Disease relevance of Ccr2

• Genetic deficiency in Ccr2 reduced food intake and attenuated the development of obesity in mice fed a high-fat diet [1].
• Prior to 30 min of ischemia as well as at 5, 30, 60, 90, and 120 min after onset of reperfusion, migration parameters were determined in wild-type, Ccr1-/-, Ccr2-/-, and Ccr5-/- mice [2].
• Here, we show that following intradermal infection with Mycobacterium avium, a similar arthritis phenotype was detected in Ccr2-null mice in the DBA/1j, but not in the BALB/c background [3].
• An animal model of age-related macular degeneration in senescent Ccl-2- or Ccr-2-deficient mice [4].
• After intravenous injection with yeast beta-glucan, wild-type mice formed numerous large, well-defined granulomas throughout the liver parenchyma, whereas CCR2-deficient mice had much fewer and smaller granulomas [5].
• Application of anti-CCR2 Ab MC21 to block the CCL2-CCR2 axis in CCL2 overexpressing mice, though completely abrogating bronchiolitis obliterans, led to progressive pneumococcal pneumonia [6].

High impact information on Ccr2

• Pax5-repressed genes are also reexpressed in plasma cells, which depend for normal function on Cd28 and Ccr2 reactivation [7].
• Infection with the intracellular bacterial pathogen Listeria monocytogenes induces CCR2-dependent monocyte recruitment and activation, an essential response for host survival [8].
• CD8 and CD4 T cell responses to L. monocytogenes antigens are preserved in CCR2-deficient mice, indicating that Tip-DCs are not essential for T cell priming [9].
• We have identified a TNF/iNOS-producing (Tip)-DC subset in spleens of Listeria monocytogenes-infected mice that is absent from CCR2-deficient mice [9].
• Ccr2(-/-) mice had fewer circulating Ly6C(hi) monocytes and, after infection with Listeria monocytogenes, accumulated activated monocytes in bone marrow [10].

Psychiatry related information on Ccr2

• Alzheimer disease mice deficient in Ccr2 accumulated Abeta earlier and died prematurely, in a manner that correlated with Ccr2 gene dosage, indicating that absence of early microglial accumulation leads to decreased Abeta clearance and increased mortality [11].

Chemical compound and disease context of Ccr2

• To achieve this goal, we investigated renal interstitial fibrosis induced by a unilateral ureteral obstruction in CCR2 gene-targeted mice and mice treated with propagermanium or RS-504393, CCR2 inhibitors [12].
• Pulmonary fibrosis was induced in CCR2-/- and wild-type (CCR2+/+) mice by intratracheal instillation of bleomycin [13].
• Monocyte chemoattractant protein-1 mediates cockroach allergen-induced bronchial hyperreactivity in normal but not CCR2-/- mice: the role of mast cells [14].
• The ability of IL-13 to increase lung size, alveolar size, and lung compliance, to stimulate pulmonary inflammation, hyaluronic acid accumulation, and tissue fibrosis, and to cause respiratory failure and death were markedly decreased, whereas mucus metaplasia was not altered in CCR2(-/-) mice [15].
• CONCLUSIONS: Leukocyte-derived CCR2 is critical in Ang II-induced atherosclerosis and abdominal aneurysm formation [16].

Biological context of Ccr2

• In obese mice matched for adiposity, Ccr2 deficiency reduced macrophage content and the inflammatory profile of adipose tissue, increased adiponectin expression, ameliorated hepatic steatosis, and improved systemic glucose homeostasis and insulin sensitivity [1].
• To determine what role CCR2 plays in the development of metabolic phenotypes, we studied the effects of Ccr2 genotype on the development of obesity and its associated phenotypes [1].
• CCR2 modulates inflammatory and metabolic effects of high-fat feeding [1].
• These data suggest that CCR2 influences the development of obesity and associated adipose tissue inflammation and systemic insulin resistance and plays a role in the maintenance of adipose tissue macrophages and insulin resistance once obesity and its metabolic consequences are established [1].
• Creation of receptor chimeras suggested that the amino terminus was critically involved in mediating signal transduction and ligand specificity of the mJE receptor, but not the mMIP-1alpha receptor [17].

Anatomical context of Ccr2

• Wild-type choroidal macrophages degrade C5 and IgG in eye sections of Ccl2(-/-) or Ccr2(-/-) mice [4].
• Ccr2 regulates the level of MCP-1/CCL2 in vitro and at inflammatory sites and controls T cell activation in response to alloantigen [18].
• Additionally, T cells from CCR2(-/)- immunized mice showed decreased antigen-induced proliferation and production of IFN-gamma compared with wild-type immunized controls, suggesting that CCR2 enhances the T helper cell type 1 immune response in EAE [19].
• The C-C motif chemokine receptor-2 (CCR2) regulates monocyte and macrophage recruitment and is necessary for macrophage-dependent inflammatory responses and the development of atherosclerosis [1].
• 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 [5].

Associations of Ccr2 with chemical compounds

• Ethanol treatment (2.5 g/kg, i.p.) induced stronger conditioned taste aversion in Ccr2, Ccl2 or Ccl3 null mutant mice than in controls [20].
• The CCR7 and CCR2 chemokine ligands are required for both T cell sequestration in LN and thymic T cell egress following FTY720 administration [21].
• Wild-type mice treated with MC21 to block CCR2 function or with anti-Gr-1 to deplete neutrophils did not exhibit the vascular leakage that typically accompanies inflammation triggered by CCL2 and LPS in wild-type mice [22].
• At days 14 and 21, lung remodelling and the hydroxyproline content of lung tissues were significantly reduced in CCR2-/- mice [13].
• RESULTS: Estrogen and tamoxifen significantly decreased expression of CCR2 and, to a lesser extent, CXCR3 on murine monocytes [23].

Physical interactions of Ccr2

• Evidence that MCP-1 levels are regulated by receptor binding and internalization was suggested by its rapid decline when added to WT macrophages at 37 degrees C but not 4 degrees C. These studies indicate that CCR2 plays an important role in regulating T cell responses and controlling the level of MCP-1 at inflammatory sites [18].
• Lastly, CCL2-induced mØ transendothelial migration was blocked by treatment of WT BMEC with pertussis toxin, suggesting that CCR2 is functionally coupled to the inhibitory G protein Galphai, much as it is in other cell types [24].

Regulatory relationships of Ccr2

• Macrophage invasion was significantly impaired in CCR2-knockout mice when compared with wildtype controls and CCR5-deficient mice [25].
• Expression of matrix metalloproteinases and tumor necrosis factor-alpha mRNAs was up-regulated in infarcted regions from WT mice compared to CCR2(-/-) mice at 3 days after MI [26].
• CCR2 is required for CD8-induced graft-versus-host disease [27].

Other interactions of Ccr2

• Supplementation of CCR2-/- mice with IFN-gamma normalized early thrombus resolution without increasing monocyte influx [28].
• Already after 5 min of reperfusion, this increase was reduced significantly in Ccr1-/- and Ccr5-/- mice, whereas only in Ccr2-/- mice, was adherence attenuated significantly at 120 min after onset of reperfusion [2].
• Early fibrinolysis was not impaired in CCR2-/- mice, but a significant reduction in both matrix metalloproteinase (MMP)-2 and MMP-9 activity was observed [28].
• Differential role of CCR2 in islet and heart allograft rejection: tissue specificity of chemokine/chemokine receptor function in vivo [29].
• CCR2 is required for monocyte recruitment in many inflammatory processes, as well as conferring Th1 lymphokine responses [28].

Analytical, diagnostic and therapeutic context of Ccr2

• Mice deficient for the major MCP-1 receptor, CC chemokine receptor (CCR)2, did not develop EAE after active immunization but generated effector cells that could transfer the disease to naive wild-type recipients [30].
• Furthermore, in contrast to the islet transplants, CCR2 deficiency offered only marginal prolongation of heart allograft survival [29].
• In addition, CCR2-/- recipients had a reduced Th1 and increased Th2 alloresponse in the periphery (by ELISPOT analysis) as well as in the grafts (by RT-PCR) [29].
• Three weeks after femoral artery ligation, LDI perfusion ratio of operated versus nonoperated distal hindlimb in BALB/c wild-type mice increased to 0.45+/-0.06 and in CCR2(-/-) animals only to 0.21+/-0.03 (P<0.01) [31].
• A critical role for CCR2/MCP-1 interactions in the development of idiopathic pneumonia syndrome after allogeneic bone marrow transplantation [32].

References