CCR2 receptor blockade alters blood monocyte subpopulations but does not affect atherosclerotic lesions in apoE(-/-) mice.
OBJECTIVE
The CCR2 receptor plays a crucial role in monocyte recruitment and has been implicated as a contributing factor to atherosclerosis. CCR2 receptor deletion leads to significant inhibition of lesion development. Our objective was to determine if CCR2 receptor blockade with a small molecule would have a beneficial effect of decreasing established lesions.


RESULTS
We demonstrated that CCR2 blockade had no significant effect on advanced lesions or the progression of fatty streaks. CCR2 blockade in mice resulted in elevations in plasma CCL2 levels and a significant reduction in the plasma Ly-6C(hi) subpopulations of monocytes expressing the CCR2 receptor. Neither CCL2 elevation nor margination of the Ly-6C(hi) population was observed in CCR2(-/-) mice.


CONCLUSIONS
CCR2 receptor blockade with a small molecule antagonist at dose levels showing efficacy in several inflammatory models did not show a beneficial effect in murine models of atherosclerosis. Elevations in CCL2 and margination of Ly-6C(hi) cells demonstrate that the role of CCR2 in controlling monocyte levels goes beyond the control of monocyte emigration.
Aiello
Robert J
RJ
Pfizer Global Research and Development, Department of Cardiovascular and Metabolic Diseases, Eastern Point Road, Groton, CT 06340, United States. robert.j.aiello@pfizer.com
Perry
Bret D
BD
Bourassa
Patricia-Ann
PA
Robertson
Andrew
A
Weng
Weifan
W
Knight
Delvin R
DR
Smith
Andrew H
AH
Frederick
Kosea S
KS
Kalgutkar
Amit
A
Gladue
Ronald P
RP
D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D001021:Aortic Valve / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics*; D050197:Atherosclerosis / Q000235:genetics* / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D018932:Chemokine CCL2 / Q000378:metabolism; D008252:Macaca fascicularis; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009000:Monocytes / Q000378:metabolism*; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors*
D000950:Antigens, Ly; D001057:Apolipoproteins E; D018932:Chemokine CCL2; C494192:Ly-6C antigen, mouse; D054390:Receptors, CCR2