Airway epithelial ITGB4 deficiency induces airway remodeling in a mouse model

Lin Yuan; Huijun Liu; Xizi Du; Ye Yao; Ling Qin; Zhenkun Xia; Kai Zhou; Xinyu Wu; Yunchang Yuan; Bei Qing; Yang Xiang; Xiangping Qu; Xiaoqun Qin; Ming Yang; Chi Liu

doi:10.1016/j.jaci.2022.09.032

Airway epithelial ITGB4 deficiency induces airway remodeling in a mouse model

J Allergy Clin Immunol. 2023 Feb;151(2):431-446.e16. doi: 10.1016/j.jaci.2022.09.032. Epub 2022 Oct 13.

Authors

Lin Yuan¹, Huijun Liu², Xizi Du², Ye Yao², Ling Qin³, Zhenkun Xia⁴, Kai Zhou², Xinyu Wu², Yunchang Yuan⁴, Bei Qing⁴, Yang Xiang², Xiangping Qu², Xiaoqun Qin², Ming Yang⁵, Chi Liu⁶

Affiliations

¹ Department of Respiratory Medicine, National Clinical Research Center for Respiratory Diseases, Xiangya Hospital, Central South University, Changsha, China; Department of Physiology, School of Basic Medicine Science, Central South University, Changsha, China; Basic and Clinical Research Laboratory of Major Respiratory Diseases, Central South University, Changsha, China.
² Department of Physiology, School of Basic Medicine Science, Central South University, Changsha, China.
³ Department of Respiratory Medicine, National Clinical Research Center for Respiratory Diseases, Xiangya Hospital, Central South University, Changsha, China; Basic and Clinical Research Laboratory of Major Respiratory Diseases, Central South University, Changsha, China.
⁴ Department of Thoracic Surgery, the Second Xiangya Hospital, Central South University, Changsha, China.
⁵ the Centre for Asthma and Respiratory Disease, School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle and Hunter Medical Research Institute, Callaghan, Australia.
⁶ Department of Respiratory Medicine, National Clinical Research Center for Respiratory Diseases, Xiangya Hospital, Central South University, Changsha, China; Department of Physiology, School of Basic Medicine Science, Central South University, Changsha, China. Electronic address: liu.chi@csu.edu.cn.

PMID: 36243221
DOI: 10.1016/j.jaci.2022.09.032

Abstract

Background: Airway epithelial cells (AECs) with impaired barrier function contribute to airway remodeling through the activation of epithelial-mesenchymal trophic units (EMTUs). Although the decreased expression of ITGB4 in AECs is implicated in the pathogenesis of asthma, how ITGB4 deficiency impacts airway remodeling remains obscure.

Objective: This study aims to determine the effect of epithelial ITGB4 deficiency on the barrier function of AECs, asthma susceptibility, airway remodeling, and EMTU activation.

Methods: AEC-specific ITGB4 conditional knockout mice (ITGB4^-/-) were generated and an asthma model was employed by the sensitization and challenge of house dust mite (HDM). EMTU activation-related growth factors were examined in ITGB4-silenced primary human bronchial epithelial cells of healthy subjects after HDM stimulation. Dexamethasone, the inhibitors of JNK phosphorylation or FGF2 were administered for the identification of the molecular mechanisms of airway remodeling in HDM-exposed ITGB4^-/- mice.

Results: ITGB4 deficiency in AECs enhanced asthma susceptibility and airway remodeling by disrupting airway epithelial barrier function. Aggravated airway remodeling in HDM-exposed ITGB4^-/- mice was induced through the enhanced activation of EMTU mediated by Src homology domain 2-containing protein tyrosine phosphatase 2/c-Jun N-terminal kinase/Jun N-terminal kinase-dependent transcription factor/FGF2 (SHP2/JNK/c-Jun/FGF2) signaling pathway, which was partially independent of airway inflammation. Both JNK and FGF2 inhibitors significantly inhibited the aggravated airway remodeling and EMTU activation in HDM-exposed ITGB4^-/- mice.

Conclusions: Airway epithelial ITGB4 deficiency induces airway remodeling in a mouse model of asthma through enhanced EMTU activation that is regulated by the SHP2/JNK/c-Jun/FGF2 pathway.

Keywords: Integrin β4; airway epithelium; airway remodeling; asthma; epithelial-mesenchymal trophic unit.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Airway Remodeling* / physiology
Animals
Asthma* / pathology
Dermatophagoides pteronyssinus
Disease Models, Animal
Epithelial Cells / metabolism
Fibroblast Growth Factor 2 / metabolism
Humans
Integrin beta4 / genetics
Integrin beta4 / metabolism
Mice
Mice, Knockout
Pyroglyphidae
Respiratory System / metabolism

Substances

Fibroblast Growth Factor 2
ITGB4 protein, human
Integrin beta4