Severe reduction in leukocyte adhesion and monocyte extravasation in mice deficient in CC chemokine receptor 2

Severe reduction in leukocyte adhesion and monocyte extravasation in mice deficient in CC chemokine receptor 2

^*Department of Pathology and Laboratory Medicine, University of North Carolina Medical School, 702 Brinkhous-Bullitt Building, Chapel Hill, NC 27599-7525; ^‡Department of Biomedical Engineering, The University of Virginia Medical School, Box 377 Health Sciences Center, Charlottesville, VA 22908; and ^§Department of Microbiology, University of Texas, Austin, TX 78712-1095

Contributed by Oliver Smithies

Abstract

CC chemokine receptor 2 (CCR2) is a prominent receptor for the monocyte chemoattractant protein (MCP) group of CC chemokines. Mice generated by gene targeting to lack CCR2 exhibit normal leukocyte rolling but have a pronounced defect in MCP-1-induced leukocyte firm adhesion to microvascular endothelium and reduced leukocyte extravasation. Constitutive macrophage trafficking into the peritoneal cavity was not significantly different between CCR2-deficient and wild-type mice. However, after intraperitoneal thioglycollate injection, the number of peritoneal macrophages in CCR2-deficient mice did not rise above basal levels, whereas in wild-type mice the number of macrophages at 36 h was ≈3.5 times the basal level. The CCR2-deficient mice showed enhanced early accumulation and delayed clearance of neutrophils and eosinophils. However, by 5 days neutrophils and eosinophils in both CCR2-deficient and wild-type mice had returned to near basal levels, indicating that resolution of this inflammatory response can occur in the absence of macrophage influx and CCR2-mediated activation of the resident peritoneal macrophages. After intravenous injection with yeast β-glucan, wild-type mice formed numerous large, well-defined granulomas throughout the liver parenchyma, whereas CCR2-deficient mice had much fewer and smaller granulomas. These results demonstrate that CCR2 is a major regulator of induced macrophage trafficking in vivo.

Footnotes

↵ † To whom reprint requests should be sent at the present address: Department of Microbiology and Institute for Cellular and Molecular Biology, University of Texas, Austin, TX 78712-1095. e-mail: wakuziel{at}mail.utexas.edu.
↵ ¶ To whom reprint requests should be addressed. e-mail: nobuyo{at}med.unc.edu.
ABBREVIATIONS:

CCR,

CC chemokine receptor;

MCP,

monocyte chemoattractant protein;

ES cell,

embryonic stem cell;

NK,

natural killer