Disease relevance of CCR1

• This has further implications for neuroinflammatory diseases such as multiple sclerosis, where both cells bearing CCR1/CCR5 plus their ligands, as well as HHV-6A, have been linked [1].
• Potential interaction between CCR1 and its ligand, CCL3, induced by endogenously produced interleukin-1 in human hepatomas [2].
• Although CCR4 surface expression was not altered, hepatitis C virus (HCV)-infected patients had lower proportions of CD8 T cells with CCR1 and CCR5 surface expression (P<.05) [3].
• Human cytomegalovirus inhibits the migration of immature dendritic cells by down-regulating cell-surface CCR1 and CCR5 [4].
• Inactivated virus particles did not significantly alter the responsiveness induced by CCR1 and CCR5 agonists [5].

Psychiatry related information on CCR1

• CCR1 is an early and specific marker of Alzheimer's disease [6].
• This expanded immunohistochemical study shows that the number of CCR1-positive plaque-like structures in the hippocampus and entorhinal cortex is highly correlated to dementia state as measured by the clinical dementia rating score [6].

High impact information on CCR1

• SMAD4-deficient intestinal tumors recruit CCR1(+) myeloid cells that promote invasion [7].
• A heightened expression of the CCR1 and CCR5 chemokine receptors may facilitate their preferential localization in lymphoid tissues near epithelial surfaces [8].
• These data demonstrate that HCC-1 is a chemoattractant and identify CCR1 as a functional HCC-1 receptor on human monocytes [9].
• The present study was designed to investigate the effect of bacterial lipopolysaccharide (LPS) on C-C chemokine receptors (CCR) expressed in human mononuclear phagocytes [10].
• We show that Th1, Th2, Th0, and nonpolarized T cells in blood and tissue can express any of the CKRs studied but that each CKR defines a characteristic pool of polarized and nonpolarized CD4 T cells [11].

Chemical compound and disease context of CCR1

• Results from these ongoing studies indicate that substance P acting via neurokinin-1 (NK1) receptors, chemokines interacting with CCR1 receptors and platelet activating factor play an important pro-inflammatory role in regulating the severity of pancreatitis and associated lung injury [12].
• Berlex and its parent company, Schering AG, are developing BX-471 (also known as ZK-811752), the lead in a series of non-peptide chemokine receptor 1 (CCR1) antagonists, for the potential treatment of autoimmune diseases, in particular multiple sclerosis (MS) [291682], [376290], [411184] [13].
• The C-C chemokine receptor-1 (CKR-1), the MCP-1 receptor-A (MCP-1Ra), and MCP-1Rb can reconstitute ligand-induced accumulation of inositol phosphates with PLC beta2 in a pertussis toxin-sensitive manner, presumably through G beta gamma released from the Gi proteins [14].

Biological context of CCR1

• LEC induces chemotaxis and adhesion by interacting with CCR1 and CCR8 [15].
• LEC induced maximal migration of CCR1 and CCR8 transfected cells at 89.3 nmol/L and cell adhesion at 5.6 nmol/L [15].
• We report chemotaxis and competitive binding studies that show LEC binds to and activates CCR1 and CCR8 transfected HEK-293 cells [15].
• Thus, the MPIF-1 signal transduction pathway appears to include binding to CCR1; transduction by G proteins; effector function by phospholipase C, protein kinase C, calcium flux, and PLA2; and cytoskeletal remodeling [16].
• However, CCR1 and CCR5 were lost from the cell surface within 3 h, due to receptor down-regulation mediated by chemokines produced by maturing DC [17].

Anatomical context of CCR1

• Immunoprecipitation and Western blotting with polyclonal antibodies to cytoplasmic peptides clearly showed the presence of CCR1 and CCR4 in platelets in amounts comparable to monocytes and CCR4 transfected cells, respectively [18].
• CCL16 may be specifically cross-linked to CCR1 expressed on endothelial cells [19].
• Considering CC receptors, CCR1 was expressed in 70% of patients with CLL and 40% of those with HCL but was lacking in patients with MCL, MZL, SLL, and normal B cells [20].
• In contrast, MIP-1alpha induced a potent response in eosinophils from a small and previously undescribed subgroup of donors via a non-CCR3 pathway likely to be CCR1 mediated [21].
• Here, we report that cross-talk between CCR1-mediated signaling pathway and FcepsilonRI-mediated signaling pathway affects degranulation positively but affects chemotaxis of mast cells adversely [22].

Associations of CCR1 with chemical compounds

• The strong allergen dinitrochlorobenzene slightly increased CCR7 expression on DCs but down-regulated CCR1 surface expression [23].
• CCR1 down-regulation was not mediated by a classical maturation pathway, as it was unaffected by the corticosteroid dexamethasone [23].
• Our study suggests shikonin may be a target for the future design of more potent, highly selective therapeutics that could be useful antiinflammatory agents for selectively blocking the binding of CCR1 ligands [24].
• In vitro, CCR1 protein was also present on the surface of EVTs that grew out from chorionic villous explants cultured under 20% O2 [25].
• CP-481,715, a potent and selective CCR1 antagonist with potential therapeutic implications for inflammatory diseases [26].

Physical interactions of CCR1

• Additionally, shikonin blocked RANTES and MIP-1alpha binding to stable CC chemokine receptor-1 (CCR1) transfected human embryonic kidney (HEK)/293 cells with IC50 values of 2.63 x 10(-6) and 2.57 x 10(-6) M, respectively [24].
• Eotaxin-3 bound to cells transfected with either CCR1 or -5 as well as to monocytes expressing both receptors [27].
• In the present study, we use enzymatic and chemical cleavage methods on wild-type and mutated CCR1 receptors to show that the N terminus of the chemokine MIP-1alpha interacts in a specific manner with the second extracellular loop of the CCR1 receptor, within a segment comprising amino acids 178 to 194 [28].
• The present manuscript details the discovery and early fundamental structure-activity relationship studies involving compound 3, a novel hydroxyethylene peptide isostere derived molecule that provides micromolar inhibition of CCL3 binding to its receptor CCR1 [29].
• Macrophage inflammatory peptide-1alpha (MIP-1alpha)/CC-chemokine receptor ligand 3 is an 8-kDa peptide that induces chemotaxis of various lymphocytes to sites of inflammation through interaction with the G protein-coupled chemokine receptors CCR1 and CCR5 [28].

Enzymatic interactions of CCR1

• Interestingly, CCR1 cross-phosphorylated and cross-desensitized CXCR2, but not CXCR1 [30].

Co-localisations of CCR1

• Indirect immunofluorescence analysis revealed that PLP2/A4 was predominantly located in plasma membrane and colocalized with CCR1 in transfected human HEK293 cells [31].

Regulatory relationships of CCR1

• Toll-like receptor (TLR)2 and TLR4 agonists regulate CCR expression in human monocytic cells [32].
• Further investigation of TLR-induced down-modulation of CCR1 revealed differences in the signaling pathways activated, and chemokines generated, via the two TLR agonists [32].
• MC stimulated with interferon-gamma (IFN-gamma) expressed mRNA for the chemokine receptor CCR1 [33].
• Consistent with this binding data, MIP-5 was only able to induce calcium fluxes in CHO cells stably transfected with CCR1 or CCR3 [34].
• CCR1 protein was also up-regulated by GM-CSF stimulation [35].

Other interactions of CCR1

• Constitutive expression of CCR1 and CCR3 mRNA in PMN was detected by ribonuclease protection assay [35].
• By stably expressing five CC chemokine receptors (CCR1 to 5) and five orphan receptors, ELC-SEAP was found to bind specifically to an orphan receptor EBI1 [36].
• Both CCR1- and CCR2B-transfected 293 cells showed significant migration in response to MCP-2, in addition to responding to other specific chemokines [37].
• The CC chemokine receptor (CCR) 1 to 7, 9, and CXC chemokine receptor (CXCR) 1 to 4 were determined by flow cytometric analysis of whole blood and unseparated BAL cells [38].
• However, all three active chemokines have been reported to bind to CCR1 and cross-desensitization studies demonstrate that RANTES and MIP-1alpha can partially inhibit the chemotactic response elicited by CKbeta-8 [39].

Analytical, diagnostic and therapeutic context of CCR1

• METHODS AND RESULTS: We analyzed 169 sequential human endomyocardial biopsies by immunocytochemistry for infiltration by CD3(+) T cells and the expression of the chemokine receptors CCR1, CCR3, CCR5, and CXCR3 [40].
• In particular, CCR1 and CXCL10, which showed increased expression prior to rejection and returned to baseline levels with antirejection therapy, may have potential use in immunomonitoring and as predictive factors of rejection prior to its clinical manifestation [41].
• Lymphocyte phenotypes and chemokine receptor (CCR) expression were evaluated by flow cytometry on fresh PBMC from 20 PPMS patients enrolled in a placebo (PLC)-controlled trial of MX [42].
• Chemokines that can bind to CCR1 (CCR1 ligands), such as regulated on activation, normal T cell expressed and secreted (RANTES) and macrophage inflammatory protein-1alpha (MIP-1alpha), were confirmed in the decidual tissues by RT-PCR and immunohistochemistry [25].
• Molecular cloning of cDNAs encoding a LD78 receptor and putative leukocyte chemotactic peptide receptors [43].

References