosis, and mucus production in airway epithelium, which might be an essential mechanism associated with hRV-induced airway remodeling.
Authors: Irene H Heijink; Virinchi N S Kuchibhotla; Mirjam P Roffel; Tania Maes; Darryl A Knight; Ian Sayers; Martijn C Nawijn Journal: Allergy Date: 2020-06-16 Impact factor: 13.146