N-cadherin antagonism is bronchoprotective in severe asthma models
Severe asthma induces substantial mortality and chronic disability due to intractable airway obstruction, which may become resistant to currently available therapies including corticosteroids and β-adrenergic agonist bronchodilators. A key effector of these changes is exaggerated airway smooth muscle (ASM) cell contraction to spasmogens. No drugs in clinical use effectively prevent ASM hyperresponsiveness in asthma across all severities. We find that N-cadherin, a membrane cell-cell adhesion protein up-regulated in ASM from patients with severe asthma, is required for the development of airway obstruction induced by allergic airway inflammation in mice. Inhibition of N-cadherin by ADH-1 reduced airway hyperresponsiveness independent of allergic inflammation, prevented bronchoconstriction, and actively promoted bronchodilation of airways ex vivo. ADH-1 inhibited ASM contraction by disrupting N-cadherin-δ-catenin interactions, which decreased intracellular actin remodeling. These data provide evidence for an intercellular communication pathway mediating ASM contraction and identify N-cadherin as a potential therapeutic target for inhibiting bronchoconstriction in asthma.
Authors
- Erika T. Lin (ORCID: https://orcid.org/0000-0001-9775-0868)
- Kirk M. Druey (ORCID: https://orcid.org/0000-0002-5834-6501)
- Ramaswamy Krishnan (ORCID: https://orcid.org/0000-0003-4994-0709)
- Nicolas L. Pereira (ORCID: https://orcid.org/0000-0003-3654-4029)
- Sangita Choudhury (ORCID: https://orcid.org/0000-0001-7357-1988)
- Zheming An (ORCID: https://orcid.org/0000-0002-6325-1494)
- Nariman Balenga (ORCID: https://orcid.org/0000-0002-2741-9595)
- Eric Gebski (ORCID: https://orcid.org/0009-0007-2748-5975)
- Sundar Ganesan (ORCID: https://orcid.org/0000-0003-1132-2016)
- Abhishek Desai (ORCID: https://orcid.org/0000-0002-6770-4876)
- William F. Jester (ORCID: https://orcid.org/0000-0002-2872-6095)
- Niccole Schaible (ORCID: https://orcid.org/0000-0002-4765-5966)
- Cynthia Koziol‐White (ORCID: https://orcid.org/0000-0003-1101-2747)
- Ararat J. Ablooglu (ORCID: https://orcid.org/0009-0002-8692-4572)
- Reynold A. Panettieri (ORCID: https://orcid.org/0000-0003-0834-4636)
- Jacqueline Capuano
- Eunice C. Chan (ORCID: https://orcid.org/0000-0003-0599-5898)
Institutions
- Rutgers, The State University of New Jersey (US)
- Boston Children's Hospital (US)
- National Institutes of Health (US)
- Beth Israel Deaconess Medical Center (US)
- National Institute of Allergy and Infectious Diseases (US)
- Center for Vascular Biology Research (US)
Publication Details
- Journal
- Science Advances
- Published
- 2024-11-29
- DOI
- https://doi.org/10.1126/sciadv.adp8872
- Citations
- 2
- Primary Topic
- Wnt/β-catenin signaling in development and cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.47