Kuziel, W.A. et al. Severe reduction in leukocyte adhesion and monocyte extravasation in mice deficient in CC chemokine receptor 2. Proc. Natl. Acad. Sci. USA 94, 12053-12058

Department of Pathology and Laboratory Medicine, University of North Carolina Medical School, 702 Brinkhous-Bullitt Building, Chapel Hill, NC 27599-7525, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 10/1997; 94(22):12053-12058. DOI: 10.1073/pnas.94.22.12053
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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.

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    • "presented here confirms these results with respect to the expression of MCP-1, IL-6, and IL-8 but further demonstrates expression at the protein level and documents synergy with OSM stimulation. The demonstration that MCP-1 and macrophages were present in atherosclerotic plaques [26] and that MCP-1 causes monocyte/macrophage chemoattraction and extravasation [27] has implicated MCP-1 in the atherosclerotic process. Mice lacking both the LDL receptor and the MCP-1 genes were found to be protected from atherosclerosis compared to LDL receptor knockout mice [7]. "
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    • "Genetic deletion of Csf1r or Csf1 also results in loss of monocytes and tissue macrophages, but experiments in these mice are difficult to interpret because of additional severe pleiotropic effects, including infertility, osteoporosis , neural development, low body weight, and severe skeletal abnormalities (Wiktor-Jedrzejczak et al., 1990; Dai et al., 2002). The most frequently used mouse model to study monocyte function is the Ccr2 / mouse (Boring et al., 1997; Kuziel et al., 1997), wherein monocytes accumulate in the bone marrow due to a defect in migration (Boring et al., 1997; Peters et al., 2004; Serbina and Pamer, 2006; Tsou et al., 2007; Hohl et al., 2009; Nakano et al., 2009). Most importantly , however, CCR2 is also expressed on CD103 + DCs, NK cells, mature T cells, and activated Th1 cells (Kim et al., 2001; Egan et al., 2009; Hohl et al., 2009; Zhang et al., 2010), and therefore the precise role of monocytes in Ccr2 / and Ccr2 DTR mice is difficult to discern with confidence. "
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    • "À/À mice to determine whether CCR2-dependent migration of candidate progenitor cells, including monocytes and hematopoietic progenitors, contribute to the recovery of tissue-resident macrophages after turnover (Boring et al., 1997). Consistent with prior work (Kuziel et al., 1997; Serbina and Pamer, 2006), Ccr2 À/À mice indeed had lower circulating monocyte numbers (Figure S3A) and also lower steady-state monocyte numbers in the lung and spleen (Figure S3B and data not shown) than did Ccr2 +/À littermates, but they had comparable numbers of BM and lung macrophages (Figures 3B and 3C). Consistent with the lack of a CCR2-depen- dent contribution to steady-state tissue macrophages, we also found that both the extent of the depletion and the kinetics of the recovery were equivalent in DT-infused CD169 "
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