Defective STING expression potentiates IL-13 signaling in epithelial cells in eosinophilic chronic rhinosinusitis with nasal polyps

• Published in: Journal of allergy and clinical immunology 2021-05, Vol.147 (5), p.1692-1703
• Main Authors: Wang, Hai, Hu, Dan-Qing, Xiao, Qiao, Liu, Yi-Bo, Song, Jia, Liang, Yuxia, Ruan, Jian-Wen, Wang, Zhe-Zheng, Li, Jing-Xian, Pan, Li, Wang, Meng-Chen, Zeng, Ming, Shi, Li-Li, Xu, Kai, Ning, Qin, Zhen, Guohua, Yu, Di, Wang, De-Yun, Wenzel, Sally E., Liu, Zheng
• Format: Article
• Language: English
• Subjects: Binding sites; Cell culture; Chemokine (C-C motif) ligand 26; Epithelial cells; Experiments; Flow cytometry; Immune response; Immunohistochemistry; Infections; Inflammation; Innate immunity; Interferon; Interferon regulatory factor 3; Interleukin 13; Interleukin 4; Kinases; Leukocytes (eosinophilic); Mucosa; nasal polyp; Plasmids; Polymerase chain reaction; Polyps; Proteins; Rhinitis; Rhinosinusitis; signal transducer and activator of transcription 6; Sinusitis; SOCS-1 protein; Stat6 protein; stimulator of interferon genes; suppressor of cytokine signaling 1; Transcription activation; Viral infections; Viruses; Western blotting
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2020.12.623

Stimulator of interferon genes (STING) activation favors effective innate immune responses against viral infections. Its role in chronic rhinosinusitis with nasal polyps (CRSwNP) remains unknown. Our aim was to explore the expression, regulation, and function of STING in CRSwNP. STING expression in sinonasal mucosal samples was analyzed by means of quantitative RT-PCR, immunohistochemistry, flow cytometry, and Western blotting. Regulation and function of STING expression were explored by using cultured primary human nasal epithelial cells (HNECs) and cells of the line BEAS-2B in vitro. STING expression was reduced in eosinophilic nasal polyps compared with that in noneosinophilic nasal polyps and control tissues. STING was predominantly expressed by epithelial cells in nasal tissue and was downregulated by IL-4 and IL-13 in a signal transducer and activator of transcription 6 (STAT6)-dependent manner. HNECs derived from eosinophilic polyps displayed compromised STING-dependent type I interferon production but heightened IL-13–induced STAT6 activation and CCL26 production as compared with HNECs from noneosinophilic polyps and control tissues, which were rescued by exogenous STING overexpression. Knocking down or overexpressing STING decreased or enhanced expression of suppressor of cytokine signaling 1 (SOCS1) in BEAS-2B cells, respectively, independent of the canonic STING pathway elements TBK1 and IRF3. Knocking down SOCS1 abolished the inhibitory effect of STING on IL-13 signaling in BEAS-2B cells. STING expression was positively correlated with SOCS1 expression but negatively correlated with CCL26 expression in nasal epithelial cells from patients with CRSwNP. Reduced STING expression caused by the type 2 milieu not only impairs STING-dependent type I interferon production but also amplifies IL-13 signaling by decreasing SOCS1 expression in nasal epithelial cells in eosinophilic CRSwNP. [Display omitted]