IL-17A negatively regulates lymphatic vessel formation

Abstract

Lymphatic vessels (LVs), well-known conduits of immune cells, enable antigen presenting cells (APCs) to enter draining lymph node resulting in the induction of adaptive immune responses against various antigens. During inflammation, LVs are increased and enlarged by the effect of pro-lymphangiogenic factors including vascular endothelial growth factor -A, C, and D secreted by APCs and stromal cells, and facilitate the migration of activated immune cells. However, after antigen clearance, these expanded LVs should be shrunk similar to apoptotic cell death of activated immune cells to maintain homeostasis. It is known that, failure of inflammation resolution causes chronic inflammation in many diseases. Chronic inflammation often accompanies increased LVs which enable continuous antigen delivery and immune cell trafficking from infection sites to draining lymph node. Previously, it was discovered that several cytokines secreted by type 1 and 2 helper T (Th) cells inhibit lymphangiogenesis during resolution phase but less is known about the effect of Th17 cytokines. Here, we show that interleukin-17A (IL-17A) secreted from Th17 cells is a putative negative regulator of lymphangiogenesis in Th17-mediated immune responses, especially during resolution phase. IL-17A suppressed gene expression of lymphatic specific markers in lymphatic endothelial cells. Also, we utilized cholera toxin mixed with chicken egg ovalbumin peptide (CTO) challenge model which induces Th17 dominant inflammation to examine the in vivo effect of IL-17A. Blockade of IL-17A increased LVs and enhanced their function. Thus, this study will provide expanded knowledge on unidentified role of IL-17A as a negative regulator of lymphangiogenesis.