Cytokine-1nduced meningitis is dramatically attenuated in MICh deficient in endothelial selectins

Leukocyte (WBC) accumulation in cerebrospinal fluid (CSF) and disruption of the blood-brain barrier (BBB) are central components of meningitis and are associated with a poor prognosis. Genetically engineered deficiencies of leukocyte adhesion receptors P-, or P- plus E-selectins lead to deficits in leukocyte rolling and extravasation whereas E-selectin deficiency alone has no effect. The impact of endothelial selectins on meningeal inflammation has not been previously tested. In this study, an acute cytokine-induced meningitis model was developed in adult mice. Human recombinant IL-I and TNFa were inoculated via lumbar puncture at vertebrate level LI or L2. FITC-BSA was i.v. injected and served as a marker of BBB permeability. At 2.5,4,6,8, and 24 hrs post cytokine inoculation, CSF and blood sample were collected and total leukocyte counts were determined. Fluorescence intensity of FITC-BSA in CSF(Icsf) and blood (Iblood) samples were measured and the BBB-index was calculated as Icsf /Iblood m w'd type mice, WBC influx into CSF was prominent as early as 2.5 hrs {200-300 cell/u.1), increased sharply by 4 hrs (1215,000 cell/ul), peaked at 6 hrs and was reversible {<1000 cell/ill) by 24 hrs. Cytokine-induced meningitis applied to P-selectin-deficient mice yielded a partial inhibition of CSF WBC influx and BBB permeability whereas in mice doubly deficient in P- and E-selectin, a near complete inhibition of these parameters was observed. Our results suggest that P- and E-selectin cooperatively contribute to meningitis and that functional blocking of both endothelial selectins in conjunction with antibiotics may provide a therapeutic approach for treatment of bacterial meningitis.