Airway epithelial ITGB4 deficiency in early life mediates pulmonary spontaneous inflammation and enhanced allergic immune response.

Sha Tang,Xizi Du,Zhen Duan,Xiaoqun Qin,Leyuan Wang,Gelei Xiao,Ling Qin,Yizhou Zou,Chi Liu,Xiangping Qu,Yang Xiang,Shuangyan Wu,Mengping Wu,Huijun Liu,Lin Yuan

doi:10.1111/jcmm.15000

Abstract

Lung immune responses to respiratory pathogens and allergens are initiated in early life which will further influence the later onset of asthma. The airway epithelia form the first mechanical physical barrier to allergic stimuli and environmental pollutants, which is also the key regulator in the initiation and development of lung immune response. However, the epithelial regulation mechanisms of early‐life lung immune responses are far from clear. Our previous study found that integrin β4 (ITGB4) is decreased in the airway epithelium of asthma patients with specific variant site. ITGB4 deficiency in adult mice aggravated the lung Th2 immune responses and enhanced airway hyper‐responsiveness (AHR) with a house dust mite (HDM)‐induced asthma model. However, the contribution of ITGB4 to the postnatal lung immune response is still obscure. Here, we further demonstrated that ITGB4 deficiency following birth mediates spontaneous lung inflammation with ILC2 activation and increased infiltration of eosinophils and lymphocytes. Moreover, ITGB4 deficiency regulated thymic stromal lymphopoietin (TSLP) production in airway epithelial cells through EGFR pathways. Neutralization of TSLP inhibited the spontaneous inflammation significantly in ITGB4‐deficient mice. Furthermore, we also found that ITGB4 deficiency led to exaggerated lung allergic inflammation response to HDM stress. In all, these findings indicate that ITGB4 deficiency in early life causes spontaneous lung inflammation and induces exaggerated lung inflammation response to HDM aeroallergen.

Highlights

Asthma is a chronic airway inflammation disease characterized by aberrant immune responses to contact aerosol allergen and other environmental insulants.[1,2] Accumulating evidence shows that the lung immune responses to inhaled allergens are initiated early in embryonic development, in utero, and during infancy.[3-5]
We have demonstrated that epithelial ITGB4 deficiency aggravated the Th2 inflammation and airway hyper-responsiveness (AHR) in an adult house dust mite (HDM)-induced mouse model.[22]
Using our well-established conditional knockout in vivo system, we demonstrated that airway epithelial postnatal ITGB4 deficiency mediates regulate spontaneous lung inflammation response with ILC2 activation and infiltration of eosinophils and lymphocytes

Summary

Introduction

Asthma is a chronic airway inflammation disease characterized by aberrant immune responses to contact aerosol allergen and other environmental insulants.[1,2] Accumulating evidence shows that the lung immune responses to inhaled allergens are initiated early in embryonic development, in utero, and during infancy.[3-5]. Using our well-established conditional knockout in vivo system, we demonstrated that airway epithelial postnatal ITGB4 deficiency mediates regulate spontaneous lung inflammation response with ILC2 activation and infiltration of eosinophils and lymphocytes.

Results

Conclusion