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 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.
Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Montreal, Quebec H1T 2M4, Canada.|Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, Quebec H3C 3J7, Canada.
Nougboli A E
NA
Oussa
Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Montreal, Quebec H1T 2M4, Canada.
Amina
A
Dahmani
Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Montreal, Quebec H1T 2M4, Canada.
Marie
M
Gomis
Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Montreal, Quebec H1T 2M4, Canada.
Manon
M
Richaud
Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Montreal, Quebec H1T 2M4, Canada.
Emil
E
Andreev
Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Montreal, Quebec H1T 2M4, Canada.
Ali-Reza
0000-0002-2942-1103
AR
Navab-Daneshmand
Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Montreal, Quebec H1T 2M4, Canada.
Julie
J
Taillefer
Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Montreal, Quebec H1T 2M4, Canada.
Cédric
C
Carli
Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Montreal, Quebec H1T 2M4, Canada.
Salix
S
Boulet
Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Montreal, Quebec H1T 2M4, Canada.|Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, Quebec H3C 3J7, Canada.
Laurent
0000-0002-5097-4298
L
Sabbagh
Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Montreal, Quebec H1T 2M4, Canada.|Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, Quebec H3C 3J7, Canada.|Département de Médecine, Université de Montréal, Montreal, Quebec H3C 3J7, Canada.
Nathalie
N
Labrecque
Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Montreal, Quebec H1T 2M4, Canada.|Département d'Ophtalmologie, Université de Montréal, Montreal, Quebec H3C 3J7, Canada; and.
Przemyslaw
0000-0002-9171-2825
P
Sapieha
Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Montreal, Quebec H1T 2M4, Canada; js.delisle@umontreal.ca.|Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, Quebec H3C 3J7, Canada.|Département de Médecine, Université de Montréal, Montreal, Quebec H3C 3J7, Canada.|Division d'Hématologie-Oncologie, Hôpital Maisonneuve-Rosemont, Montreal, Quebec H1T 2M4, Canada.
Jean-Sébastien
JS
Delisle
D000818:Animals; D051940:B7-2 Antigen / Q000187:drug effects / Q000235:genetics; D001854:Bone Marrow Cells / Q000276:immunology / Q000502:physiology; D019013:CD40 Antigens / Q000187:drug effects / Q000235:genetics; D002454:Cell Differentiation; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology / Q000502:physiology*; D005802:Genes, MHC Class II / Q000187:drug effects / Q000235:genetics; D007108:Immune Tolerance / Q000187:drug effects; D008070:Lipopolysaccharides / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D052002:NF-kappa B p50 Subunit / Q000502:physiology; D039942:Neuropilin-1 / Q000172:deficiency / Q000276:immunology* / Q000378:metabolism*; D011070:Poly I-C / Q000494:pharmacology; D015398:Signal Transduction / Q000276:immunology / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism* / Q000494:pharmacology
D051940:B7-2 Antigen; D019013:CD40 Antigens; C497965:Cd86 protein, mouse; D016207:Cytokines; D008070:Lipopolysaccharides; D052002:NF-kappa B p50 Subunit; D051197:Toll-Like Receptor 4; D042461:Vascular Endothelial Growth Factor A; D039942:Neuropilin-1; C073701:Nfkb1 protein, mouse; D011070:Poly I-C