MiR-223 plays a protecting role in neutrophilic asthmatic mice through the inhibition of NLRP3 inflammasome

Wenjuan Xu,Yimin Wang,Ying Ma,Jiong Yang

doi:10.1186/s12931-020-01374-4

Abstract

BackgroundNeutrophilic subtype asthma occurs in approximately 15–25% of the asthma cases and is associated with severe airflow obstruction, corticosteroid resistance. MicroRNA plays a vital role in regulating many immune processes, but how miRNA circuits coordinate airway inflammation during neutrophilic asthma is unclear.MethodsTo investigate the molecular mechanism of miR-223 in regulation of neutrophilic airway inflammation, miR-223 knockout mice were used to the OVA/CFA-induced neutrophilic asthma or treated with NLRP3 inhibitor and IL-1β receptor antagonist. Based on the results obtained, wide-type mice were subsequently treated with miR-223 agomirs or negative control agomirs, and the effects on airway inflammation were assessed using morphometric techniques, quantitative RT-PCR, western blot, ELISA and other molecular approaches.ResultsThe expression of miR-223 was upregulated in lung tissues of experimental mice model. Furthermore, miR-223−/− mice led to aggravated neutrophilic airway inflammation with heightened histopathological, inflammatory cells and cytokines readouts. Moreover, miR-223−/− mice also presented with enhanced NLRP3 inflammasome level with elevated IL-1β. Blocking NLRP3 or IL-1β diminished this phenotype. Finally, overexpression of miR-223 via treatment with miR-223 agomirs attenuated airway inflammation, NLRP3 levels and IL-1β release.ConclusionsThe findings of this study revealed a crucial role for miR-223 in regulating the immunoinflammatory responses by depressing the NLRP3/ IL-1β axis in neutrophilic asthma.

Highlights

Neutrophilic subtype asthma occurs in approximately 15–25% of the asthma cases and is associated with severe airflow obstruction, corticosteroid resistance
Increased miR-223 expression in mice with OVA-induced neutrophilic asthma To investigate the role of specific miRNAs in the OVAinduced neutrophilic asthmatic mice model (Fig. 1.a), we identified that the miR-223 expression level in the lungs of the OVA-induced mice model (23 day) was significantly upregulated compared with the phosphate-buffered saline (PBS) –induced mice (Fig. 1.b)
MiR-223−/− mice exposed to OVA had markedly increased the number of total inflammatory cells, neutrophils, eosinophils and lymphocytes in bronchoalveolar lavage fluid (BALF) when compared to OVA-challenged WT mice (Fig. 1.f)

Summary

Introduction

Neutrophilic subtype asthma occurs in approximately 15–25% of the asthma cases and is associated with severe airflow obstruction, corticosteroid resistance. Asthma is a heterogeneous chronic disease of the airways characterized by airway inflammation, reversible airway obstruction, and airway hyperresponsiveness (AHR) [1, 2]. Their etiologies are still elusive, because they involve complex interactions between environmental, genetic and immunoregulatory factors. Some with neutrophilic inflammation are often poorly responsive to corticosteroid therapy even at high doses and are at risk of developing refractory asthma [8, 9]. There are no effective treatments for severe, steroid-resistant and neutrophilic asthma and these patients take up more than half of health care costs [10, 11].

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