© 2000 American Heart Association, Inc.
Integrative Physiology |
A Role for Platelets and Endothelial Selectins in Tumor Necrosis Factor-
–Induced Leukocyte Recruitment in the Brain Microvasculature
From the Immunology Research Group (J.C.-T., M.J.H., P.K.), University of Calgary, Calgary, Alberta, and Division of the Intensive Care, Department of Pediatrics (J.H.); Department of Laboratory Medicine (J.M.); and Department of Cellular and Molecular Medicine (I.T.S.), University of Ottawa, Ontario, Canada.
Correspondence to Dr Paul Kubes, Immunology Research Group, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, T2N 4N1, Canada. E-mail pkubes{at}ucalgary.ca
Abstract—The
mechanisms mediating leukocyte recruitment into the cerebral nervous
system during inflammation are still poorly understood. The objective
of this study was to investigate the leukocyte recruitment in the brain
microcirculation by intravital microscopy. Superfusion of the brain
with artificial cerebrospinal fluid did not induce leukocyte rolling or
adhesion. However, intraperitoneal tumor necrosis factor-
(TNF-)
caused marked leukocyte rolling and adhesion in the brain
microcirculation. Histology revealed that the recruitment was primarily
of neutrophils. Both E- and P-selectin were required for
TNF-–induced leukocyte recruitment, as rolling was reduced after
treatment with either anti–E- or anti–P-selectin antibody and
eliminated in E- or P-selectin–deficient mice. A significant increase
in brain P- and E-selectin expression was seen after TNF- treatment,
but both were an order of magnitude less than in any other tissue. We
observed significant platelet paving of TNF-–stimulated endothelium
and found that anti-platelet antibody reduced leukocyte rolling and
adhesion, as did acetylsalicylic acid (aspirin). However, depletion of
platelets did not reduce cerebral P-selectin expression. Moreover,
chimeric mice lacking P-selectin on endothelium but not platelets had
significantly decreased P-selectin expression and reduced leukocyte
recruitment in the brain. This suggests a role for endothelial
P-selectin in cerebral leukocyte recruitment. In conclusion,
TNF-–induced neutrophil recruitment into the brain requires both
endothelial E-selectin and P-selectin as well as platelets, but
platelet P-selectin was not a major contributor to this
process.
Key Words: selectin • tumor necrosis factor- • neutrophil • inflammation • cerebral
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