上皮细胞中 IL-37-Mex3B-Toll 样受体 3 轴在伴鼻息肉的嗜酸性慢性鼻-鼻窦炎患者中的作用
The IL-37-Mex3B-Toll-like receptor 3 axis in epithelial cells in patients with eosinophilic chronic rhinosinusitis with nasal polyps.
机构信息
Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
出版信息
J Allergy Clin Immunol. 2020 Jan;145(1):160-172. doi: 10.1016/j.jaci.2019.07.009. Epub 2019 Jul 19.
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 α, 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 α, 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.
背景
白细胞介素-37（IL-37）是一种免疫抑制细胞因子，其在炎症性疾病患者中的作用尚不清楚。
目的
本研究旨在探讨 IL-37 在慢性鼻-鼻窦炎（CRS）患者中的表达及致病作用。
方法
采用实时定量 RT-PCR、免疫组织化学、Western blot 和 ELISA 检测鼻组织中 IL-37、IL-18 受体α（IL-18Rα）、IL-1 受体 8（IL-1R8）、Mex3B RNA 结合家族成员 B（Mex3B）和胸腺基质淋巴细胞生成素（TSLP）的表达水平。用各种细胞因子和 Toll 样受体（TLR）激动剂刺激人鼻上皮细胞（HNECs）和 BEAS-2B 细胞系。在某些实验中，用 Mex3B 小干扰 RNA 或过表达慢病毒转染 BEAS-2B 细胞。用 RNA 测序分析研究 IL-37b 在 HNECs 中调控的基因。在体内实验中验证 IL-37b 的功能。
结果
与对照组相比，尽管在无鼻息肉的 CRS 患者或伴有鼻息肉的 CRS（CRSwNP）患者的病变组织中，尤其是在鼻上皮细胞中，IL-37 的 mRNA 和蛋白表达上调，但在伴有嗜酸性粒细胞的 CRSwNP 患者的鼻分泌物中，IL-37 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-18Rα 和 IL-1R8。IL-37b 下调 HNECs 中 TLR3 共受体 Mex3B 的表达。IL-37b 体外抑制多聚肌苷酸-多聚胞苷酸诱导的 TSLP 在 HNECs 中的产生，并在体内抑制鼠鼻上皮细胞中的 TSLP 产生。在 BEAS-2B 细胞中敲低或过表达 Mex3B 可消除 IL-37b 的抑制作用。伴有嗜酸性粒细胞的 CRSwNP 患者中，分泌的 IL-37 水平与 Mex3B 和 TSLP 水平及嗜酸性粒细胞计数呈负相关。
结论
2 型细胞因子微环境下抑制 IL-37 的分泌可增强鼻上皮细胞中 Mex3B 介导的 TLR3 激活及随后的 TSLP 产生，从而促进伴有嗜酸性粒细胞的 CRSwNP 患者的嗜酸性粒细胞炎症。
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