IL-17 Contributes to Angiogenesis in Rheumatoid Arthritis

Abstract

Angiogenesis is an early and a critical event in the pathogenesis of rheumatoid arthritis (RA). Neovascularization is dependent on endothelial cell activation, migration and proliferation, and inhibition of angiogenesis may provide a novel therapeutic approach in RA. In this study, we document a novel role of IL-17 in mediating angiogenesis. Local expression of IL-17 in mouse ankles increases vascularity. We further demonstrate that IL-17 is angiogenic by showing its ability to promote blood vessel growth in Matrigel plugs in vivo. Additionally, IL-17, in concentrations present in the RA joint, induces human lung microvascular endothelial cell (HMVEC) migration mediated through the PI3K/AKT1 pathway. Furthermore, suppression of the PI3K pathway markedly reduces IL-17–induced tube formation. We also show that both IL-17–induced HMVEC chemotaxis and tube formation are mediated primarily through IL-17 receptor C. Neutralization of either IL-17 in RA synovial fluids or IL-17 receptor C on HMVECs significantly reduces the induction of HMVEC migration by RA synovial fluid. Finally, RA synovial fluid immunoneutralized with anti–IL-17 and antivascular endothelial growth factor does not reduce HMVEC migration beyond the effect detected by immunodepleting each factor alone. These observations identify a novel function for IL-17 as an angiogenic mediator in RA, supporting IL-17 as a therapeutic target in RA.

A Heterodimeric Cytokine, Consisting of IL-17A and IL-17F, Promotes Migration and Capillary-Like Tube Formation of Human Vascular Endothelial Cells

“…Therefore, IL-17A/F uses PI3K signaling pathway to stimulate the migration of vascular endothelial cells, as is the same as IL-17A (Pickens et al 2010). Similar finding has been reported that the PI3K signaling plays an important role in VEGF-A-mediated migration of endothelial cells (Hayashi et al 2009).…”

“…express IL-17RA and IL-17RC on the cell surface (Moseley et al 2003;Pickens et al 2010;Fujie et al 2012). Thus, we examined the biological effects of IL-17A/F on in vitro angiogenesis-related functions of HMVECs.…”

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

“…IL-17A and IL-17F, which are the main members of the IL-17 family, have the greatest homology (20) and share the same receptor and regulatory elements (21). IL-17A and IL-17F have been reported to be involved in vascular regeneration in some diseases (11,12,16,(22)(23)(24). In our study, we found that neutralization of IL-17A led to reduced vascularity in the lung of OVA-challenged mice, whereas IL-17F antagonism did not markedly influence the microvascular regeneration.…”

“…The total perimeter of completely enclosed tubes in one field was calculated by Image-Pro Plus5.1, and the average of the total perimeter measurements was used for quantification. In addition, node formation (defined as a nodular contact formation of at least three adherent endothelial cell tubes) in five randomly selected microscopic fields (3100 magnification) was evaluated blindly (11,15).…”

“…IL-17A induces endothelial migration and tube formation in rheumatoid arthritis through activation of the PI3K pathway and ligation of both IL-17Rs (11). IL-17F levels show a statistically significant correlation with the number of activated circulating endothelial cells and disease activity in systemic lupus erythematosus patients, suggesting a role in activating vascular endothelial cells and consequent blood vessel formation (12).…”