Disease relevance of Ccr2

• A 2-fold increase in the number of mononuclear cells that express CCR2 was also found in rats with orchitis compared with controls [1].
• The histopathological analysis of tissues from the delayed-type hypersensitivity model demonstrates that inhibition of CCR2 leads to a substantial reduction in tissue inflammation, suggesting that macrophages play an orchestrating role in immune-based inflammatory reactions [2].
• Recent studies demonstrated that the chemokine monocyte chemoattractant protein-1 (MCP-1)/CCL2 and its receptor, CCR2, play important roles in various brain diseases [3].
• We used a reproducible model of focal excitotoxic brain injury elicited by intrahippocampal injection of NMDA (10 nmol) in 7-day-old rats, to examine injury-induced alterations in MCP-1 and CCR2 expression [4].
• These results demonstrate that CCR2 expression is markedly upregulated in this brain tumor model [5].

High impact information on Ccr2

• Flow cytometry revealed novel expression of the CC chemokine receptors CCR1 and CCR2 on neutrophils from adjuvant-immunized animals [6].
• MCP-1/CCR2 signaling is directly involved with a chronic compression injury and may contribute to associated neuronal hyperexcitability and neuropathic pain [7].
• Using a neuropathic pain model, chronic compression of the DRG (CCD), we compared anatomically separate populations of noncompressed lumbar DRG (L3/L6) with compressed lumbar DRG (L4/L5) for changes in the gene expression of CCR2 [7].
• Endothelial cell (EC) CCR2 was down-regulated as arthritis progressed, inversely correlating with inflammation [8].
• At baseline, primed macrophages expressed a small subset of IFN-gamma-inducible genes, including CCR2, and exhibited increased migration in response to CCL2 [9].

Chemical compound and disease context of Ccr2

• PPARgamma activation with pioglitazone prevented coronary arteriosclerosis, possibly by its antiinflammatory effects (downregulation of CCR2 in circulating monocytes) [10].
• OBJECTIVE: To investigate the importance of monocyte recruitment in thrombus resolution and the role of cysteine-cysteine (CC) chemokines and the CC chemokine receptor, CCR2, in this process [11].
• In contrast, Ang II-induced left ventricular hypertrophy developed in CCR2-/- and BMT-CCR2-/- mice [12].

Biological context of Ccr2

• Furthermore, using dual fluorescent immunohistochemistry we studied the chemical phenotype of labeled neurons and demonstrated the coexistence of CCR2 with classical neurotransmitters [13].
• CONCLUSION: CCR1, CCR2, and CCR5 mRNA expression and tyrosine phosphorylation increased with peak inflammation in the AIA model [14].
• Antagonist 37 had a CCR2 IC50 of 59 nM and excellent potency in a functional assay measuring inhibition of MCP-1 induced monocyte chemotaxis (IC50 of 41 nM) [15].
• Inhibition of the MCP-1 to CCR2 pathway may represent novel anti-inflammatory actions of amlodipine beyond blood pressure lowering [16].

Anatomical context of Ccr2

• Finally, we show that the preferential CCR2 ligand, MCP-1/CCL2, elicits Ca(2+) transients in primary cultured neurons from various rat brain regions including the cortex, hippocampus, hypothalamus, and mesencephalon [13].
• Indeed, localization of CCR2 immunostaining is observed in dopaminergic neurons in the substantia nigra pars compacta and in the ventral tegmental area as well as in cholinergic neurons in the substantia innominata and caudate putamen [13].
• METHODS AND RESULTS: Both MCP-1 and CCR2 mRNAs and proteins increased in old (30-month) versus young (8-month) F344xBN rat aortas in vivo [17].
• Rat aortic MCP-1 and its receptor CCR2 increase with age and alter vascular smooth muscle cell function [17].
• Moreover, using double fluorescent immunohistochemistry, we showed that CCR2 receptors were constitutively expressed on neurons and astrocytes [3].

Associations of Ccr2 with chemical compounds

• Because arterial angiotensin II, which induces MCP-1 expression, increases with age, we hypothesized that aortic MCP-1 and its receptor CCR2 are also upregulated and affect VSMC properties [17].
• Inhibition of the CCR2-mediated inflammation may represent novel antiinflammatory actions of pioglitazone beyond improvement of metabolic state [10].
• CCR2 deficiency has the same effect as blockade of all CC chemokines [11].
• Treatment of 21 normocholesterolemic men with simvastatin (20 mg/d for 2 weeks) decreased CCR2 protein and mRNA expression in circulating monocytes [18].
• Enhanced CCR2 intensity on monocytes was observed in hypertensive patients and rats, and was reduced by treatment with the Ang II receptor blocker, supporting the clinical relevance of the observation in mice [12].

Physical interactions of Ccr2

• In this study, using quantitative autoradiography, we studied the pharmacological properties of [125l]MCP-1/CCL2 binding in rat brain and we clearly showed the distribution of CCR2 receptors in cerebral cortex, nucleus accumbens, striatum, amygdala, thalamus, hypothalamus, hippocampus, substantia nigra, mammillary bodies and raphe nuclei [3].

Other interactions of Ccr2

• Neuronal expression of CCR2 was observed in the anterior olfactory nucleus, cerebral cortex, hippocampal formation, caudate putamen, globus pallidus, supraoptic and paraventricular hypothalamic nuclei, amygdala, substantia nigra, ventral tegmental area, and in the brainstem and cerebellum [13].
• Additionally, increases in tyrosine phosphorylation of CCR1 (days 14, 18, 21, and 24), CCR2 (days 14 and 18), and CCR5 (days 14, 18, and 21) were detected in AIA rats compared with control (nonarthritic) rats [14].
• As to their receptors, the levels of CCR1, CCR2, and CXCR3 mRNAs showed significant and prominent elevations, CCR5 mRNA also increased moderately, and their receptor protein-expressing cells also increased [19].
• Moreover, CCR2 was associated with JAK-2, STAT-1, and STAT-3 on day 18 [14].

Analytical, diagnostic and therapeutic context of Ccr2

• In situ hybridization revealed that CCR2 mRNA was up-regulated in neurons and nonneuronal cells present in both compressed L4/L5 and ipsilateral noncompressed L3/L6 DRGs at postoperative day 5 (POD5) [7].
• These data are largely in accordance with results obtained using quantitative autoradiography with [(125)I]MCP-1/CCL2 and RT-PCR CCR2 mRNA analysis [13].
• In this work, using a semiquantitative immunohistochemistry approach, we provide the first neuroanatomical mapping of constitutive neuronal CCR2 localization [13].
• RT-PCR analysis showed high levels of both MCP-1 and CCR2 mRNA and Western blot analysis demonstrated increased CCR2 protein in tumor extracts [5].
• Expression of the MCP-1 receptor CCR2 in neurosphere cultures was verified by RT-PCR and immunofluorescence microscopy [20].

References