Oncotarget

Research Papers: Immunology:

Lymphatic endothelial cells attenuate inflammation via suppression of dendritic cell maturation

Ailsa J. Christiansen _, Lothar C. Dieterich, Isabel Ohs, Samia B. Bachmann, Roberta Bianchi, Steven T. Proulx, Maija Hollmén, David Aebischer and Michael Detmar

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Oncotarget. 2016; 7:39421-39435. https://doi.org/10.18632/oncotarget.9820

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Abstract

Ailsa J. Christiansen1, Lothar C. Dieterich1, Isabel Ohs1, Samia B. Bachmann1, Roberta Bianchi1, Steven T. Proulx1, Maija Hollmén1, David Aebischer1 and Michael Detmar1

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.


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