The alpha v beta 6 integrin modulates airway hyperresponsiveness in mice by regulating intraepithelial mast cells

Abstract

Allergic asthma is the most common form of asthma, affecting more than 10 million Americans. Although it is clear that mast cells have a key role in the pathogenesis of allergic asthma, the mechanisms by which they regulate airway narrowing in vivo remain to be elucidated. Here we report that mice lacking alpha v beta 6 integrin are protected from exaggerated airway narrowing in a model of allergic asthma. Expression microarrays of the airway epithelium revealed mast cell proteases among the most prominent differentially expressed genes, with expression of mouse mast cell protease 1 (mMCP-1) induced by allergen challenge in WT mice and expression of mMCP-4, -5, and -6 increased at baseline in beta 6-deficient mice. These findings were most likely explained by loss of TGF-beta activation, since the epithelial integrin alpha v beta 6 is a critical activator of latent TGF-beta, and in vitro-differentiated mast cells showed TGF-beta-dependent expression of mMCP-1 and suppression of mMCP-4 and -6. In vitro, mMCP-1 increased contractility of murine tracheal rings, an effect that depended on intact airway epithelium, whereas mMCP-4 inhibited IL-beta-induced epithelial-independent enhancement of contractility. These results suggest that intraepithelial activation of TGF-beta by the alpha v beta 6 integrin regulates airway responsiveness by modulating mast cell protease expression and that these proteases and their proteolytic substrates could be novel targets for improved treatment of allergic asthma.

Published in

Journal of Clinical Investigation
2012, volume: 122, number: 2, pages: 748-758
Publisher: AMER SOC CLINICAL INVESTIGATION INC

SLU Authors

• Åbrink, Magnus

  • Department of Animal Biosciences, Swedish University of Agricultural Sciences
    

UKÄ Subject classification

Immunology in the medical area
Immunology

Publication identifier

• DOI: https://doi.org/10.1172/JCI58815

Permanent link to this page (URI)

https://res.slu.se/id/publ/41338