Cytokine-induced meningitis is dramatically attenuated in mice deficient in endothelial selectins.
Leukocyte accumulation in cerebrospinal fluid and disruption of the blood-brain barrier are central components of meningitis and are associated with a poor prognosis. Genetically engineered deficiencies or functional inhibition of endothelial leukocyte adhesion receptors P-, or P- plus E-selectins, lead to deficits in leukocyte rolling and extravasation. However, their impact on meningeal inflammation has not been tested previously. An acute cytokine-induced meningitis model associated with significant cerebrospinal fluid leukocyte accumulation (averaging 14,000 leukocytes/microl as early as 4 h) and blood-brain barrier permeability was developed in adult mice. This model was applied to mice deficient in P-selectin and mice doubly deficient in P- and E-selectins. Partial inhibition of cerebrospinal fluid leukocyte influx and permeability was noted in P-selectin-deficient mice. Mice doubly deficient in P- and E-selectins displayed a near complete inhibition of these parameters. Our results suggest that P- and E-selectins 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.
Tang
T
T
Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Frenette
P S
PS
Hynes
R O
RO
Wagner
D D
DD
Mayadas
T N
TN
D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000473:pathology / Q000503:physiopathology; D002555:Cerebrospinal Fluid / Q000166:cytology; D016207:Cytokines; D019040:E-Selectin / Q000235:genetics / Q000502:physiology*; D004730:Endothelium, Vascular / Q000276:immunology*; D007962:Leukocytes / Q000502:physiology; D008297:Male; D008581:Meningitis / Q000139:chemically induced / Q000503:physiopathology* / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D009504:Neutrophils / Q000502:physiology; D019007:P-Selectin / Q000235:genetics / Q000502:physiology*; D013997:Time Factors
D016207:Cytokines; D019040:E-Selectin; D019007:P-Selectin