Brain endothelium lack one of two pathways of P-selectin-mediated neutrophil adhesion.
P-selectin, an endothelial leukocyte adhesion receptor, is rapidly translocated to the cell surface upon release from storage granules called Weibel-Palade bodies and is also transcriptionally upregulated upon cytokine stimulation of endothelial cells (ECs). These two pathways of surface expression are coincident with the rapid and cytokine-inducible pathway of neutrophil adhesion to ECs. Constitutive P-selectin expression is largely absent in cultured murine brain microvascular EC (BMEC) monolayers, but interleukin-1beta and tumor necrosis factor-alpha stimulation for 4 hours leads to dramatic P-selectin upregulation. The functional relevance of differential P-selectin expression in these cells was examined by studying BMECs derived from wild-type mice and P-selectin-deficient mice. We show that P-selectin deficiency does not affect Weibel-Palade body formation or their release in response to short-acting agonists. However, in the absence of P-selectin, the brain endothelium is unable to support neutrophil adhesion after stimulation with these agonists, which may contribute to the immune privilege status of the brain. We show that P-selectin does play a major role in supporting neutrophil adhesion in the cytokine-induced pathway in BMECs in the context of other cytokine-inducible endothelial-leukocyte adhesion receptors, E-selectin, ICAM-1, and VCAM-1.
Barkalow
F J
FJ
Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Goodman
M J
MJ
Gerritsen
M E
ME
Mayadas
T N
TN
D000818:Animals; D001921:Brain / Q000098:blood supply; D001923:Brain Chemistry / Q000502:physiology*; D002448:Cell Adhesion / Q000502:physiology; D003594:Cytoplasmic Granules / Q000737:chemistry / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology* / Q000648:ultrastructure; D051379:Mice; D008833:Microcirculation / Q000737:chemistry; D009504:Neutrophils / Q000166:cytology*; D019007:P-Selectin / Q000494:pharmacology*
D019007:P-Selectin