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 3

Early life allergen exposure leads to immune-cell recruitment and MC activation in the lung adventitia.

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Early life allergen exposure leads to immune-cell recruitment and MC act...
(A) 3D rendering of a PCLS in the lung adventitia in PBS- and HDM-exposed mice at P28 showing CD31 (green, endothelial cells), α-SMA (blue, SMCs), and CD45 (magenta, leukocytes). Scale bars: 200 μm. Representative of 4 independent experiments. (B) CD45+ cell number. n = 3–8 mice per group from 4 independent experiments. (C) Representative 3D image of lung adventitia showing the distribution of CTMCs (avidin, blue) around a large airway and associated vasculature (CD31, green) and images showing degranulated MCs adjacent to large airways and blood vessels (see Supplemental Video 3). Scale bars: 150 μm (left); 50 μm (right). Representative of 4 independent experiments. (D) Number of degranulated MCs. n = 3–6 mice per group. (E and F) Number of extracellular CTMC granules per mm3 (E) and volume (F). n = 3–6 mice per group from 3 independent experiments. (G) Correlation between vascular-associated HIF-1α+ and number of degranulated CTMC granules. n = 23 images from 4 PBS- and 4 HDM-treated mice. (H) Correlation between pericyte coverage and volume of extracellular CTMC granules. n = 39 images from 4 PBS- and 4 HDM-treated mice. Data are represented as means ± SEM. *P < 0.05; **P < 0.01;***P < 0.001, 2-way ANOVA followed by Šidák’s post hoc test (B, D, and E); Spearman’s rank correlation test (G and H).