Disease relevance of CCR2

• The role of CCR5 and CCR2 polymorphisms in HIV-1 transmission and disease progression [1].
• Augmentation of monocyte CCR2 expression may underlie unexplained in vivo effects of GC as well as some of their actions on HIV infection [2].
• However, the involved pathways are different, although in either case coupling of CCR2 to pertussis toxin-sensitive heterotrimeric G proteins is necessary [3].
• The present study was designed to investigate the expression of CCR2 in tumor-associated macrophages (TAM) from ovarian cancer patients [4].
• Roles of CCR2 and CXCR3 in the T cell-mediated response occurring during lupus flares [5].

High impact information on CCR2

• A chemokine receptor CCR2 allele delays HIV-1 disease progression and is associated with a CCR5 promoter mutation [6].
• A recent study showed that a conservative substitution (V64I) in the coding region of CCR2 also has a significant impact on disease progression, but not on HIV-1 transmission [6].
• Here we focus on findings in the CCL2-CCR2 and CCL3-CCR5 ligand-receptor systems [7].
• First, we examined whether prominent CCRs on different monocyte subsets, CCR2 or CX3CR1, mediated migration events upstream of the accumulation of monocyte-derived DCs in lymph nodes (LNs) [8].
• In contrast, IL-2 augmented CCR2 expression and MCP-1 itself had no effect [9].

Chemical compound and disease context of CCR2

• Finally, Dex treatment induced productive replication of the HIV strain 89.6, which utilizes CCR2 as entry coreceptor, in freshly isolated monocytes [2].
• A transition causing a valine to isoleucine substitution in transmembrane domain I of the CCR2 gene (CCR2-64I) that has a protective effect against the progression of human immunodeficiency virus-1 (HIV-1) disease has been described [10].
• 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 [11].
• The effect of a valine to isoleucine switch in the CCR2 first transmembrane domain (CCR2 64I) on the clinical course of human immunodeficiency virus type 1 (HIV-1) infection was analyzed in relation to the presence or absence of syncytium-inducing (SI) HIV-1 variants [12].
• Chemokines in the MPTP model of Parkinson's disease: Absence of CCL2 and its receptor CCR2 does not protect against striatal neurodegeneration [13].

Biological context of CCR2

• We conjecture a role for CCR2 as a coreceptor for HIV-1 infection and map the HIV-1 binding site to the amino-terminal part of this receptor [14].
• We have shown previously that in human monocytes, bacterial lipopolysaccharide, IL-1, and tumor necrosis factor-alpha induce a rapid down-regulation of the monocyte chemotactic protein-1 receptor CCR2 (CC chemokine receptor-2) [15].
• Augmentation of CCR2 expression by Dex was associated with increased chemotaxis [2].
• CCR2 gene expression and chemotactic response to MCP-1 were decreased to a lesser extent in blood monocytes from cancer patients [4].
• It is conceivable that the intracellular signal transduction pathway that is activated by eotaxin could cause an attenuation of proinflammatory responses mediated by CCR2 [3].

Anatomical context of CCR2

• Consistent with these results, MCP-5 induced a calcium flux in human embryonic kidney (HEK)-293 cells transfected with human and murine CCR2, a CC chemokine receptor expressed on monocytes [16].
• CCR2, the receptor for CCL2, was more frequently expressed by iNKT compared with natural killer and T cells from blood (P < 0.001) [17].
• Differentiation of monocytes into macrophages also resulted in an increased secretion of MCP-1 that, at least in part, was responsible for the downmodulation of its receptor (CCR2) [18].
• The loss of CCR2 mRNA expression in 7-day-cultured macrophages was associated with a strong reduction in the receptor expression at the plasma membrane, as well as in the monocyte chemotactic protein (MCP-1) binding, as compared with freshly isolated monocytes [18].
• Using the monocyte cell line THP-1, we investigated the relative abilities of eotaxin and MCPs 1-4 to induce CCR2 signaling, employing assays of directed cell migration and intracellular calcium flux [19].

Associations of CCR2 with chemical compounds

• In human monocytes, the antioxidant pyrrolidine dithiocarbamate (PDTC) rapidly inhibited CCR2 (95-100% of inhibition) and CCR5 (77-100% of inhibition) mRNA expression by strongly decreasing transcript stability [15].
• Accordingly, H(2)O(2) and the glutathione-depleting drug buthionine sulfoximine increased to different extents CCR2, CCR5, and CXCR4 mRNA expression [15].
• FXa-induced CCR2 mRNA expression was completely abolished by JNK and tyrosine kinase inhibition [20].
• To identify the regions of MCP-1 that contact its receptor, CCR2, we substituted all surface-exposed residues with alanine [21].
• This effect of irbesartan on MCP-1 occurred without an effect on CCR2, the receptor of MCP-1 [22].

Physical interactions of CCR2

• Here we show that eotaxin-3 also binds to CCR2 on monocytes and CCR2-transfected cells [23].
• This study shows that eotaxin also interacts with CCR2 and CCR5 and can, thus, affect the responses of monocytes, which express both receptors [24].
• MCP-1 binds the chemokine receptor CCR2 [4].
• CONCLUSION: These results suggest that CCR2A binds to CCR5 in the cytoplasm and down-modulates its surface expression [25].

Regulatory relationships of CCR2

• Monocyte chemoattractant protein-1-induced CCR2B receptor desensitization mediated by the G protein-coupled receptor kinase 2 [26].
• Induction of heme oxygenase-1 in monocytes suppresses angiotensin II-elicited chemotactic activity through inhibition of CCR2: role of bilirubin and carbon monoxide generated by the enzyme [27].
• The chemokine monocyte chemoattractant protein-1 induces functional responses through dimerization of its receptor CCR2 [28].
• However, not all CD163-positive cells expressed CCR2, which could be interpreted as a mechanism for retaining the macrophages in the skin [29].
• Pro-activatory anti-CD43 monoclonal antibody (MoAb) induced polarization of T lymphocytes with redistribution of CD43 to the uropod and the CCR2 chemokine receptor to the leading edge of the cell [30].

Other interactions of CCR2

• We show that, in the chemokine response, heterodimerization is also permitted between given receptor pairs, specifically between CCR2 and CCR5 [31].
• Direct receptor binding experiments with the CysL24-51 peptide confirmed binding to cells transfected with CCR2 and CCR3 [32].
• Eotaxin-3 is a natural antagonist for CCR2 and exerts a repulsive effect on human monocytes [23].
• Eotaxin is a natural antagonist for CCR2 and an agonist for CCR5 [24].
• RESULTS: Most normal PB monocytes expressed CCR1 (87%) and CCR2 (84%), but not CCRs 3, 4, 5, or 6 or CXCR3 [33].

Analytical, diagnostic and therapeutic context of CCR2

• TAM isolated from ascitic or solid ovarian carcinoma displayed defective CCR2 mRNA (Northern blot and PCR) and surface expression and did not migrate in response to MCP-1 [4].
• Expression of CCR2 by peripheral blood lymphocytes was determined by flow cytometry [34].
• The increase in CCR2(+) LPLs in SBCD was confirmed by both immunohistochemistry (p = 0.0002) and enhanced chemotactic responses to CCL2 [34].
• RANTES, CCR2, and CCR5 expression did not change in ischemic vs. reperfusion biopsies [35].
• By immunohistochemistry and in situ hybridization we have observed that CCR2 isoforms were expressed by different cell subsets in both normal and IIM muscle [36].

References