The cardiomyocyte protein αT-catenin contributes to asthma through regulating pulmonary vein inflammation Stephen Sai Folmsbee, G.R. Scott Budinger,

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The cardiomyocyte protein αT-catenin contributes to asthma through regulating pulmonary vein inflammation Stephen Sai Folmsbee, G.R. Scott Budinger, MD, Paul J. Bryce, PhD, Cara J. Gottardi, PhD Journal of Allergy and Clinical Immunology Volume 138, Issue 1, Pages 123-129.e2 (July 2016) DOI: 10.1016/j.jaci.2015.11.037 Copyright © 2016 Terms and Conditions

Fig 1 αT-catenin is necessary for development of an HDM-induced murine model of atopic asthma. A-D, HDM-asthma model, with female mice at least 6 weeks old (Fig 1, A), with airway resistance measurements with forced oscillation (Fig 1, B), airway inflammation measured by using bronchoalveolar lavage (Fig 1, C), and goblet cell metaplasia measured by using PAS staining (purple; Fig 1, D). E, Airways with the greatest goblet cell metaplasia from each mouse were quantified to avoid bias in choosing a “representative airway” (WT, n = 5; KO, n = 6). EO, Eosinophil; LY, lymphocyte; MØ, macrophage; NE, neutrophil. *P < .05 and **P < .01, Student t test. Error bars = SEMs. Journal of Allergy and Clinical Immunology 2016 138, 123-129.e2DOI: (10.1016/j.jaci.2015.11.037) Copyright © 2016 Terms and Conditions

Fig 2 Only the large PVs contain cardiomyocytes. A, Hematoxylin and eosin–stained large and small PVs. The large vein inset shows a region containing morphologically characteristic cardiac cells. The small vein inset shows the absence of this layer. B, Immunofluorescence image of large and small PVs stained with the intermediate filament protein desmin (green), marking cardiomyocyte striations (inset, double arrow) and demonstrating the loss of cardiac cells in small veins. Nuclei are stained blue with Hoechst dye. Journal of Allergy and Clinical Immunology 2016 138, 123-129.e2DOI: (10.1016/j.jaci.2015.11.037) Copyright © 2016 Terms and Conditions

Fig 3 αT-catenin (αTcat) is expressed only in the large cardiomyocyte-containing PVs. Immunofluorescence of the large (A) and small (B) PVs double-labeled for both αT-catenin (red) and the more ubiquitously expressed αE-catenin (αEcat; green). Note that αE-catenin was detected in endothelial junctions (arrowheads) of both the large and small veins, as well as cardiomyocyte junctions (arrows) of the large veins. αT-catenin was found only in cardiomyocyte junctions of the large veins (arrows). The white line defines the outer cardiomyocyte boundary of the large PV. Boxed insets (right) are vertically arranged as progressive increases in magnification to show cardiac junction staining. Nuclei are stained blue with Hoechst dye. Journal of Allergy and Clinical Immunology 2016 138, 123-129.e2DOI: (10.1016/j.jaci.2015.11.037) Copyright © 2016 Terms and Conditions

Fig 4 αT-catenin loss decreases large but not small PV inflammation. A and C, Hematoxylin and eosin–stained large (Fig 4, A) and small (Fig 4, C) PVs of both WT and αT-catenin KO mice exposed to HDM. B and D, Inflammatory cuff size was measured by dividing the area by the thickness of the muscle (large vein) or lumen size (small vein). ns, Not significant. *P < .05, Student t test (n = 5). Error bars = SEMs. Journal of Allergy and Clinical Immunology 2016 138, 123-129.e2DOI: (10.1016/j.jaci.2015.11.037) Copyright © 2016 Terms and Conditions

Fig 5 The PVs are an important mediator of airway inflammation. A, Hematoxylin and eosin–stained airways of both WT and αT-catenin KO mice exposed to HDM, showing inflammation from the PVs in WT mice. AW, Airway; PA, Pulmonary artery. B, Percentage of PAS-positive staining as a function of distance to the nearest PV. Each of the 21 data points in the regression analysis represents a single PAS-positive airway from HDM-treated WT mice, 1 tissue section each, from Fig 1 (n = 5 mice). C, Measurement of raw intensity of αE-catenin in PV junctions of WT (n = 50) and KO (n = 98) mice exposed to HDM and normalized to WT. *P < .05, Student t test. Error bars = SEMs. Journal of Allergy and Clinical Immunology 2016 138, 123-129.e2DOI: (10.1016/j.jaci.2015.11.037) Copyright © 2016 Terms and Conditions

Fig E1 β-Catenin protein expression and localization in the airway are not affected by loss of αT-catenin. Exposure-matched immunofluorescence images from WT (A) and αT-catenin KO (B) airways stained for β-catenin (green; BD Biosciences Clone 14; C19220). High magnification (A′, A″, B′, and B″) shows no obvious redistribution of β-catenin from airway epithelial cell-cell junctions. Journal of Allergy and Clinical Immunology 2016 138, 123-129.e2DOI: (10.1016/j.jaci.2015.11.037) Copyright © 2016 Terms and Conditions

Fig E2 αE-catenin protein expression and localization in the airway is not affected by loss of αT-catenin. Exposure-matched immunofluorescence images from WT (A) and αT-catenin KO (B) airways stained for αE-catenin (green; BD Biosciences clone 5 mAb; 610194). This antibody does not cross-react with αT-catenin (C.J.G., unpublished observations). High magnification (A′, A″, B′, and B″) shows no compensatory increase in αE-catenin protein levels in αT-catenin KO airway epithelial cell-cell junctions relative to WT. Because there is no evidence for αT-catenin expression in lung epithelia, compensatory upregulation of αE-catenin as a result of loss of αT-catenin appears restricted to cardiac cells, where both proteins are coexpressed (see Fig 4, C). Journal of Allergy and Clinical Immunology 2016 138, 123-129.e2DOI: (10.1016/j.jaci.2015.11.037) Copyright © 2016 Terms and Conditions