L-selectin stimulation enhances functional expression of surface CXCR4 in lymphocytes: implications for cellular activation during adhesion and migration.
L-selectin mediates leukocyte tethering and rolling, the first step in a sequential process of leukocyte adhesion and migration. Additionally, L-selectin has important signaling roles perhaps contributing to leukocyte activation and integrin-mediated adhesion. Because chemokines are critically involved in leukocyte activation, we questioned whether L-selectin signaling affects chemokine receptor expression and function. We observed that whereas only 5% to 15% of freshly isolated lymphocytes expressed CXCR4 on the cell surface, intracellular CXCR4 was detectable in all cells. Engagement of L-selectin by antibody cross-linking or the L-selectin ligands fucoidan or sulfatide mobilized intracellular CXCR4 to significantly increase surface CXCR4 expression but did not affect CCR5, CCR7, or beta2-integrin expression. L-selectin stimulation also inhibited stromal-derived factor 1 (SDF-1)-induced CXCR4 internalization. The combined effects of L-selectin on CXCR4 trafficking are likely important in markedly enhancing cell activation by SDF-1. Blockade of SDF-1-induced CXCR4 internalization resulted in enhanced actin polymerization on subsequent exposure to SDF-1. Physiologically more important, L-selectin stimulation increased SDF-1-induced lymphocyte adhesion and transendothelial migration, which were inhibited by anti-leukocyte function-associated antigen 1 antibodies, tyrosine kinase inhibitors, and pertussis toxin. To further corroborate the additive stimulating effects, L-selectin signaling and SDF-1 increased beta2-integrin activation. Taken together, L-selectin-mediated signals specifically enhance CXCR4 expression and function, suggesting a novel mechanism for the modulation of lymphocyte activation during cell adhesion and transmigration.
Ding
Ziqiang
Z
Department of Surgery, Toronto General Research Institute of the University Health Network, Toronto, ON, Canada.
Issekutz
Thomas B
TB
Downey
Gregory P
GP
Waddell
Thomas K
TK
D000199:Actins / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology; D006801:Humans; D019041:L-Selectin / Q000378:metabolism / Q000502:physiology*; D008024:Ligands; D008213:Lymphocyte Activation; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D008214:Lymphocytes / Q000166:cytology / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000378:metabolism*
D000199:Actins; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D008024:Ligands; D016169:Lymphocyte Function-Associated Antigen-1; D019718:Receptors, CXCR4; D019041:L-Selectin