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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

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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 5

Pathological angiogenesis and airway inflammation blocked by KLF10-deficient or PAR-2–deficient bone marrow transplantation.

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Pathological angiogenesis and airway inflammation blocked by KLF10-defic...
(A) KLF10–/– or PAR-2–/– bone marrow transplantation in WT mice inhibited pathological angiogenesis in the HDM model. (B) Blood vessel density, but not lymphatic vessel density, was decreased in KLF10–/– or PAR-2–/– recipients. The number of vessels per 2,500 μm2 area is shown. Scale bar, 400 μm. (C) The number of mucus-producing cells (black arrows), (eosinophilic) inflammation (brown arrow), and IgE levels were significantly lower in KLF10–/– or PAR-2–/– bone marrow chimera. Scale bar, 100 μm. Lowercase a indicates airway. Mean ± SE values of 4 mice in each group are shown. ANOVA test was used in all panels.

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