Kuziel WA, Morgan SJ, Dawson TC, Griffin S, Smithies O, Ley K, Maeda NSevere reduction in leukocyte adhesion and monocyte extravasation in mice deficient in CC chemokine receptor 2. Proc Natl Acad Sci USA 94:12053-12058
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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"In an atheroma model, CXCL8/CXCR2 interactions were necessary for firm adhesion of monocytes to vascular endothelium (Gerszten et al. 1999). CCR2 signaling then promotes proinflammatory monocyte migration into peripheral tissues in response to stable extracellular matrix –associated CCL2 gradients (Fig. 1) (Kuziel et al. 1997; Proudfoot et al. 2003). "
"We also examined the outcome of TBI in wt mice compared to homozygous Ccr2-deficient mice  three days postinjury. Lysozyme 2 (Lyz2) previously identified by microarray analysis as injury-induced in neocortex1 was among the transcripts found reduced in the injured Ccr2−/− cortex. "
[Show abstract][Hide abstract] ABSTRACT: Brain trauma is known to activate inflammatory cells via various chemokine signals although their interactions remain to be characterized. Mice deficient in Ccl3, Ccr2 or Cxcl10 were compared with wildtype mice after controlled cortical impact injury. Expression of Ccl3 in wildtypes was rapidly upregulated in resident, regularly spaced reactive microglia. Ccl3-deficiency enhanced endothelial expression of platelet selectin and invasion of peripheral inflammatory cells. Appearance of Ccr2 transcripts, encoding the Ccl2 receptor, reflected invasion of lysozyme 2-expressing phagocytes and classical antigen-presenting dendritic cells expressing major histocompatibility complex class II. Ccr2 also directed clustered plasmacytoid dendritic cells positive for the T-cell attracting chemokine Cxcl10. A reduction in Ccr2 and dendritic cells was found in injured wildtype cortex after cyclophosphamide treatment resembling effects of Ccr2-deficiency. The findings demonstrate the feasibility to control inflammation in the injured brain by regulating chemokine-dependent pathways.
"However, some chemokines fall into both categories. In addition to cell migration, other biological functions have been ascribed to chemokine receptors, e.g., angiogenic effects (13, 14), cell-adhesion and cell-extravasation (15, 16), as well as anti-apoptotic signaling (17, 18). "
[Show abstract][Hide abstract] ABSTRACT: Biased signaling or functional selectivity occurs when a 7TM-receptor preferentially activates one of several available pathways. It can be divided into three distinct forms: ligand bias, receptor bias, and tissue or cell bias, where it is mediated by different ligands (on the same receptor), different receptors (with the same ligand), or different tissues or cells (for the same ligand-receptor pair). Most often biased signaling is differentiated into G protein-dependent and β-arrestin-dependent signaling. Yet, it may also cover signaling differences within these groups. Moreover, it may not be absolute, i.e., full versus no activation. Here we discuss biased signaling in the chemokine system, including the structural basis for biased signaling in chemokine receptors, as well as in class A 7TM receptors in general. This includes overall helical movements and the contributions of micro-switches based on recently published 7TM crystals and molecular dynamics studies. All three forms of biased signaling are abundant in the chemokine system. This challenges our understanding of "classic" redundancy inevitably ascribed to this system, where multiple chemokines bind to the same receptor and where a single chemokine may bind to several receptors - in both cases with the same functional outcome. The ubiquitous biased signaling confers a hitherto unknown specificity to the chemokine system with a complex interaction pattern that is better described as promiscuous with context-defined roles and different functional outcomes in a ligand-, receptor-, or cell/tissue-defined manner. As the low number of successful drug development plans implies, there are great difficulties in targeting chemokine receptors; in particular with regard to receptor antagonists as anti-inflammatory drugs. Un-defined and putative non-selective targeting of the complete cellular signaling system could be the underlying cause of lack of success. Therefore, biased ligands could be the solution.
Full-text · Article · Jun 2014 · Frontiers in Immunology