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Neutrophil-derived glutamate regulates vascular endothelial barrier function
Charles D Collard1, Kellie A Park, Michael C Montalto
1Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
The Journal of Biological Chemistry
|February 16, 2002
Summary
Polymorphonuclear leukocytes (PMNs) release glutamate, which activates specific receptors on brain endothelial cells. This process reduces VASP phosphorylation and impairs blood-brain barrier function during inflammation.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Inflammation disrupts endothelial barrier function via soluble mediators.
- Endogenous pathways regulating these changes are emerging.
- Polymorphonuclear leukocytes (PMNs) are key inflammatory cells.
Purpose of the Study:
- To investigate the role of PMN-derived mediators in endothelial barrier function.
- To identify specific molecules and receptors involved in PMN-mediated endothelial changes.
- To explore the therapeutic potential of targeting these pathways.
Main Methods:
- In vitro endothelial paracellular permeability model.
- Biophysical and biochemical analysis of PMN supernatants.
- Reverse transcription-PCR, in situ hybridization, immunofluorescence, and Western blot for receptor expression.
- In vivo mouse model of blood-brain barrier permeability.
Main Results:
- PMN supernatants significantly altered endothelial permeability.
- PMN-derived glutamate was identified as a key modulator.
- Human brain and dermal microvascular endothelial cells express mGluR1, mGluR4, and mGluR5.
- Glutamate and mGluR agonists decreased phosphorylated VASP and increased endothelial permeability.
- mGluR antagonists attenuated glutamate-induced barrier dysfunction in vitro and in vivo.
Conclusions:
- Activated human PMNs release glutamate.
- Endothelial expression of group I or III mGluRs decreases VASP phosphorylation and barrier function.
- PMN-derived glutamate represents a novel pathway regulating endothelial barrier integrity.