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
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 128 Issue 7 Pg. 3116-3128 (07 02 2018) ISSN: 1558-8238 [Electronic] United States
• PMID: 29911993 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Allergens
• Cytokines
• Early Growth Response Transcription Factors
• F2rl1 protein, mouse
• KLF10 protein, mouse
• Kruppel-Like Transcription Factors
• Receptor, PAR-2
• Vascular Endothelial Growth Factor Receptor-3

Topics

• Airway Remodeling (immunology)
• Allergens (administration & dosage, immunology)
• Animals
• Asthma (etiology, immunology)
• Cytokines (biosynthesis)
• Disease Models, Animal
• Early Growth Response Transcription Factors (immunology)
• Endothelial Cells (immunology, ultrastructure)
• Female
• Hematopoietic Stem Cells (immunology, pathology)
• Humans
• Hypersensitivity, Immediate (etiology, immunology, pathology)
• Immunity, Innate
• Kruppel-Like Transcription Factors (immunology)
• Lung (immunology, ultrastructure)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Knockout
• Microscopy, Electron, Transmission
• Neovascularization, Pathologic
• Pyroglyphidae (immunology)
• Receptor, PAR-2 (deficiency, genetics, immunology)
• Th2 Cells (immunology)
• Vascular Endothelial Growth Factor Receptor-3 (antagonists & inhibitors)