Blood Cell-Derived RANTES Mediates Cerebral Microvascular Dysfunction, Inflammation, and Tissue Injury After Focal Ischemia–Reperfusion

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Abstract
Background and Purpose— Although chemokines have been implicated in cardiovascular diseases, few studies have addressed the role of these inflammatory mediators in ischemic stroke. This study tested the hypothesis that RANTES (CCL5; regulated on activation, normal T-cell expressed and secreted) mediates the cerebral microvascular dysfunction, inflammation, and tissue injury induced by brain ischemia and reperfusion. Methods— After 60-minute middle cerebral artery occlusion and reperfusion, the adhesion of leukocytes and platelets in cerebral venules, infarct volume, and blood–brain barrier permeability were measured in wild-type mice (WT), RANTES-deficient mice (RANTES −/− ), WT mice transplanted with RANTES −/− bone marrow (RANTES>WT), and control bone marrow chimeras (WT>WT). The concentration of RANTES and several cytokines was also measured by enzyme-linked immunosorbent assay and a cytometric bead array. Results— The enhanced leukocyte and platelet adhesion, increased blood–brain barrier permeability, and tissue infarction elicited in WT and WT>WT mice after middle cerebral artery occlusion and reperfusion were significantly blunted in RANTES −/− mice. Similar attenuation of the middle cerebral artery occlusion and reperfusion-induced responses were noted in RANTES>WT chimeras. Although RANTES deficiency did not alter the changes in tissue cytokine levels elicited by middle cerebral artery occlusion and reperfusion, plasma concentrations interleukin-6, interleukin-10, and interleukin-12 were all reduced. Conclusions— These findings implicate blood cell-derived RANTES in the microvascular, inflammatory, and tissue injury responses of the brain to ischemia and reperfusion.