uPA/uPAR System Is Active in Immature Dendritic Cells Derived from CD14+CD34+ Precursors and Is Down-Regulated upon Maturation

• Published in: The Journal of immunology (1950) 2000-01, Vol.164 (2), p.712-718
• Main Authors: Ferrero, Elisabetta, Vettoretto, Katuscia, Bondanza, Attilio, Villa, Antonello, Resnati, Massimo, Poggi, Alessandro, Zocchi, Maria Raffaella
• Format: Article
• Language: English
• Subjects: Antigens, CD34 - biosynthesis; Cell Differentiation - immunology; Cell Movement - immunology; Cells, Cultured; Chemokine CCL19; Chemokine CCL3; Chemokine CCL4; Chemokine CCL5 - physiology; Chemokines, CC - physiology; Dendritic Cells - cytology; Dendritic Cells - enzymology; Dendritic Cells - immunology; Dendritic Cells - metabolism; Down-Regulation - immunology; Endothelium, Vascular - cytology; Enzyme Activation - immunology; Extracellular Matrix - enzymology; Extracellular Matrix - immunology; Humans; Lipopolysaccharide Receptors - biosynthesis; Macrophage Inflammatory Proteins - physiology; Receptors, Cell Surface - antagonists & inhibitors; Receptors, Cell Surface - biosynthesis; Receptors, Cell Surface - metabolism; Receptors, Cell Surface - physiology; Receptors, Urokinase Plasminogen Activator; Stem Cells - cytology; Stem Cells - enzymology; Stem Cells - immunology; Stem Cells - metabolism; Urokinase-Type Plasminogen Activator - antagonists & inhibitors; Urokinase-Type Plasminogen Activator - metabolism; Urokinase-Type Plasminogen Activator - physiology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.164.2.712

We recently described a subset of peripheral CD14+CD34+ cells able to migrate across endothelial cell monolayers and differentiate into immunostimulatory dendritic cells (DC). In this paper we show that immature DC derived from CD14+CD34+ precursors are also capable of reverse transendothelial migration and extracellular matrix (ECM) invasion using the urokinase plasminogen activator receptor (uPAR). We found that these cells respond to macrophage-inflammatory protein (MIP)-1alpha, enhancing their ability to invade ECM and supporting the idea that immature DC are selectively recruited at the site of inflammation to expand the pool of APCs. Interestingly, MIP-1alpha was also capable of preventing the decreased matrix invasion observed by blocking uPAR, suggesting that the uPA/uPAR system and MIP-1alpha cooperate in driving immature DC migration through the subendothelial matrix. Upon exposure to maturating stimuli, such as TNF-alpha, CD14+CD34+-derived DC enhance their APC function and decrease the capacity of invading ECM; these changes are accompanied by altered expression and function of uPAR. Moreover, mature DC shift their sensitivity from MIP-1alpha to MIP-3beta, enhancing their transendothelial migration capability in response to the latter chemokine. Our data support the hypothesis that bloodborne DC can move through ECM toward the site of pathogen entry where they differentiate into fully mature APCs with their motility and function regulated by microenvironmental stimuli, including MIP-1alpha, MIP-3beta, and TNF-alpha.