Proangiogenic Hematopoietic Progenitor-Derived Eotaxins Promote Pathological Angiogenesis and Airway Inflammation in Asthma

Emerging evidence shows a critical role for pathological angiogenesis in asthma. Eosinophils are key effector cells in severe asthma and are recruited into the airways by a family of eosinophil specific chemoattractants called eotaxins. Eotaxins are expressed by structural cells of the lungs including endothelial cells, smooth muscles cells and airway epithelial cells, and by hematopoietic cells. We recently demonstrated that proangiogenic hematopoietic progenitors in the OVA mouse model of allergic airway inflammation express high levels of eotaxin-1 which is released upon contact with endothelial cells in allergen exposed lung resulting in migration of eosinophils from the blood circulation into the lung tissue. However, the contribution of bone marrow-derived eotaxins to airway inflammation and angiogenesis relative to eotaxins secreted by structural cells of the lungs remains unknown. Here we used bone marrow transplantation and adoptive proangiogenic hematopoietic progenitor cell transfer in eotaxin-1/-2 double knockout (KO) mouse to address this question. Wild type (WT) mice transplanted with eotaxin deficient, but not WT, bone marrow had significantly reduced eosinophilic airway inflammation. Adoptive transfer of proangiogenic progenitors from WT asthmatic mice, but not naive mice, into eotaxin1/2 knockout mice induced angiogenesis and eosinophilic allergic lung disease. Lung endothelial cells in asthma exhibited up-regulated expression of eotaxin receptor CCR3 and ex-vivo stimulation of endothelial cells with eotaxins induced migration and angiogenic sprouting. Bone marrow engraftment of eGFP proangiogenic progenitors showed differentiation into all hematopoietic lineages, demonstrating that the eotaxin-expressing cells were multipotent hematopoietic progenitors. Eotaxin expression by these progenitors was induced via Th2-dependent mechanism. The data reveal that Th2-polarized hematopoietic progenitor cell-derived eotaxins have a critical dual role in asthma by promoting airway eosinophilia and pathological angiogenesis.