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House Dust Mite-Derived Protease Allergen Sensing by Lung Endothelial and Proangiogenic Cells Induces Asthma
Description
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A5955 - House Dust Mite-Derived Protease Allergen Sensing by Lung Endothelial and Proangiogenic Cells Induces Asthma
Author Block: K. Asosingh1, K. Queisser1, N. Wanner1, M. Jin2, M. A. Aronica3, S. C. Erzurum4; 1Pathobiology, Cleveland Clinic, Cleveland, OH, United States, 2Imaging Core, Cleveland Clinic, Cleveland, OH, United States, 3Lerner Research Inst, Cleveland, OH, United States, 4Cleveland Clinic Foundation, Cleveland, OH, United States.
Introduction
Airway epithelial and dendritic cells are well-established cells sensing allergens at the surface of the airway epithelium via protease-activated receptors (PPRs). Protease-activated receptor-2 (PAR-2) is an airway epithelial PPR that induces TH2-promoting cytokines GM-CSF, IL-1α and has an established role in house dust mite (HDM) induced-asthma. Here we hypothesize that PAR-2 is expressed by airway mucosal endothelial and proangiogenic hematopoietic cell (PAC) and binding of HDM-derived protease allergens to these cells contribute to the genesis of allergic asthma.
Method
Disruption of lung endothelial barrier by HDM extract (HDME) was analyzed by transmission electron microscopy. Flow cytometry was performed to evaluate PAR-2 expression on lung endothelial cells and PAC. HDME induced secretion of GM-CSF, IL-1α, and VEGF-C by endothelial cells and PAC were quantified using ELISA. Ex-vivo tube formation assays were utilized the study the HDME induced angiogenesis. VEGF-C receptor (VEGFR3) inhibition, PAC depletion, and PAR-2 deficient bone marrow transplantation were performed in a standard mouse HDM model of asthma. Adoptive transfer of HDME exposed PAC into allergen sensitized mice were performed.
Results
HDME protease allergens penetrated deep into the airway mucosa and breached the endothelial barrier. Lung endothelial cells and PAC expressed high levels of PAR-2. Exposure of lung endothelial cells and PAC to HDME resulted in the release of IL-1α and GM-CSF, and VEGF-C-dependent new blood vessel formation. Blunting the PAR-2-driven angiogenic response by PAR-2 deficient bone marrow, blocking of PAC or inhibition of VEGF-C signaling in the mouse HDM-model of asthma significantly reduced airway inflammation and remodeling. Induction of a TH2-promoting vascular response by adoptive transfer of HDME exposed PAC caused airway inflammation, remodeling, and airway hyperreactivity, without airway epithelial allergen challenge.
Conclusion
The findings suggest that in addition to the airway epithelium, lung endothelium and PAC in the airway mucosa are also able to sense HDM-derived protease allergens and elicit an innate TH2-promoting angiogenic response that contributes to HDM-induced asthma.
Author Block: K. Asosingh1, K. Queisser1, N. Wanner1, M. Jin2, M. A. Aronica3, S. C. Erzurum4; 1Pathobiology, Cleveland Clinic, Cleveland, OH, United States, 2Imaging Core, Cleveland Clinic, Cleveland, OH, United States, 3Lerner Research Inst, Cleveland, OH, United States, 4Cleveland Clinic Foundation, Cleveland, OH, United States.
Introduction
Airway epithelial and dendritic cells are well-established cells sensing allergens at the surface of the airway epithelium via protease-activated receptors (PPRs). Protease-activated receptor-2 (PAR-2) is an airway epithelial PPR that induces TH2-promoting cytokines GM-CSF, IL-1α and has an established role in house dust mite (HDM) induced-asthma. Here we hypothesize that PAR-2 is expressed by airway mucosal endothelial and proangiogenic hematopoietic cell (PAC) and binding of HDM-derived protease allergens to these cells contribute to the genesis of allergic asthma.
Method
Disruption of lung endothelial barrier by HDM extract (HDME) was analyzed by transmission electron microscopy. Flow cytometry was performed to evaluate PAR-2 expression on lung endothelial cells and PAC. HDME induced secretion of GM-CSF, IL-1α, and VEGF-C by endothelial cells and PAC were quantified using ELISA. Ex-vivo tube formation assays were utilized the study the HDME induced angiogenesis. VEGF-C receptor (VEGFR3) inhibition, PAC depletion, and PAR-2 deficient bone marrow transplantation were performed in a standard mouse HDM model of asthma. Adoptive transfer of HDME exposed PAC into allergen sensitized mice were performed.
Results
HDME protease allergens penetrated deep into the airway mucosa and breached the endothelial barrier. Lung endothelial cells and PAC expressed high levels of PAR-2. Exposure of lung endothelial cells and PAC to HDME resulted in the release of IL-1α and GM-CSF, and VEGF-C-dependent new blood vessel formation. Blunting the PAR-2-driven angiogenic response by PAR-2 deficient bone marrow, blocking of PAC or inhibition of VEGF-C signaling in the mouse HDM-model of asthma significantly reduced airway inflammation and remodeling. Induction of a TH2-promoting vascular response by adoptive transfer of HDME exposed PAC caused airway inflammation, remodeling, and airway hyperreactivity, without airway epithelial allergen challenge.
Conclusion
The findings suggest that in addition to the airway epithelium, lung endothelium and PAC in the airway mucosa are also able to sense HDM-derived protease allergens and elicit an innate TH2-promoting angiogenic response that contributes to HDM-induced asthma.
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