Related Experiment Video
Updated: Jul 6, 2026
Humanized Mouse Model to Study Bacterial Infections Targeting the Microvasculature
Published on: April 1, 2014
Cytokine-induced meningitis is dramatically attenuated in mice deficient in endothelial selectins
T Tang1, P S Frenette, R O Hynes
1Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Abstract:
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.
Insights
Blocking P- and E-selectins significantly reduces leukocyte infiltration and blood-brain barrier disruption in meningitis models. This suggests targeting these selectins could be a novel therapeutic strategy for bacterial meningitis.
Area of Science:
- Neuroimmunology
- Vascular Biology
- Inflammation Research
Background:
- Leukocyte accumulation in cerebrospinal fluid and blood-brain barrier disruption are hallmarks of meningitis.
- Endothelial selectins (P-selectin and E-selectin) mediate leukocyte adhesion and extravasation, but their role in meningitis was unexplored.
Purpose of the Study:
- To investigate the role of P-selectin and E-selectin in a mouse model of acute meningitis.
- To assess the therapeutic potential of blocking these selectins in meningitis.
Main Methods:
- Developed an acute cytokine-induced meningitis model in adult mice.
- Utilized mice genetically deficient in P-selectin and doubly deficient in P- and E-selectins.
- Quantified cerebrospinal fluid leukocyte influx and blood-brain barrier permeability.
Main Results:
- P-selectin deficiency partially inhibited leukocyte influx and blood-brain barrier permeability.
- Mice lacking both P- and E-selectins showed near-complete inhibition of these meningitis parameters.
- Significant cerebrospinal fluid leukocyte accumulation (14,000 cells/microl) and BBB permeability were observed in control mice.
Conclusions:
- P- and E-selectins play a cooperative role in meningeal inflammation during meningitis.
- Combined blockade of P- and E-selectins, alongside antibiotics, may offer a promising therapeutic strategy for bacterial meningitis.
