PSGL-1 regulates platelet P-selectin-mediated endothelial activation and shedding of P-selectin from activated platelets.
We have previously shown that activated platelets in circulation stimulate release of endothelial Weibel-Palade bodies thus increasing leukocyte rolling in venules. P-selectin on the activated platelets mediates adhesion to leukocytes via PSGL-1 and is rapidly shed into plasma. We were interested in studying the role of PSGL-1 in regulating expression and function of platelet P-selectin. We show here that PSGL-1 is critical for the activation of endothelial cells in venules of mice infused with activated platelets. The interaction of platelet P-selectin with PSGL-1 is also required for P-selectin shedding, as P-selectin was retained significantly longer on the surface of activated platelets infused into PSGL-1(-/-) compared to wild-type mice. The leukocyte integrin alphaMbeta2 (Mac-1) was not required for P-selectin shedding. In addition to shedding, P-selectin can be downregulated from the platelet surface through internalization and this is the predominant mechanism in the absence of PSGL-1. We demonstrate that leukocyte-neutrophil elastase, known to cleave P-selectin in vitro, is not the major sheddase for P-selectin in vivo. In conclusion, interaction of platelet P-selectin with PSGL-1 is crucial for activation of the endothelium andWeibel-Palade body secretion. The interaction with PSGL-1 also results in rapid shedding of P-selectin thus downregulating the inflammatory potential of the platelet.
Dole
Vandana S
VS
CBR Institute for Biomedical Research, 800 Huntington Avenue, Boston, MA 02115, USA.
Bergmeier
Wolfgang
W
Patten
Ian S
IS
Hirahashi
Junichi
J
Mayadas
Tanya N
TN
Wagner
Denisa D
DD
D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D004727:Endothelium / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005786:Gene Expression Regulation; D019272:Leukocyte Elastase / Q000378:metabolism; D007962:Leukocytes / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D019007:P-Selectin / Q000097:blood* / Q000378:metabolism; D015539:Platelet Activation; D020302:Weibel-Palade Bodies / Q000276:immunology* / Q000378:metabolism
D008562:Membrane Glycoproteins; D019007:P-Selectin; C084882:P-selectin ligand protein; D019272:Leukocyte Elastase