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. 2020 Jan;145(1):160-172.
doi: 10.1016/j.jaci.2019.07.009. Epub 2019 Jul 19.

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

Jin-Xin Liu  1 , Bo Liao  1 , Qi-Hong Yu  2 , Hai Wang  1 , Yi-Bo Liu  1 , Cui-Lian Guo  1 , Zhi-Chao Wang  1 , Zhi-Yong Li  1 , Zhe-Zheng Wang  1 , Jian-Wen Ruan  1 , Li Pan  1 , Yin Yao  1 , Cai-Ling Chen  1 , Heng Wang  1 , Yuxia Liang  3 , Guohua Zhen  3 , Zheng Liu  4
Affiliations

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

Jin-Xin Liu et al. J Allergy Clin Immunol. 2020 Jan.

Abstract

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.

Keywords: Eosinophil; IL-37; Mex3 RNA binding family member B; Toll-like receptor 3; chronic rhinosinusitis; epithelial cell; nasal polyp.

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