A role for platelets and endothelial selectins in tumor necrosis factor-alpha-induced leukocyte recruitment in the brain microvasculature

The mechanisms mediating leukocyte recruitment into the cerebral nervous sy stem during inflammation are still poorly understood. The objective of this study was to investigate the leukocyte recruitment in the brain microcircu lation by intravital microscopy. Superfusion of the brain with artificial c erebrospinal fluid did not induce leukocyte rolling or adhesion. However, i ntraperitoneal tumor necrosis factor-alpha: (TNF-alpha) caused marked leuko cyte 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-alpha -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 b rain P- and E-selectin expression was seen after TNF-alpha treatment, but b oth were an order of magnitude less than in any other tissue. We observed s ignificant platelet paving of TNF-alpha -stimulated endothelium and found t hat anti-platelet antibody reduced leukocyte rolling and adhesion, as did a cetylsalicylic acid (aspirin). However, depletion of platelets did not redu ce cerebral P-selectin expression. Moreover, chimeric mice lacking P-select in 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 concl usion, TNF-cu-induced neutrophil recruitment into the brain requires both e ndothelial E-selectin and P-selectin as well as platelets, but platelet P-s electin was not a major contributor to this process.