IL-17A negatively regulates lymphangiogenesis In Th17 cell-mediated inflammation

Abstract

During inflammation lymphatic vessels (LVs) are enlarged and their density is increased through the effects of pro-lymphangiogenic factors including vascular endothelial growth factors, which facilitate the migration of activated immune cells and antigens. After antigen clearance the expanded LVs shrink and activated immune cells undergo apoptotic cell death to maintain homeostasis. Several cytokines secreted from T helper type 1 (Th1) and Th2 cells have been discovered to have anti-lymphangiogenic roles in inflammatory conditions. However, less is known about the effects of cytokines from Th17 cells. Here, we show that interleukin (IL)-17A, secreted from Th17 cells, is a negative regulator of lymphangiogenesis in Th17-mediated immune responses, especially during the resolution phase of inflammation. Moreover, IL-17A suppresses expression of major lymphatic markers in lymphatic endothelial cells and decreases in vitro LV formation. To investigate the role of IL-17A in vivo, we utilized a cholera toxin-mediated Th17 inflammation model and identified inflammation and resolution phases based on the numbers of recruited immune cells. IL-17A, markedly produced by Th17 cells even after the peak of inflammation, was found to participate in the negative regulation of LV formation. Moreover, blockade of IL-17A resulted in not only increased density of LVs in tissues, but also their enhanced function. Taken together, these findings improve the current understanding of the relationship between LVs and inflammatory cytokines in pathologic conditions.