CXCL12 is displayed by rheumatoid endothelial cells through its basic amino-terminal motif on heparan sulfate proteoglycans

Chemokines are a large family of soluble proteins involved in leukocyte activation and traffic during inflammatory responses. Chemokines signal through G-protein-coupled receptors [1]. In vivo, chemokine-dependent directional migration of leukocytes is supposed to require the immobilization of chemokines either to the extracellular matrix or to cell surfaces. Chemokines induce cell-matrix or cell-cell adhesion through the activation of integrins, and studies in vivo demonstrate that the presence of chemokines immobilized on the luminal side of endothelium is a critical step for firm adhesion and transendothelial migration of rolling leukocytes [2-6]. This phenomenon can be reproduced in vitro in cultured endothelial cells (ECs) and depends on the addition of exogenous chemokines and the presence of fluid shear-induced mechanical stress on leukocytes [5,6]. Endothelial cells secrete a limited number of chemokines, suggesting that many of the homeostatic or inflammatory chemokines presented at the EC surface come from other cell sources by transcytosis and docking of chemokines on the EC luminal surface [7-9].CXCL12 (also known as stromal cell-derived factor, SDF-1) is the unique identified natural ligand of the G-protein-coupled receptor CXCR4 and exhibits both homeostatic and proinflammatory functions in humans. The main cellular sources of CXCL12 are resident stromal fibroblasts and epithelial cells. CXCL12 participates in the homeostatic traffic of hematopoietic cells and lymphocytes. Indeed, CXCL12 is constitutively displayed by endothelial cells (ECs) in the bone marrow and secondary lymphoid organs, where it seems to be produced by nearby osteoblasts, stromal cells, or tonsil epithelium [10-12]. The CXCL12/CXCR4 axis also participates in the recruitment of inflammatory cells as shown in animal models of allergic airway disease and rheumatoid arthritis (RA) [13-15]. CXCL12 is constitutively expressed by synovial fibroblasts and lung epithelium and is not a cytok