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

ABSTRACT Background 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. Objective To explore the expression, regulation, and function of STING in CRSwNP. Methods STING expression in sinonasal mucosal samples was analyzed by means of quantitative RT-PCR, immunohistochemistry, flow cytometry and western blotting. STING expression regulation and function were explored by using cultured primary human nasal epithelial cells (HNECs) and BEAS-2B cell lines in vitro. Results 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 STAT6-dependent manner. HNECs derived from eosinophilic polyps displayed compromised STING-dependent type I interferon production, whereas heightened IL-13-induced STAT6 activation and CCL26 production as compared to those from noneosinophilic polyps and control tissues, which were rescued by exogenous STING overexpression. Knocking down or overexpressing STING decreased or enhanced SOCS1 expression in BEAS-2B cells, respectively, independent of canonical 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 positively correlated with SOCS1 expression, but negatively correlated with CCL26 expression in nasal epithelial cells in CRSwNP patients. Conclusions 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.