The IL-37–Mex3B–Toll-like receptor 3 axis in epithelial cells in patients with eosinophilic chronic rhinosinusitis with nasal polyps

• Published in: Journal of allergy and clinical immunology 2020-01, Vol.145 (1), p.160-172
• Main Authors: Liu, Jin-Xin, Liao, Bo, Yu, Qi-Hong, Wang, Hai, Liu, Yi-Bo, Guo, Cui-Lian, Wang, Zhi-Chao, Li, Zhi-Yong, Wang, Zhe-Zheng, Ruan, Jian-Wen, Pan, Li, Yao, Yin, Chen, Cai-Ling, Wang, Heng, Liang, Yuxia, Zhen, Guohua, Liu, Zheng
• Format: Article
• Language: English
• Subjects: chronic rhinosinusitis; Eosinophil; epithelial cell; IL-37; Mex3 RNA binding family member B; nasal polyp; Toll-like receptor 3
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2019.07.009

The role of IL-37, an immunosuppressive cytokine, in patients with inflammatory diseases is unclear. We sought to explore the expression and pathogenic function of IL-37 in patients with chronic rhinosinusitis (CRS). 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. 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. 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. [Display omitted]