MicroRNA-155 differentially regulates IL-13Rα1 and IL-13Rα2 expression and signaling that drives abnormal epithelial cells functions in severe asthma

Abstract

Rationale

Asthma is a chronic airway disease characterized by a prevailing type 2 inflammation and airway remodeling. In asthma, microRNA-155 (miR-155) is known to increase in innate and adaptive immune cells and is associated with disease severity. However, little is known about its role in lung structural cells.

Objectives

This study investigated the expression of miR-155 and its regulatory role on IL-13 receptors and function in bronchial epithelial cells (BEC) isolated from healthy and severe asthmatic donors.

Methods

BECs isolated from healthy donors and severe asthma patients were stimulated with IL-13. MiR-155 expression and release were measured by RT-PCR in BECs and in their derived exosomes. Modulation of miR-155 in BECs was performed using transfection of miR-155 inhibitor and miR-155 mimic. MUC5AC, IL-8 and EOTAXIN-1 expression were measured by RT-PCR and BECs repair process was assessed by wound healing assay. IL-13Rα1 and IL-13Rα2 expression and downstream pathways were evaluated by western blot.

Main results

Severe asthma BECs showed an increased expression and exosomal release of miR-155 at baseline and amplified following IL-13 stimulation. Additionally, they expressed more IL-13Rα1 and less IL-13Rα2 than healthy BECs. IL-13Rα1 but not IL-13Rα2 induced miR-155 expression. Following miR-155 overexpression, BECs expressed more MUC5AC, IL-8 and EOTAXIN-1 through IL-13Rα1/SOCS1/STAT6 pathway and harbored a delayed repair process with a downregulated IL-13α2/ERK1/2/c-Jun signaling.

Conclusions

MiR-155 is overexpressed in severe asthma BECs and contributes to modulate IL-13Rα1 and IL-13Rα2 expression favoring mucin and eosinophils recruitment to detriment of airway repair. These results contribute to a better understanding of miR-155 role in the abnormal behavior of severe asthma BECs.