Absence of the chemokine receptor CCR2 protects against cerebral ischemia/reperfusion injury in mice.
OBJECTIVE
The chemokine, monocyte chemoattractant protein-1 (CCL2), is a major factor driving leukocyte infiltration into the brain parenchyma in a variety of neuropathologic conditions associated with inflammation, including stroke. In addition, recent studies indicate that CCL2 and its receptor (CCR2) could have an important role in regulating blood-brain barrier (BBB) permeability. This study evaluated the role of the CCL2/CCR2 axis in regulating postischemic inflammation, BBB breakdown, and vasogenic edema formation.


METHODS
CCR2(-/-) and CCR2(+/+) mice were subjected to focal transient cerebral ischemia. BBB permeability and brain edema formation were observed at days 1 and 5 of reperfusion by evaluating the product surface area for fluorescein isothiocyanate-albumin and measuring water and electrolyte contents. Immunohistochemistry was used to assess leukocyte infiltration. cDNA gene and protein arrays for inflammatory cytokines were used to assess inflammatory profiles in CCR2(+/+) and CCR2(-/-) mice.


RESULTS
CCR2(-/-) mice had reduced infarct sizes and significantly reduced BBB permeability and brain edema formation in the affected ischemic hemisphere compared with CCR2(+/+) mice. This reduction in injury was closely associated with reduced infiltration of not only monocytes but also neutrophils (7- and 4-fold decreases, respectively). In addition, CCR2(-/-) mice had reduced expression/production of inflammatory cytokines during reperfusion.


CONCLUSIONS
These data suggest that inhibiting the CCL2/CCR2 axis affects brain reperfusion outcome by reducing brain edema, leukocyte infiltration, and inflammatory mediator expression.
Dimitrijevic
Oliver B
OB
Department of Pathology, University of Michigan, Medical School, Ann Arbor, MI 48109-0532, USA.
Stamatovic
Svetlana M
SM
Keep
Richard F
RF
Andjelkovic
Anuska V
AV
D000818:Animals; D001812:Blood-Brain Barrier / Q000276:immunology / Q000503:physiopathology; D001929:Brain Edema / Q000235:genetics / Q000276:immunology / Q000503:physiopathology; D020520:Brain Infarction / Q000235:genetics / Q000276:immunology / Q000503:physiopathology; D002545:Brain Ischemia / Q000235:genetics / Q000276:immunology* / Q000503:physiopathology; D018932:Chemokine CCL2 / Q000276:immunology*; D002634:Chemotaxis, Leukocyte / Q000235:genetics / Q000276:immunology*; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D019610:Cytoprotection / Q000235:genetics / Q000276:immunology*; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D004660:Encephalitis / Q000235:genetics / Q000276:immunology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000235:genetics*; D015427:Reperfusion Injury / Q000235:genetics / Q000276:immunology* / Q000503:physiopathology
C491768:Ccl2 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D016207:Cytokines; D054390:Receptors, CCR2; D019707:Receptors, Chemokine