Lymphatic endothelial cells attenuate inflammation via suppression of dendritic cell maturation.
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.
Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, Zurich, Switzerland.
Ailsa J
AJ
Christiansen
Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, Zurich, Switzerland.
Lothar C
LC
Dieterich
Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, Zurich, Switzerland.
Isabel
I
Ohs
Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, Zurich, Switzerland.
Samia B
SB
Bachmann
Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, Zurich, Switzerland.
Roberta
R
Bianchi
Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, Zurich, Switzerland.
Steven T
ST
Proulx
Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, Zurich, Switzerland.
Maija
M
Hollmén
Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, Zurich, Switzerland.
David
D
Aebischer
Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, Zurich, Switzerland.
Michael
M
Detmar
D000818:Animals; D017951:Antigen Presentation; D001854:Bone Marrow Cells / Q000166:cytology; D039481:CD11b Antigen / Q000378:metabolism; D039521:CD11c Antigen / Q000378:metabolism; D002465:Cell Movement; D018932:Chemokine CCL2 / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology* / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D007108:Immune Tolerance; D007249:Inflammation; D016753:Interleukin-10 / Q000378:metabolism; D008198:Lymph Nodes / Q000378:metabolism* / Q000473:pathology; D042583:Lymphangiogenesis / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism*
D039481:CD11b Antigen; D039521:CD11c Antigen; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C; D016753:Interleukin-10
Immune response; Immunity; Immunology and Microbiology Section; VEGF-C; inflammation; lymphangiogenesis