IL-17A, But Not IL-17F, Is Indispensable for Airway Vascular Remodeling Induced by Exaggerated Th17 Cell Responses in Prolonged Ovalbumin-Challenged Mice

Abstract

We previously demonstrated an essential role of Th17 cells in excessive mucous secretion and airway smooth muscle proliferation in a prolonged OVA-challenged C57BL/6 mouse model. However, the impact of Th17 cells in vascular remodeling, another characteristic feature of airway remodeling in asthma, remains elusive. This issue was further investigated in this study. The time-course experiments showed that progressively increasing levels of Th17 cells and IL-17A (not IL-17F) in the lungs of prolonged allergen-challenged mice were positively correlated with microvessel density in peribronchial tissues. In addition, exaggerated airway vascular remodeling in this mouse model was exacerbated by airway administration of IL-17A or adoptive transfer of Th17 cells. This effect was dramatically alleviated by the administration of anti–IL-17A Ab, but not anti–IL-17F Ab. Boyden chamber assays indicated that IL-17A accelerates endothelial progenitor cell (EPC) migration. Furthermore, EPC accumulation in the airways of allergen-exposed mice after adoptive transfer of Th17 cells was eliminated by blockade of IL-17A. We found that IL-17A promoted tubule-like formation rather than proliferation of pulmonary microvascular endothelia cells (PMVECs) in vitro. In addition, IL-17A induced PMVEC tube formation via the PI3K/AKT1 pathway, and suppression of the PI3K pathway markedly reduced the formation of tubule-like structures. Collectively, our results indicate that Th17 cells 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.

IL-17A Contributes to the Pathogenesis of Endometriosis by Triggering Proinflammatory Cytokines and Angiogenic Growth Factors

“…To investigate whether IL-17A can induce direct tubulogenesis, HUVECs seeded on a coat of matrigel were treated with different concentrations of IL-17A in complete endothelial cell growth medium for 16 hours at 37°C prior to the analysis of tubulogenesis, unlike other methods where endothelial cells are serum starved prior to tubulogenesis assay (26). Our data showed that IL-17A induces tubulogenesis of HUVECs on matrigel in a dose dependent manner (Fig.…”

“…In literature, IL-17A is shown to promote direct endothelial cell tubulogenesis in vitro (26, 40). Here, we also show direct effect of IL-17A in promoting tubulogenesis of HUVECs.…”

“…Since then, IL-17A has been extensively linked to the pathogenesis of chronic inflammatory diseases including rheumatoid arthritis and psoriasis (25). In addition, IL-17A promotes vascular remodeling of the airways in the mouse model of asthma via the recruitment of endothelial progenitor cells to the allergen exposed airway (26). Furthermore, it confers tumor resistance to anti-VEGF therapy via induction and secretion of angiogenic and inflammatory factors such as Bv8 and IL-6 from tumor stromal cells (27).…”

The Biology of Eosinophils and Their Role in Asthma

“…In a mouse model of asthma, administration of IL-17A results in increased vascular remodelling; in vitro , IL-17A accelerates EPC migration (108). …”

The Surface-Associated Exopolysaccharide of Bifidobacterium longum 35624 Plays an Essential Role in Dampening Host Proinflammatory Responses and Repressing Local T H 17 Responses

“…sEPS neg exacerbates IL-17 responses within the lung. In order to further assess the ability of sEPS neg to promote IL-17 responses in vivo, we utilized the ovalbumin (OVA) sensitization and respiratory challenge model, as we and others previously evidenced potent T H 17 responses within the lungs of challenged animals (35). Either B. longum 35624 or its isogenic derivative sEPS neg was administered intranasally to examine the influence of these strains on IL-17 responses within the lung.…”