Endothelial cells in the innate response to allergens and initiation of atopic asthma
Kewal Asosingh, … , Mark Aronica, Serpil Erzurum
Kewal Asosingh, … , Mark Aronica, Serpil Erzurum
Published June 18, 2018
Citation Information: J Clin Invest. 2018;128(7):3116-3128. https://doi.org/10.1172/JCI97720.
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Research Article Angiogenesis Pulmonology

Endothelial cells in the innate response to allergens and initiation of atopic asthma

Abstract

Protease-activated receptor 2 (PAR-2), an airway epithelial pattern recognition receptor (PRR), participates in the genesis of house dust mite–induced (HDM-induced) asthma. Here, we hypothesized that lung endothelial cells and proangiogenic hematopoietic progenitor cells (PACs) that express high levels of PAR-2 contribute to the initiation of atopic asthma. HDM extract (HDME) protease allergens were found deep in the airway mucosa and breaching the endothelial barrier. Lung endothelial cells and PACs released the Th2-promoting cytokines IL-1α and GM-CSF in response to HDME, and the endothelium had PAC-derived VEGF-C–dependent blood vessel sprouting. Blockade of the angiogenic response by inhibition of VEGF-C signaling lessened the development of inflammation and airway remodeling in the HDM model. Reconstitution of the bone marrow in WT mice with PAR-2–deficient bone marrow also reduced airway inflammation and remodeling. Adoptive transfer of PACs that had been exposed to HDME induced angiogenesis and Th2 inflammation with remodeling similar to that induced by allergen challenge. Our findings identify that lung endothelium and PACs in the airway sense allergen and elicit an angiogenic response that is central to the innate nonimmune origins of Th2 inflammation.

Authors

Kewal Asosingh, Kelly Weiss, Kimberly Queisser, Nicholas Wanner, Mei Yin, Mark Aronica, Serpil Erzurum

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Figure 4

Inhibition of pathological angiogenesis by VEGFR3 kinase inhibitor reduced airway inflammation, remodeling, and hyperreactivity.

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Inhibition of pathological angiogenesis by VEGFR3 kinase inhibitor reduc...
(A) Flow cytometric analysis of VEGFR3 expression among hematopoietic (CD45+) and nonhematopoietic (CD45–) lung cells. Immunohistochemical analysis of VEGFR3 expression on blood vessel endothelial cells (vessels with red blood cells) showed that VEGFR3 expression is upregulated on blood vessel endothelial cells in the HDM model. Scale bar, 200 μm. Original magnification for inset is ×400. (B) Treatment with VEGFR3 kinase inhibitor MAZ51 decreased angiogenesis (vWF+ blood vessel) density, but not lymphangiogenesis (LYVE-1+ vessels). Data are mean ± SE values of 4–5 mice in each group. The number of vessels per 2,500 μm2 area is shown. Scale bar, 400 μm. (C) Treatment with VEGFR3 kinase inhibitor MAZ51 tended to reduce the number of total blood vessel endothelial cells. (D) The number of PAR-2+ blood vessel endothelial cells was significantly lower in asthmatic mice treated with MAZ51. (E) The recruitment of PACs into the lungs was reduced by MAZ51. (F) The number of mucus-producing cells (black arrows) and (eosinophilic) inflammation (brown arrows) were significantly lower in mice treated with MAZ51. Scale bar, 100 μm. (G) Th2 cytokines and airway hyperreactivity were reduced in animals treated with MAZ51. Mean ± SE values of 4–5 mice in each group are shown. Two-tailed Student’s t test was used in A and G. ANOVA test was used in B, C, and F. A linear regression model was used to compare lung resistance in G. The interaction between group and methacholine dose in the linear mixed effects model for log-transformed values demonstrates that there are differing slopes describing the relationships between methacholine and Rrs for the DMSO and MAZ51 groups (P = 0.047). The estimated slope was 0.039 (95% CI 0.026–0.053) for DMSO and 0.023 (95% CI 0.010–0.037) for MAZ51, indicating a greater change in Rrs in response to methacholine for the DMSO group. In A, B, and F, a indicates airway.