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The Adherens Junction Protein, αTcatenin, Contributes to Airway Hyperreactivity Independently of Inflammation Via the Vagus
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A1436 - The Adherens Junction Protein, αTcatenin, Contributes to Airway Hyperreactivity Independently of Inflammation Via the Vagus
Author Block: C. J. Gottardi1, S. E. Chiarella2, A. Flozak3, E. E. Rabin1; 1Pulmonary Medicine, Northwestern Univ Medical Sch, Chicago, IL, United States, 2Allergy and Immunology, Northwestern Univ, Chicago, IL, United States, 3Pulmonary Medicine, Northwestern University, Chicago, IL, United States.
Rationale: Recent genome-wide association studies have identified polymorphisms in the protein αT-catenin (αTcat; CTNNA3) that correlate with both occupational and steroid-resistant atopic asthma. α-Catenins are important mediators of cell-cell adhesion, but αTcat expression is largely restricted to cardiomyocytes of the heart, myoid cells of the testis, as well as brain and peripheral nerve, suggesting that a non-canonical cell type may contribute to the development of asthma.
Objective: To define the cell type and molecular means through which αT-cat promotes asthma.
Methods: We utilized αTcat knockout mice and a house dust-mite extract (HDM) model of atopic asthma, with assessment by forced oscillation, bronchoalveolar lavage and histologic analysis. Standard microscopy and immunodetection techniques allowed us to assess αTcat expression. RNA-sequencing of WT versus KO tissues revealed candidate molecular pathway differences.
Results: We found that the full genetic loss of αTcat robustly ablated HDM-induced airway hyperresponsiveness to methacholine and goblet cell metaplasia assessed by PAS staining. Remarkably, lung inflammation was not consistently reduced in HDM-treated αTcat KO mice, suggesting that αTcat contributes to airway responsiveness independently of altering inflammation. αTcat is abundantly expressed in the vagus, likely within the Remak Schwann cell component. αTcat KO tissue showed upregulation of the GABA-Receptor-α2.
Conclusion: These data suggest that αTcat expression in Remak Schwann cell-junctions of the vagus may contribute to airway hyperresponsiveness, possibly through regulation of GABAergic signaling at the vagus/smooth muscle contact. Evidence that αTcat is linked to both occupational and steroid resistant asthma suggests that a common genetic player can underlie
both forms of asthma, where neuromodulatory approaches might be particularly helpful in these patients.
Author Block: C. J. Gottardi1, S. E. Chiarella2, A. Flozak3, E. E. Rabin1; 1Pulmonary Medicine, Northwestern Univ Medical Sch, Chicago, IL, United States, 2Allergy and Immunology, Northwestern Univ, Chicago, IL, United States, 3Pulmonary Medicine, Northwestern University, Chicago, IL, United States.
Rationale: Recent genome-wide association studies have identified polymorphisms in the protein αT-catenin (αTcat; CTNNA3) that correlate with both occupational and steroid-resistant atopic asthma. α-Catenins are important mediators of cell-cell adhesion, but αTcat expression is largely restricted to cardiomyocytes of the heart, myoid cells of the testis, as well as brain and peripheral nerve, suggesting that a non-canonical cell type may contribute to the development of asthma.
Objective: To define the cell type and molecular means through which αT-cat promotes asthma.
Methods: We utilized αTcat knockout mice and a house dust-mite extract (HDM) model of atopic asthma, with assessment by forced oscillation, bronchoalveolar lavage and histologic analysis. Standard microscopy and immunodetection techniques allowed us to assess αTcat expression. RNA-sequencing of WT versus KO tissues revealed candidate molecular pathway differences.
Results: We found that the full genetic loss of αTcat robustly ablated HDM-induced airway hyperresponsiveness to methacholine and goblet cell metaplasia assessed by PAS staining. Remarkably, lung inflammation was not consistently reduced in HDM-treated αTcat KO mice, suggesting that αTcat contributes to airway responsiveness independently of altering inflammation. αTcat is abundantly expressed in the vagus, likely within the Remak Schwann cell component. αTcat KO tissue showed upregulation of the GABA-Receptor-α2.
Conclusion: These data suggest that αTcat expression in Remak Schwann cell-junctions of the vagus may contribute to airway hyperresponsiveness, possibly through regulation of GABAergic signaling at the vagus/smooth muscle contact. Evidence that αTcat is linked to both occupational and steroid resistant asthma suggests that a common genetic player can underlie
both forms of asthma, where neuromodulatory approaches might be particularly helpful in these patients.
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