Mast cell activation disrupts interactions between endothelial cells and pericytes during early life allergic asthma
Régis Joulia, … , Sejal Saglani, Clare M. Lloyd
Régis Joulia, … , Sejal Saglani, Clare M. Lloyd
Published March 15, 2024
Citation Information: J Clin Invest. 2024;134(6):e173676. https://doi.org/10.1172/JCI173676.
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Research Article Inflammation Vascular biology Article has an altmetric score of 28

Mast cell activation disrupts interactions between endothelial cells and pericytes during early life allergic asthma

Abstract

Allergic asthma generally starts during early life and is linked to substantial tissue remodeling 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 (PCLSs), 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 (MC) proteases, such as tryptase, that can induce pericyte retraction and loss of the critical adhesion molecule N-cadherin. Furthermore, spatial transcriptomics of pediatric asthmatic endobronchial biopsies suggests intense vascular stress and remodeling linked with increased expression of MC activation pathways in regions enriched in blood vessels. These data provide previously unappreciated insights into the pathophysiology of allergic asthma with potential long-term vascular defects.

Authors

Régis Joulia, Franz Puttur, Helen Stölting, William J. Traves, Lewis J. Entwistle, Anastasia Voitovich, Minerva Garcia Martín, May Al-Sahaf, Katie Bonner, Elizabeth Scotney, Philip L. Molyneaux, Richard J. Hewitt, Simone A. Walker, Laura Yates, Sejal Saglani, Clare M. Lloyd

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Figure 5

MC-derived proteases induce pericyte retraction and N-cadherin cleavage.

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MC-derived proteases induce pericyte retraction and N-cadherin cleavage....
(A and B) Neonate mice were exposed to HDM for 3 weeks. (A) 3D rendering of a PCLS section in the lung adventitia in HDM-exposed mice showing DAPI (blue), m-MCP6 (mouse tryptase, magenta), and MCs (avidin, green); lower panels show zoomed-in images of the white box region and the m-MCP6 signal in extracellular MC granules. Scale bars: 30 μm (upper panel); 10 μm (lower panels). (B) Colocalization analyses between intracellular and extracellular MC granules (avidin+) and m-MCP6 showing frequency of m-MCP6+ granules. Each dot represents an image from 3 independent mice. (C–F) MCs were sensitized overnight with anti-DNP IgE, then placed on a layer of pericytes (stained with CMTMR) and stimulated with increasing concentrations of DNP-BSA for 24 hours in the presence of a protease inhibitor cocktail or vehicle control (DMSO). (C) Images of unstimulated or stimulated (100 ng/ml DNP-BSA) pericyte/MC cocultures stained for DAPI (yellow), F-actin (green), and MC granules (avidin, magenta). Scale bars: 50 μm. Representative of 3 independent experiments. (D) Number of degranulated MCs normalized to the total number of MCs. Each dot represents an image from 3 independent experiments. (E) Pericyte volume and (F) cell-surface N-cadherin MFI on pericytes. Each dot represents an individual pericyte from 3 independent experiments. (G) Lung pericyte volume 24 hours following recombinant m-MCP6 exposure. Each dot represents an individual pericyte from 3 independent donors. Data are represented as means ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001, 2-tailed Student’s t test (B); 1-way ANOVA followed by Tukey’s post hoc test (D, E, F, and G).