The αvβ6 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 αvβ6 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 β6-deficient mice. These findings were most likely explained by loss of TGF-β activation, since the epithelial integrin αvβ6 is a critical activator of latent TGF-β, and in vitrodifferentiated mast cells showed TGF-β-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-13-induced epithelial-independent enhancement of contractility. These results suggest that intraepithelial activation of TGF-β by the αvβ6 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.

Targeting integrin α5β1 ameliorates severe airway hyperresponsiveness in experimental asthma

“…Contractile responses to methacholine (Mch) were evaluated in human bronchial rings that were incubated with IL-13 (or vehicle) for 12 hours and treated with human chymase (or vehicle) for 20 minutes. Recombinant human chymase (rhChy) had no effect on the contraction of control bronchial rings but inhibited IL-13-enhanced contraction ( Figure 1A), as we previously reported for contraction of mouse tracheal rings (13). This protective effect was also observed when rings were treated with IL-17A, suggesting that the mechanisms responsible for this effect are not cytokine specific and probably involve a common downstream pathway ( Figure 1B).…”

“…We have previously shown that the murine mast cell protease 4 (mMCP-4) and its human ortholog, mast cell chymase, inhibit the exaggerated force generated by murine tracheal rings that have been incubated overnight with the asthmagenic inflammatory mediator IL-13 (13). Mice lacking mMCP-4 have also been shown to develop exaggerated airway hyperresponsiveness after allergen challenge (14), whereas mice lacking the α v β 6 integrin, which we have shown have markedly increased levels of mMCP-4 in intraepithelial mast cells, are protected from allergen-induced airway hyperresponsiveness (13). We therefore reasoned that elucidation of the mechanism(s) underlying these protective effects of mMCP-4 and chymase might lead to identification of new targets for the treatment of airway hyperresponsiveness in asthma.…”

IQGAP1-dependent scaffold suppresses RhoA and inhibits airway smooth muscle contraction

“…We tested Iqgap1 -/-mice (10) in an OVA sensitization model of airway hyperresponsiveness (11,12). Both at baseline and with OVA challenge, Iqgap1 -/-mice had increased airway responsiveness compared with WT mice (Figure 1, A and B).…”

Mfge8 suppresses airway hyperresponsiveness in asthma by regulating smooth muscle contraction

“…To examine the role of Mfge8 in allergic airway disease, we evaluated the response of Mfge8 −/− mice in two models (36-d and 70-d Ova protocols) of allergen-induced asthma (11,12). In both models, Ova-treated Mfge8 −/− mice developed significantly exaggerated increases in pulmonary resistance, a measure of AHR to acetylcholine ( Fig.…”