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.We sought to investigate the role of microRNA-21-5p (miR-21-5p) in regulating mucosal type 2 inflammation in CRSwNP.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 (KO) 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.The up-regulated miR-21-5p in nasal mucosa of CRSwNP patients, compared to control subjects, was expressed higher in ECRSwNP than nonECRSwNP patients. MiR-21-5p expression was positively correlated with mucosal eosinophil infiltrations, and the expression of type 2 inflammatory cytokines. In the CRSwNP mice, miR-21KO significantly attenuated type 2 inflammation, as indicated by eosinophil infiltrations and cytokines/chemokines expression in nasal mucosa and lavage fluid; moreover, genes associated with type 2 inflammation were extensively down-regulated at the transcriptome level in miR-21KO mice. Glucagon-like peptide-1 receptor (GLP1R), 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 GLP1R agonist decreased IL-33 production in airway epithelial cells.MiR-21-5p aggravates type 2 inflammation in nasal mucosa of CRSwNP via targeting GLP1R/IL-33 signaling, which may be a potential therapeutic target for CRSwNP.Copyright © 2022. Published by Elsevier Inc.