MicroRNA-21-5p promotes mucosal type 2 inflammation via regulating GLP1R/IL-33 signaling in chronic rhinosinusitis with nasal polyps

Ge Luan; Ming Wang; Jing Yuan; Xiangting Bu; Yang Wang; Sun Ying; Chengshuo Wang; Luo Zhang

doi:10.1016/j.jaci.2022.05.030

MicroRNA-21-5p promotes mucosal type 2 inflammation via regulating GLP1R/IL-33 signaling in chronic rhinosinusitis with nasal polyps

J Allergy Clin Immunol. 2022 Dec;150(6):1460-1475. doi: 10.1016/j.jaci.2022.05.030. Epub 2022 Jul 11.

Authors

Ge Luan¹, Ming Wang¹, Jing Yuan¹, Xiangting Bu¹, Yang Wang¹, Sun Ying², Chengshuo Wang³, Luo Zhang⁴

Affiliations

¹ Department of Otolaryngology, Head and Neck Surgery, Beijing TongRen Hospital, Capital Medical University, Beijing, China; Beijing Laboratory of Allergic Diseases and Beijing Key Laboratory of Nasal Diseases, Beijing Institute of Otolaryngology, Beijing, China.
² Department of Immunology, School of Basic Medical Sciences, Capital Medical University, Beijing, China. Electronic address: ying.sun@ccmu.edu.cn.
³ Department of Otolaryngology, Head and Neck Surgery, Beijing TongRen Hospital, Capital Medical University, Beijing, China; Beijing Laboratory of Allergic Diseases and Beijing Key Laboratory of Nasal Diseases, Beijing Institute of Otolaryngology, Beijing, China. Electronic address: wangcs830@126.com.
⁴ Department of Otolaryngology, Head and Neck Surgery, Beijing TongRen Hospital, Capital Medical University, Beijing, China; Beijing Laboratory of Allergic Diseases and Beijing Key Laboratory of Nasal Diseases, Beijing Institute of Otolaryngology, Beijing, China; Department of Allergy, Beijing TongRen Hospital, Capital Medical University, Beijing, China. Electronic address: dr.luozhang@139.com.

PMID: 35835254
DOI: 10.1016/j.jaci.2022.05.030

Abstract

Background: It has been known that chronic rhinosinusitis with nasal polyps (CRSwNP) is a type 2 inflammation-dominated disease; however, the reasons causing such type of mucosal inflammation in CRSwNP are not well elucidated.

Objective: We sought to investigate the role of microRNA-21-5p (miR-21-5p) in regulating mucosal type 2 inflammation in CRSwNP.

Methods: miR-21-5p expression was detected in nasal mucosa of patients with CRSwNP. Correlations between miR-21-5p and indicators of type 2 inflammation were further analyzed. miR-21 knockout mice were used to explore the role of miR-21-5p in a murine model of eosinophilic (E) CRSwNP. Target gene of miR-21-5p related to type 2 inflammation in CRSwNP was identified.

Results: The upregulated miR-21-5p in the nasal mucosa of patients with CRSwNP, compared with control subjects, was expressed higher in patients with ECRSwNP than in patients with nonECRSwNP. miR-21-5p expression was positively correlated with mucosal eosinophil infiltrations and the expression of type 2 inflammatory cytokines. In the CRSwNP mice, miR-21 knockout significantly attenuated type 2 inflammation, as indicated by eosinophil infiltrations and expression of cytokines/chemokines in nasal mucosa and lavage fluid; moreover, genes associated with type 2 inflammation were extensively downregulated at the transcriptome level in miR-21 knockout mice. Glucagon-like peptide-1 receptor, which was negatively correlated with miR-21-5p expression in human nasal mucosa, was identified as the target of miR-21-5p. Overexpression of miR-21-5p induced IL-33 expression, whereas glucagon-like peptide-1 receptor agonist decreased IL-33 production in airway epithelial cells.

Conclusions: miR-21-5p aggravates type 2 inflammation in the nasal mucosa of patients with CRSwNP via targeting glucagon-like peptide-1 receptor/IL-33 signaling, which may be a potential therapeutic target for CRSwNP.

Keywords: Chronic rhinosinusitis with nasal polyps; glucagon-like peptide-1 receptor; microRNA-21-5p; type 2 inflammation.

MeSH terms

Animals
Glucagon-Like Peptide-1 Receptor
Humans
Interleukin-33 / genetics
Mice
Mice, Knockout
MicroRNAs* / genetics
Nasal Polyps* / genetics

Substances

Interleukin-33
Glucagon-Like Peptide-1 Receptor
MicroRNAs
MIRN21 microRNA, human
MIRN21 microRNA, mouse