Endothelial cell-derived chemerin promotes dendritic cell transmigration.
ChemR23 is a chemotactic receptor expressed by APCs, such as dendritic cells, macrophages, and NK cells. Chemerin, the ChemR23 ligand, was detected by immunohistochemistry, to be associated with inflamed endothelial cells in autoimmune diseases, such as lupus erythematosus, psoriasis, and rheumatoid arthritis. This study reports that blood and lymphatic murine endothelial cells produce chemerin following retinoic acid stimulation. Conversely, proinflammatory cytokines, such as TNF-α, IFN-γ, and LPS, or calcitriol, are not effective. Retinoic acid-stimulated endothelial cells promoted dendritic cell adhesion under shear stress conditions and transmigration in a ChemR23-dependent manner. Activated endothelial cells upregulated the expression of the atypical chemotactic receptor CCRL2/ACKR5, a nonsignaling receptor able to bind and present chemerin to ChemR23(+) dendritic cells. Accordingly, activated endothelial cells expressed chemerin on the plasma membrane and promoted in a more efficient manner chemerin-dependent transmigration of dendritic cells. Finally, chemerin stimulation of myeloid dendritic cells induced the high-affinity binding of VCAM-1/CD106 Fc chimeric protein and promoted VCAM-1-dependent arrest to immobilized ligands under shear stress conditions. In conclusion, this study reports that retinoic acid-activated endothelial cells can promote myeloid and plasmacytoid dendritic cell transmigration across endothelial cell monolayers through the endogenous production of chemerin, the upregulation of CCRL2, and the activation of dendritic cell β1 integrin affinity.
Humanitas Clinical and Research Center, Rozzano 20089, Italy;
Safiye
S
Gonzalvo-Feo
Annalisa
A
Del Prete
Monika
M
Pruenster
Valentina
V
Salvi
Li
L
Wang
Marina
M
Sironi
Susanne
S
Bierschenk
Markus
M
Sperandio
Annunciata
A
Vecchi
Silvano
S
Sozzani
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D018925:Chemokines; D002630:Chemotactic Factors / Q000235:genetics / Q000276:immunology*; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D042783:Endothelial Cells / Q000166:cytology / Q000276:immunology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D054388:Receptors, CCR; D019707:Receptors, Chemokine / Q000235:genetics / Q000276:immunology; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000276:immunology; D057705:Transendothelial and Transepithelial Migration / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D014212:Tretinoin / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000276:immunology
D000970:Antineoplastic Agents; C486456:CMKLR1 protein, mouse; C111851:Ccrl2 protein, mouse; D018925:Chemokines; D002630:Chemotactic Factors; D036341:Intercellular Signaling Peptides and Proteins; D054388:Receptors, CCR; D019707:Receptors, Chemokine; D043562:Receptors, G-Protein-Coupled; D019010:Vascular Cell Adhesion Molecule-1; C523686:chemerin protein, mouse; D014212:Tretinoin