Published Online
on March 1, 2007

A more recent version of this article appeared on April 1, 2007

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Submitted on August 3, 2006
Revised on October 25, 2006
Accepted on November 1, 2006

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

Oliver B. Dimitrijevic MD; Svetlana M. Stamatovic MD, PhD; Richard F. Keep PhD; and Anuska V. Andjelkovic MD, PhD^*

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.

^* To whom correspondence should be addressed. 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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