IL-17A,But Not IL-17F,Is Indispensable For Airway Vascular Remodeling Induced By Exaggerated Th17Cell Responses In Prolonges Ovalbumin-challenged Mice

Accumulating evidence has indicated that Th17cells and the cytokines they produce play a key role in the development of asthma. We previously demonstrated an essential role of Th17cells in excessive mucus secretion and airway smooth muscle proliferation in a prolonged ovalbumin (OVA)-challenged C57BL/6mouse model. However, the impact of Th17cells in vascular remodeling, another characteristic feature of airway remodeling in asthma, remains elusive.In this study, we established acute and prolonged allergen challenged mouse models following monoclonal antibody treatment, airway instillation of IL-17A, adoptive transfer of Thl7cells and endothelial progenitor cells (EPCs), tube formation of pulmonary microvascular endothelial cells (PMVECs) and transwell migration assay of EPCs to explore the role of Thl7and its associated cytokine in asthmatic airway vascular remodeling. The density of pulmonary microvasculature increased progressively with prolonged allergen challenge together with the level of airway-infiltrating Thl7cells in the lung. Exaggerated airway vascular remodeling in this mouse model was exacerbated by airway administration of IL-17A or adoptive transfer of Thl7cells. This effect was dramatically ameliorated by the administration of ianti-IL-17A antibody, but not anti-IL-17F antibody. IL-17A is not involved in the mobilization of EPCs from the bone marrow into the circulation in asthmatic mouse model. However, Boyden chamber assays indicated that IL-17A accelerates EPCs migration. Furthermore, EPC accumulation in the airways of allergen-exposed mice following adoptive transfer of Th17cells was eliminated by blockade of IL-17A. IL-17A promoted tubule-like formation rather than proliferation of PMVECs in vitro. Additionally, IL-17A induced PMVEC tube formation via the PI3K/AKT1pathway and suppression of the PI3K pathway markedly reduced the formation of tubule-like structures. These observations indicated that Th17cells contribute to the airway vascular remodeling in asthma by mediating EPC chemotaxis as well as PMVEC tube formation via IL-17A rather than IL-17F.