Lyn regulates mucus secretion and MUC5AC via the STAT6 signaling pathway during allergic airway inflammation

Xiaoyun Wang,Yin Li,Deyu Luo,Xing Wang,Zhigang Liu,Yun Zhang,Guoping Li,Min Wu,Nanshan Zhong

doi:10.1038/srep42675

Abstract

Hypersecretion of mucus is an important component of airway remodeling and contributes to the mucus plugs and airflow obstruction associated with severe asthma phenotypes. Lyn has been shown to down-regulate allergen-induced airway inflammation. However, the role of Lyn in mucin gene expression remains unresolved. In this study, we first demonstrate that Lyn overexpression decreased the mucus hypersecretion and levels of the muc5ac transcript in mice exposed to ovalbumin (OVA). Lyn overexpression also decreased the infiltration of inflammatory cells and the levels of IL-13 and IL-4 in OVA-challenged airways. Whereas Lyn knockdown increased the IL-4 or IL-13-induced MUC5AC transcript and protein levels in the human bronchial epithelial cell line, 16HBE, Lyn overexpression decreased IL-4- or IL-13-induced MUC5AC transcript and protein levels. Overexpression of Lyn also decreased the expression and phosphorylation of STAT6 in OVA-exposed mice, whereas Lyn knockdown increased STAT6 and MUC5AC levels in 16HBE cells. Finally, chromatin immunoprecipitation analysis confirmed that Lyn overexpression decreased the binding of STAT6 to the promoter region of Muc5ac in mice exposed to OVA. Collectively, these findings demonstrated that Lyn overexpression ameliorated airway mucus hypersecretion by down-regulating STAT6 and its binding to the MUC5AC promoter.

Highlights

Mucous metaplasia is an important component of airway remodeling associated with severe asthma phenotypes
The transcript levels for muc[1], muc[2], muc[3], muc[4], muc5b and muc[13] in lung tissue were unaltered, whereas the Muc5ac transcript was significantly increased in the wild type (WT) mice exposed to OVA (Fig. 1F; Supplementary Figure S1C)
We observed a robust decrease in muc5ac transcript levels in the Lyntg mice exposed to OVA compared with WT mice (Fig. 1F; P < 0.001)

Summary

Introduction

Mucous metaplasia is an important component of airway remodeling associated with severe asthma phenotypes. Receptor and STAT6 play key roles in the IL-13-induced mucus production in mouse airway epithelial cells[14]. STAT6-knockout mice were protected from airway inflammation in the murine model of OVA-induced allergic airway inflammation[15] It remains unclear whether STAT6 directly regulates the levels of MUC5AC or of other mucus regulators. We examined the regulatory role of Lyn knockdown and over-expression in mucous secretion using our recently created Lyn-transgenic mice and human airway epithelial cells. These findings demonstrated that Lyn overexpression ameliorated airway mucus hypersecretion via down-regulation of STAT6 as well as binding to the MUC5AC promoter

Methods

Results

Conclusion