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

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.

Airway epithelial integrin β4‐deficiency exacerbates lipopolysaccharide‐induced acute lung injury

“…Mice were housed under 12-h light/dark cycles with ad libitum access to food and water. ITGB4 −/− mice had been successfully constructed in the early stages (Tang et al, 2020;Yuan et al, 2019). Only male mice were used in this study.…”

DNA methylation down‐regulates integrin β4 expression in asthmatic airway epithelial cells

“…The protein concentration was determined by BCA protein assay (Beyotime). Then, Western blot analysis was conducted in accordance with previously procedures 28 . Briefly, 10% SDS‐PAGE isolated 50 μg protein in HBE cells, which was transferred to a polyvinylidene difluoride (PVDF) membrane.…”

CTNNAL1 participates in the regulation of mucus overproduction in HDM‐induced asthma mouse model through the YAP‐ROCK2 pathway

“…on Days 14, 21, 28 and 34. The allergen challenge was done via an atomization treatment of HDM on four consecutive days (Day [35][36][37][38], and the mice were sacrificed 24 h after the last challenge (Day 39). The control group received sterile PBS via i.n.…”