1. Lymphatic endothelial cells attenuate inflammation via suppression of dendritic cell maturation.
- Author
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Christiansen AJ, Dieterich LC, Ohs I, Bachmann SB, Bianchi R, Proulx ST, Hollmén M, Aebischer D, and Detmar M
- Subjects
- Animals, Antigen Presentation, Bone Marrow Cells cytology, CD11b Antigen metabolism, CD11c Antigen metabolism, Cell Movement, Chemokine CCL2 metabolism, Dendritic Cells metabolism, Flow Cytometry, Humans, Immune Tolerance, Inflammation, Interleukin-10 metabolism, Lymph Nodes pathology, Lymphangiogenesis drug effects, Mice, Mice, Transgenic, Phenotype, Vascular Endothelial Growth Factor A metabolism, Dendritic Cells cytology, Endothelial Cells metabolism, Lymph Nodes metabolism, Vascular Endothelial Growth Factor C metabolism
- 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., Competing Interests: The authors declare no conflicts of interest.
- Published
- 2016
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