Defect in regulated secretion of P-selectin affects leukocyte recruitment in von Willebrand factor-deficient mice.
Stimulation of endothelial cells by various inflammatory mediators leads to release of Weibel--Palade bodies and therefore to exocytosis of both P-selectin (adhesion receptor for leukocytes) and von Willebrand factor (vWf) (platelet ligand). The potential role of vWf in leukocyte recruitment was investigated with the use of vWf-deficient mice. We report a strong reduction of leukocyte rolling in venules of vWf-deficient mice. Similarly, vWf deficiency led to a decrease in neutrophil recruitment in a cytokine-induced meningitis model as well as in early skin wounds. In all instances with an antibody that preferentially recognizes plasma membrane P-selectin, we observed a dramatic reduction in P-selectin expression at the cell surface of vWf-deficient endothelium. With confocal microscopy, we found that the typical rodlike shape of the Weibel--Palade body is missing in vWf -/- endothelial cells and that part of the P-selectin content in the vWf -/- cells colocalized with LAMP-1, a lysosomal marker. However, intracellular P-selectin levels were similar in tumor necrosis factor alpha- and lipopolysaccharide-activated cells of both genotypes. We conclude that the absence of vWf, as found in severe von Willebrand disease, leads to a defect in Weibel--Palade body formation. This defect results in decreased P-selectin translocation to the cell surface and reduced leukocyte recruitment in early phases of inflammation.
Denis
C V
CV
Center for Blood Research, Harvard Medical School, Boston, MA 02115, USA.
André
P
P
Saffaripour
S
S
Wagner
D D
DD
D000818:Animals; D002464:Cell Migration Inhibition; D002465:Cell Movement / Q000502:physiology; D016207:Cytokines; D004730:Endothelium, Vascular / Q000378:metabolism; D007962:Leukocytes / Q000502:physiology*; D008297:Male; D008581:Meningitis / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration / Q000502:physiology*; D019007:P-Selectin / Q000378:metabolism*; D012867:Skin / Q000293:injuries / Q000473:pathology / Q000503:physiopathology; D014699:Venules / Q000502:physiology; D014841:von Willebrand Factor / Q000235:genetics / Q000378:metabolism*
D016207:Cytokines; D019007:P-Selectin; D014841:von Willebrand Factor