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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.

Attenuation of the immune response contributes to the high rate of neonatal infections, particularly in premature infants. Whereas our knowledge of innate immune functions in mature neonates is growing, little is known about the ontogeny of neutrophil recruitment. We investigated neutrophils and ECs in the course of gestation with respect to rolling and adhesive functions. With the use of microflow chambers, we demonstrate that the neutrophil's ability to roll and adhere directly correlates with gestational age. These adhesion-related abilities are very rare in extremely premature infants (<30 weeks of gestation), which may correlate with our observation of markedly reduced expression of PSGL-1 and Mac-1 on neutrophils in preterm infants. In parallel, the capacity of HUVECs to mediate neutrophil adhesion under flow increases with gestational age. In addition, HUVECs from extremely premature infants exerting the lowest ability to recruit adult neutrophils show a diminished up-regulation of E-selectin and ICAM-1. Finally, by following neutrophil function postnatally, we show that maturation of PMN recruitment proceeds equivalently during extra- and intrauterine development. Thus, PMN recruitment and EC adhesion-related functions are ontogenetically regulated in the fetus, which might contribute significantly to the high risk of life-threatening infections in premature infants.