The cardiomyocyte protein αT-catenin contributes to asthma through regulating pulmonary vein inflammation

Abstract

Background Recent genome-wide association studies have identified single nucleotide polymorphisms in the protein αT-catenin (αT-cat; CTNNA3) that correlate with both steroid-resistant atopic asthma and asthmatic exacerbations. α-catenins are important mediators of cell-cell adhesion and αT-cat is predominantly expressed in cardiomyocytes. In the lung, αT-cat appears exclusively expressed in the cardiomyocytes surrounding pulmonary veins, but its contribution to atopic asthma remains unknown. Objective To understand the role of αT-cat in the pathogenesis of asthma. Methods We utilized αT-cat knockout mice and a house dust-mite extract (HDM) model of atopic asthma, with assessment by forced oscillation, bronchoalveolar lavage, and histologic analysis. Results We found that the genetic loss of αT-cat in mice largely attenuated HDM-induced airway inflammation and airway hyperresponsiveness to methacholine. Mice lacking αT-cat exposed to HDM extract showed reduced pulmonary vein inflammation, specifically near the large veins surrounded by cardiac cells. The proximity of airways to pulmonary veins correlated with the severity of airway goblet cell metaplasia, suggesting that pulmonary veins may influence the inflammatory milieu of adjacent airways. Loss of αT-cat led to the compensatory upregulation of αE-cat, which itself has a defined anti-inflammatory function. Conclusion These data mechanistically support previous clinical and genetic associations between αT-cat and the development of atopic asthma, and suggest that pulmonary veins may have an under-appreciated role in allergic airway inflammation.

microRNA‐218‐5p plays a protective role in eosinophilic airway inflammation via targeting δ‐catenin, a novel catenin in asthma

“…Our in vivo findings provide direct evidence for a protective role of miR‐218‐5p‐CTNND2 pathway in eosinophilic airway inflammation in asthma. It was reported that CTNNA3 (encoding αT‐catenin) plays an important role in asthma airway inflammation because CTNNA3 knockout mice manifested attenuated AHR and airway inflammation after allergen challenge . Although CTNNA3 expression was reported to be predominantly in cardiomyocytes surrounding pulmonary veins, we demonstrated that CTNNA3 transcripts were increased in asthma bronchial brushings and IL‐13‐stimulated HBE cells.…”

“…We found that CTNND2 (encoding δ‐catenin) was one of the candidate targets. Since CTNNA3 plays a role in asthma airway inflammation, we next focused on the role of CTNND2 in asthma. miRNA regulates gene expression via acting on the 3′‐UTR of the mRNA.…”

“…Remarkably, CTNND2 was the most significantly up‐regulated epithelial catenin in asthma patients (Figure E). The transcripts of CTNNA3 , a catenin with an established role in asthma airway inflammation, were also significantly increased in asthma. Moreover, we examined the expression of the 12 catenins in IL‐13‐stimulated HBE cells and BEAS‐2B cells.…”

“…We next verified that CTNND2 , a catenin never described in asthma, is a target of miR‐218‐5p. Although catenin was implicated in the pathogenesis of asthma, there was no comprehensive examination of the catenin family members in asthma airway epithelium. In a head‐to‐head comparison of the 12 catenins’ expression, we demonstrated that CTNND2 was the most significantly up‐regulated catenin in bronchial brushings of asthma patients.…”

“…In asthma airway epithelium, it was reported that α‐catenin expression was decreased, whereas β‐catenin expression was not altered . CTNNA3 (encoding αT‐catenin) was identified as a promising locus for asthma exacerbation through multiple genome‐wide association studies, and genetic loss of αT‐catenin attenuated airway inflammation and AHR in allergen‐challenged mice . So far, there is no comprehensive comparison of the 12 catenin members’ expression in asthma airway epithelium.…”