uPA/uPAR system is active in immature dendritic cells derived from CD14(+)CD34(+) precursors and is down-regulated upon maturation

We recently described a subset of peripheral CD14(+)CD34(+) cells able to m igrate across endothelial cell monolayers and differentiate into immunostim ulatory dendritic cells (DC), In this paper we show that immature DC derive d from CD14(+)CD34(+) precursors are also capable of reverse transendotheli al migration and extracellular matrix (ECM) invasion using the urokinase pl asminogen activator receptor (uPAR), We found that these cells respond to m acrophage-inflammatory protein (MIP)-1 alpha, enhancing their ability to in vade ECM and supporting the idea that immature DC are selectively recruited at the site of inflammation to expand the pool of APCs, Interestingly, MIP -1 alpha was also capable of preventing the decreased matrix invasion obser ved by blocking uPAR, suggesting that the uPA/uPAR system and MIP-1 alpha c ooperate in driving immature DC migration through the subendothelial matrix , Upon exposure to maturating stimuli, such as TNF-alpha, CD14(+)CD34(+)-de rived DC enhance their APC function and decrease the capacity of invading E CM; these changes are accompanied by altered expression and function of uPA R, Moreover, mature DC shift their sensitivity from MIP-1 alpha to MIP-3 be ta, enhancing their transendothelial migration capability in response to th e 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 micro environmental stimuli, including MIP-1 alpha, MIP-3 beta, and TNF-alpha.