Lymphatic endothelial cells attenuate inflammation via suppression of dendritic cell maturation

// Ailsa J. Christiansen 1 , Lothar C. Dieterich 1 , Isabel Ohs 1 , Samia B. Bachmann 1 , Roberta Bianchi 1 , Steven T. Proulx 1 , Maija Hollmén 1 , David Aebischer 1 and Michael Detmar 1 1 Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, Zurich, Switzerland Correspondence to: Michael Detmar, email: // Keywords : inflammation, lymphangiogenesis, VEGF-C, Immunology and Microbiology Section, Immune response, Immunity Received : November 10, 2015 Accepted : May 25, 2016 Published : June 05, 2016 Abstract Vascular endothelial growth factor-C (VEGF-C)-induced lymphangiogenesis and increased tissue drainage have been reported to inhibit acute and chronic inflammation, and an activated lymphatic endothelium might mediate peripheral tolerance. Using transgenic mice overexpressing VEGF-C in the skin, we found that under inflammatory conditions, VEGF-C-mediated expansion of the cutaneous lymphatic network establishes an immune-inhibitory microenvironment characterised by increased regulatory T (Treg) cells, immature CD11c+CD11b+ dendritic cells (DCs) and CD8+ cells exhibiting decreased effector function. Strikingly, lymphatic endothelial cell (LEC)-conditioned media (CM) potently suppress DC maturation with reduced expression of MHCII, CD40, and IL-6, and increased IL-10 and CCL2 expression. We identify an imbalance in prostaglandin synthase expression after LEC activation, favoring anti-inflammatory prostacyclin synthesis. Importantly, blockade of LEC prostaglandin synthesis partially restores DC maturity. LECs also produce TGF-ß1, contributing to the immune-inhibitory microenvironment. This study identifies novel mechanisms by which the lymphatic endothelium modulates cellular immune responses to limit inflammation.