Epithelial microRNA-30a-3p targets RUNX2/HMGB1 axis to suppress airway eosinophilic inflammation in asthma

Wenliang Wu,Yuchen Feng,Shengchong Chen,Jiali Gao,Lingling Yi,Chenli Chang,Guohua Zhen,Dian Chen,Gongqi Chen

doi:10.1186/s12931-022-01933-x

Abstract

BackgroundType 2-high asthma is a prominent endotype of asthma which is characterized by airway eosinophilic inflammation. Airway epithelial cells play a critical role in the pathogenesis of asthma. Our previous miRNA profiling data showed that miR-30a-3p was downregulated in bronchial epithelial cells from asthma patients. We hypothesize that epithelial miR-30a-3p plays a role in asthma airway inflammation.MethodsWe measured miR‐30a-3p expression in bronchial brushings of asthma patients (n = 51) and healthy controls (n = 16), and analyzed the correlations between miR‐30a-3p expression and airway eosinophilia. We examined whether Runt-related transcription factor 2 (RUNX2) was a target of miR‐30a-3p and whether RUNX2 bound to the promoter of high mobility group box 1 (HMGB1) by using luciferase reporter assay and chromatin immunoprecipitation (ChIP)-PCR. The role of miR‐30a-3p was also investigated in a murine model of allergic airway inflammation.ResultsWe found that miR-30a-3p expression were significantly decreased in bronchial brushings of asthma patients compared to control subjects. Epithelial miR-30a-3p expression was negatively correlated with parameters reflecting airway eosinophilia including eosinophils in induced sputum and bronchial biopsies, and fraction of exhaled nitric oxide in asthma patients. We verified that RUNX2 is a target of miR-30a-3p. Furthermore, RUNX2 bound to the promoter of HMGB1 and upregulated HMGB1 expression. RUNX2 and HMGB1 expression was both enhanced in airway epithelium and was correlated with each other in asthma patients. Inhibition of miR-30a-3p enhanced RUNX2 and HMGB1 expression, and RUNX2 overexpression upregulated HMGB1 in BEAS-2B cells. Intriguingly, airway overexpression of mmu-miR-30a-3p suppressed Runx2 and Hmgb1 expression, and alleviated airway eosinophilia in a mouse model of allergic airway inflammation.ConclusionsEpithelial miR-30a-3p could possibly target RUNX2/HMGB1 axis to suppress airway eosinophilia in asthma.

Highlights

Type 2-high asthma is a prominent endotype of asthma which is characterized by airway eosinophilic inflammation
We found that miR‐30a‐3p expression was significantly decreased in bronchial brushings in asthma patients compared with controls (Fig. 1a)
We found that miR-30a-3p had a strong negative correlation with parameters reflecting airway eosinophilia including eosinophil in induced sputum (Fig. 1c) and bronchial biopsies (Fig. 1d), and fraction of exhaled nitric oxide (Fig. 1e) in asthma patients

Summary

Introduction

Type 2-high asthma is a prominent endotype of asthma which is characterized by airway eosinophilic inflammation. Airway epithelial cells play a critical role in the pathogenesis of asthma. Our previous miRNA profiling data showed that miR-30a-3p was downregulated in bronchial epithelial cells from asthma patients. We hypothesize that epithelial miR-30a-3p plays a role in asthma airway inflammation. Type 2 immune response driven by the type 2 cytokines, IL-4, IL-5, and IL-13, plays an important role in the pathogenesis of asthma. Airway eosinophilic inflammation is a key feature of type 2-high asthma [3,4,5,6]. MicroRNAs (miRNAs) are ~ 22 nucleotide long, noncoding RNAs that play a critical role in the regulation of gene expression. Our miRNA profiling data showed that a set of epithelial miRNAs including miR-30a-3p was downregulated in asthma patients [12]. We hypothesized that epithelial miR-30a-3p is involved in airway eosinophilic inflammation in asthma

Methods

Results

Conclusion