VEGF Requires the Receptor NRP-1 To Inhibit Lipopolysaccharide-Dependent Dendritic Cell Maturation

To stimulate a productive T cell response, dendritic cells (DC) must undergo maturation characterized by heightened cell surface expression of MHC and costimulatory molecules as well as cytokine production. Conversely, the inhibition of DC maturation is a central mechanism of immune tolerance. The c...

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Bibliographic Details
Published in:	The Journal of immunology (1950) Vol. 197; no. 10; pp. 3927 - 3935
Main Authors:	Oussa, Nougboli A E, Dahmani, Amina, Gomis, Marie, Richaud, Manon, Andreev, Emil, Navab-Daneshmand, Ali-Reza, Taillefer, Julie, Carli, Cédric, Boulet, Salix, Sabbagh, Laurent, Labrecque, Nathalie, Sapieha, Przemyslaw, Delisle, Jean-Sébastien
Format:	Journal Article
Language:	English
Published:	United States 15-11-2016
Subjects:	Animals B7-2 Antigen - drug effects B7-2 Antigen - genetics Bone Marrow Cells - immunology Bone Marrow Cells - physiology CD40 Antigens - drug effects CD40 Antigens - genetics Cell Differentiation Cells, Cultured Cytokines - biosynthesis Cytokines - drug effects Cytokines - genetics Dendritic Cells - drug effects Dendritic Cells - immunology Dendritic Cells - physiology Genes, MHC Class II - drug effects Genes, MHC Class II - genetics Immune Tolerance - drug effects Lipopolysaccharides - immunology MAP Kinase Signaling System - physiology Mice Neuropilin-1 - deficiency Neuropilin-1 - immunology Neuropilin-1 - metabolism NF-kappa B p50 Subunit - physiology Poly I-C - pharmacology Signal Transduction - immunology Signal Transduction - physiology Toll-Like Receptor 4 - metabolism Vascular Endothelial Growth Factor A - metabolism Vascular Endothelial Growth Factor A - pharmacology
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Summary:	To stimulate a productive T cell response, dendritic cells (DC) must undergo maturation characterized by heightened cell surface expression of MHC and costimulatory molecules as well as cytokine production. Conversely, the inhibition of DC maturation is a central mechanism of immune tolerance. The control of the DC maturation process relies on the integration of several cellular stimulatory or inhibitory signals. The soluble factors and their receptors controlling this central aspect of DC biology are incompletely characterized. We show that murine bone marrow-derived DC (BMDC) maturation induced by LPS, as opposed to polyinosinic:polycytidylic acid or cytosine-phosphate-guanine, is robustly inhibited by vascular endothelial growth factor (VEGF), a previously identified immunosuppressive cytokine. Using BMDC from wild type and conditional knockout mice, we show that neuropilin-1 (NRP-1), a known receptor of VEGF, is necessary to suppress LPS-dependent BMDC maturation. The absence of NRP-1 had no ostensible effects on the biology of BMDC in the absence of VEGF. However, NRP-1-deficient BMDC remained completely insensitive to the VEGF-dependent inhibition of BMDC maturation in culture. In the presence of VEGF, NRP-1 directly interacted with the LPS receptor TLR4 and suppressed downstream signaling through ERK and NF-κβ, resulting in a sharp inhibition of MHC class II and costimulatory molecules (CD40, CD86) expression as well as proinflammatory cytokine production. Consequently, we identify NRP-1 as a target to optimize DC maturation within environments that are rich in VEGF, such as tumors.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0022-1767 1550-6606
DOI:	10.4049/jimmunol.1601116