Sammanfattning

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.

Publicerad i

Journal of Clinical Investigation
2012, Volym: 122, nummer: 2, sidor: 748-758
Utgivare: AMER SOC CLINICAL INVESTIGATION INC

SLU författare

• Åbrink, Magnus

  • Institutionen för husdjurens biovetenskaper, Sveriges lantbruksuniversitet
    

UKÄ forskningsämne

Immunologi inom det medicinska området
Immunologi


Publikationens identifierare

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

Permanent länk till denna sida (URI)

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