Defective STING expression potentiates IL-13 signaling in epithelial cells in eosinophilic chronic rhinosinusitis with nasal polyps
Defective STING expression potentiates IL-13 signaling in epithelial cells in eosinophilic chronic rhinosinusitis with nasal polyps
复制标题
STING 表达缺陷会增强嗜酸性慢性鼻窦炎伴鼻息肉的上皮细胞中的 IL-13 信号传导。
DOI：
10.1016/j.jaci.2020.12.623
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发表时间：
2021-05-05
影响因子：
14.2
通讯作者：
Liu, Zheng
中科院分区：
文献类型：
--
作者：
Wang, Hai;Hu, Dan-Qing;Liu, Zheng
背景：干扰素基因刺激剂 (STING) 激活有利于针对病毒感染的有效先天免疫反应。其在慢性鼻窦炎伴鼻息肉（CRSwNP）中的作用尚不清楚。 目的：探讨STING在CRSwNP中的表达、调控和功能。方法：采用定量RT-PCR、免疫组化、流式细胞术和Western blotting等方法分析鼻窦粘膜样本中STING的表达。利用体外培养的原代人鼻上皮细胞（HNEC）和BEAS-2B系细胞，探讨STING表达的调控和功能。结果：与非嗜酸性鼻息肉和对照组织相比，嗜酸性鼻息肉中STING表达减少。 STING 主要由鼻组织中的上皮细胞表达，并以信号转导器和转录激活剂 6 (STAT6) 依赖性方式被 IL-4 和 IL-13 下调。与来自非嗜酸性息肉和对照组织的 HNEC 相比，来自嗜酸性息肉的 HNEC 表现出 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，后者通过外源性 STING 过表达而得以挽救。敲除或过度表达 STING 分别会降低或增强 BEAS-2B 细胞中细胞因子信号传导抑制因子 1 (SOCS1) 的表达，与经典 STING 通路元件 TBK1 和 IRF3 无关。敲低 SOCS1 消除了 STING 对 BEAS-2B 细胞中 IL-13 信号传导的抑制作用。 CRSwNP 患者鼻上皮细胞中 STING 表达与 SOCS1 表达呈正相关，但与 CCL26 表达呈负相关。结论：2 型环境引起的 STING 表达减少不仅损害 STING 依赖性 I 型干扰素的产生，而且还通过降低嗜酸性 CRSwNP 鼻上皮细胞中 SOCS1 的表达来放大 IL-13 信号传导。 （过敏临床免疫杂志 2021 年；147：1692-703。）
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: Our aim was 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. 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.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 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.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. (J Allergy Clin Immunol 2021;147:1692-703.)