Adventitial Mast Cell Activation Disrupts Endothelial Cell/Pericyte Interactions  During Early Life Allergic Asthma

Allergic asthma generally starts during early life and is linked to significant tissue remodelling and lung dysfunction. Although angiogenesis is a feature of the disrupted airway, the impact of allergic asthma on the pulmonary microcirculation during early life is unknown. Here, using quantitative imaging in precision-cut lung slices (PCLS), we report that exposure of neonatal mice to house dust mite (HDM) extract disrupts endothelial cell/pericyte interactions in adventitial areas. Central to the blood vessel structure, the loss of pericyte coverage was driven by mast cell (MCs) proteases, such as tryptase, that can induce pericyte retraction and loss of the critical adhesion molecule N-Cadherin. Furthermore, spatial transcriptomics of paediatric asthmatic endobronchial biopsies revealed intense remodelling associated with increased expression of MC proteases in regions enriched in blood vessels. These data provide previously unappreciated insights into the pathophysiology of allergic asthma with potential long-term vascular defects.

Note:
Funding Information: This work was supported by funds from the Wellcome Trust (107059/Z/15/Z and 220254/Z/20/Z) to C.M.L. R.J. is supported by fellowships from the British Heart Foundation Imperial College Centre for Research Excellence (RE/18/4/34215).

Declaration of Interests: The authors declare no competing interests. L.J.E. is now an employee of GSK however GSK did not contribute to any of the work in this study.

Ethics Approval Statement: The study was approved by the institutional ethics committee, and written, informed parental consent and child assent were obtained. The human ethic had been approved by the research ethics committees: Wales REC3 (17/WA/0161), 17/LO/0013 and 15/SC/0101. Animal ethics had been approved by the UK home Office ( PPL P996A24E1 and PP8328343).

MISSING - animal ethics

Keywords: early life, lung, allergic asthma, vasculature, pericyte, mast cell, protease, imaging

Suggested Citation: Suggested Citation

Joulia, Régis and Puttur, Franz and Stölting, Helen and Entwistle, Lewis J. and Voitovich, Anna and Al-Sahaf, May and Bonner, Katie and Scotney, Elizabeth and Molyneaux, Philip and Hewitt, Richard J. and Walker, Simone A. and Yates, Laura and Saglani, Sejal and Lloyd, Clare, Adventitial Mast Cell Activation Disrupts Endothelial Cell/Pericyte Interactions During Early Life Allergic Asthma. Available at SSRN: https://ssrn.com/abstract=4389971 or http://dx.doi.org/10.2139/ssrn.4389971

This version of the paper has not been formally peer reviewed.