The CC chemokine MCP-1 stimulates surface expression of CX3CR1 and enhances the adhesion of monocytes to fractalkine/CX3CL1 via p38 MAPK.
The membrane-anchored form of CX3CL1 has been proposed as a novel adhesion protein for leukocytes. This functional property of CX3CL1 is mediated through CX3CR1, a chemokine receptor expressed predominantly on circulating white blood cells. Thus far, it is still uncertain at what stage of the trafficking process CX3CR1 becomes importantly involved and how the CX3CR1-dependent adhesion of leukocytes is regulated during inflammation. The objective of this study was to examine the functional effects of chemokine stimulation on CX3CR1-mediated adhesion of human monocytes. Consistent with previous reports, our data indicate that the activity of CX3CR1 on resting monocytes is sufficient to mediate cell adhesion to CX3CL1. However, the basal, nonstimulated adhesion activity is low, and we hypothesized that like the integrins, CX3CR1 may require a preceding activation step to trigger firm leukocyte adhesion. Compatible with this hypothesis, stimulation of monocytes with MCP-1 significantly increased their adhesion to immobilized CX3CL1, under both static and physiological flow conditions. The increase of the adhesion activity was mediated through CCR2-dependent signaling and obligatory activation of the p38 MAPK pathway. Stimulation with MCP-1 also induced a rapid increase of CX3CR1 protein on the cell surface. Inhibition of the p38 MAPK pathway prevented this increase of CX3CR1 surface expression and blunted the effect of MCP-1 on cell adhesion, indicating a causal link between receptor surface density and adhesion activity. Together, our data suggest that a chemokine signal is required for firm CX3CR1-dependent adhesion and demonstrate that CCR2 is an important regulator of CX3CL1-dependent leukocyte adhesion.
Green
Simone R
SR
Department of Medicine, University of California, San Diego, La Jolla, 92093, USA.
Han
Ki Hoon
KH
Chen
Yiming
Y
Almazan
Felicidad
F
Charo
Israel F
IF
Miller
Yury I
YI
Quehenberger
Oswald
O
D000818:Animals; D017951:Antigen Presentation; D000073883:CX3C Chemokine Receptor 1; D002448:Cell Adhesion / Q000187:drug effects / Q000276:immunology; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000502:physiology*; D054428:Chemokine CX3CL1; D020523:Chemokines, CX3C / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D009000:Monocytes / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D037342:Pertussis Toxin / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*
C515334:CCR2 protein, human; D000073883:CX3C Chemokine Receptor 1; C515538:CX3CL1 protein, human; C095235:CX3CR1 protein, human; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D054428:Chemokine CX3CL1; D020523:Chemokines, CX3C; C515539:Cx3cl1 protein, mouse; D008565:Membrane Proteins; D047428:Protein Kinase Inhibitors; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D037342:Pertussis Toxin; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases