The IL-37-Mex3B-Toll-like receptor 3 axis in epithelial cells in patients with eosinophilic chronic rhinosinusitis with nasal polyps
The IL-37-Mex3B-Toll-like receptor 3 axis in epithelial cells in patients with eosinophilic chronic rhinosinusitis with nasal polyps
复制标题
嗜酸性慢性鼻窦炎伴鼻息肉患者上皮细胞IL-37-Mex3B-Toll样受体3轴
DOI：
10.1016/j.jaci.2019.07.009
复制
发表时间：
2020-01-01
影响因子：
14.2
通讯作者：
Liu, Zheng
中科院分区：
文献类型：
--
作者：
Liu, Jin-Xin;Liao, Bo;Liu, Zheng
背景：IL-37是一种免疫抑制细胞因子，在炎症性疾病患者中的作用尚不清楚。目的：探讨IL-37在慢性鼻-鼻窦炎(CRS)中的表达及其致病作用。方法：采用定量RT-PCR、免疫组织化学、Western blotting和ELISA法检测IL-37、IL-18受体α、IL-1受体8、Mex3 RNA结合家族成员B(Mex3B)和胸腺基质淋巴细胞生成素(TSLP)在鼻腔组织中的表达水平。用多种细胞因子和Toll样受体(TLR)激动剂刺激人鼻上皮细胞和BEAS-2B细胞。在一些实验中，将Mex3B小干扰RNA或过表达慢病毒导入BEAS-2B细胞。采用RNA测序技术研究IL-37B对HNECs的调控基因。结果：在无鼻息肉的CRS患者或慢性鼻窦炎合并鼻息肉(CRSwNP)患者中，尽管IL-37mRNA和蛋白在病变组织中表达上调，尤其是在鼻上皮细胞中，但在嗜酸性鼻息肉患者中，鼻分泌物中IL-37的水平降低。2型细胞因子抑制HNECs分泌IL-37。HNECs表达IL-37受体、IL-18受体α和IL-1受体8。IL-37B下调TLR3辅受体Mex3B的表达。IL-37B在体外可抑制多聚肌苷多胞酸诱导的HNECs和体内小鼠鼻上皮细胞TSLP的产生。在BEAS-2B细胞中下调或过表达Mex3B可阻断IL-37B的抑制作用。CRSwNP患者IL-37分泌水平与Mex3B、TSLP水平及嗜酸性粒细胞数量呈负相关。结论：2型环境抑制IL-37分泌可促进Mex3B介导的鼻黏膜上皮细胞TLR3活化及TSLP的产生，从而促进嗜酸性炎症反应。
Background: The role of IL-37, an immunosuppressive cytokine, in patients with inflammatory diseases is unclear. Objective: We sought to explore the expression and pathogenic function of IL-37 in patients with chronic rhinosinusitis (CRS).Methods: Expression levels of IL-37, IL-18 receptor alpha, IL-1 receptor 8, Mex3 RNA binding family member B (Mex3B), and thymic stromal lymphopoietin (TSLP) in nasal samples were studied by using quantitative RT-PCR, immunohistochemistry, Western blotting, and ELISA. Human nasal epithelial cells (HNECs) and the BEAS-2B cell line were stimulated with various cytokines and Toll-like receptor (TLR) agonists. In some experiments BEAS-2B cells were transfected with Mex3B small interfering RNA or overexpressing lentiviruses. Genes regulated by IL-37b in HNECs were studied by using RNA sequencing analysis. IL-37b function was confirmed in mice in vivo.Results: Compared with control subjects, although mRNA and protein expression of IL-37 were upregulated in diseased tissues, especially in nasal epithelial cells, in patients with CRS without nasal polyps or in patients with chronic rhinosinusitis with nasal polyps (CRSwNP), IL-37 levels in nasal secretions were reduced in patients with eosinophilic CRSwNP. Type 2 cytokines inhibited IL-37 secretion from HNECs. HNECs expressed IL-37 receptors, IL-18 receptor alpha, and IL-1 receptor 8. IL-37b downregulated the expression of Mex3B, a TLR3 coreceptor, in HNECs. IL-37b suppressed polyinosinic-polycytidylic acid- induced TSLP production in HNECs in vitro and in murine nasal epithelial cells in vivo. Knocking down or overexpressing Mex3B in BEAS-2B cells abolished the inhibitory effect of IL-37b. Secreted IL-37 levels negatively correlated with Mex3B and TSLP levels and eosinophil numbers in patients with eosinophilic CRSwNP.Conclusions: The suppressed IL-37 secretion caused by a type 2 milieu can enhance Mex3B-mediated TLR3 activation and subsequent TSLP production in nasal epithelial cells and therefore promotes eosinophilic inflammation in patients with CRSwNP.