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(Stroke. 2007;38:1345.)
© 2007 American Heart Association, Inc.

Original Contributions

Absence of the Chemokine Receptor CCR2 Protects Against Cerebral Ischemia/Reperfusion Injury in Mice

From the Departments of Pathology (O.B.D., S.M.S., A.V.A.), Neurosurgery (R.F.K., A.V.A.), and Integrative and Molecular Physiology (R.F.K.), University of Michigan, Medical School, Ann Arbor.

Correspondence to Anuska V. Andjelkovic, Department of Pathology, University of Michigan, 7520 MSRB I, Ann Arbor, MI 48109-0532. E-mail anuskaa{at}umich.edu

Background and Purpose— 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.

Key Words: blood-brain barrier permeability • CCL2 • chemokines • inflammation • stroke

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