Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Infectious Disease, Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
J Allergy Clin Immunol. 2021 May;147(5):1692-1703. doi: 10.1016/j.jaci.2020.12.623. Epub 2020 Dec 17.
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.
干扰素基因刺激物（STING）的激活有利于针对病毒感染产生有效的先天免疫反应。但其在慢性鼻-鼻窦炎伴鼻息肉（CRSwNP）中的作用尚不清楚。
本研究旨在探索 STING 在 CRSwNP 中的表达、调控和功能。
采用实时定量 RT-PCR、免疫组织化学、流式细胞术和 Western blot 分析鼻黏膜组织中 STING 的表达。通过体外培养的原代人鼻上皮细胞（HNECs）和 BEAS-2B 细胞探索 STING 表达的调控和功能。
与非嗜酸性鼻息肉和对照组织相比，嗜酸性鼻息肉中 STING 的表达减少。STING 主要在鼻组织的上皮细胞中表达，并通过信号转导和转录激活因子 6（STAT6）依赖性方式被白细胞介素-4（IL-4）和白细胞介素-13（IL-13）下调。与非嗜酸性鼻息肉和对照组织相比，来源于嗜酸性鼻息肉的 HNECs 显示出 STING 依赖性 I 型干扰素产生受损，但 IL-13 诱导的 STAT6 激活和 CCL26 产生增加，这可通过外源性 STING 过表达得到挽救。在 BEAS-2B 细胞中，敲低或过表达 STING 分别减少或增强了细胞因子信号转导抑制因子 1（SOCS1）的表达，而不依赖于经典的 STING 通路元件 TBK1 和 IRF3。敲低 SOCS1 消除了 STING 对 BEAS-2B 细胞中 IL-13 信号的抑制作用。CRSwNP 患者鼻上皮细胞中 STING 表达与 SOCS1 表达呈正相关，与 CCL26 表达呈负相关。
由 2 型微环境引起的 STING 表达减少不仅损害了 STING 依赖性 I 型干扰素的产生，而且通过降低鼻上皮细胞中 SOCS1 的表达，放大了 IL-13 信号。
