Blood cell-derived RANTES mediates cerebral microvascular dysfunction, inflammation, and tissue injury after focal ischemia-reperfusion.
OBJECTIVE
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.
Terao
Satoshi
S
Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130, USA.
Yilmaz
Gokhan
G
Stokes
Karen Y
KY
Russell
Janice
J
Ishikawa
Mami
M
Kawase
Takeshi
T
Granger
D Neil
DN
D000818:Animals; D001773:Blood Cells / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000378:metabolism / Q000503:physiopathology; D020520:Brain Infarction / Q000097:blood* / Q000235:genetics / Q000503:physiopathology; D002545:Brain Ischemia / Q000097:blood* / Q000235:genetics / Q000503:physiopathology; D018946:Chemokine CCL5 / Q000235:genetics* / Q000378:metabolism*; D004195:Disease Models, Animal; D004660:Encephalitis / Q000097:blood* / Q000235:genetics / Q000503:physiopathology; D020244:Infarction, Middle Cerebral Artery / Q000097:blood / Q000235:genetics / Q000503:physiopathology; D007378:Interleukins / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008833:Microcirculation / Q000502:physiology; D010973:Platelet Adhesiveness / Q000502:physiology; D015427:Reperfusion Injury / Q000097:blood* / Q000235:genetics / Q000503:physiopathology
D018946:Chemokine CCL5; D007378:Interleukins