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Korbecki, Jan, Klaudyna Kojder, Katarzyna Barczak, Donata Simińska, Izabela Gutowska, Dariusz Chlubek i Irena Baranowska-Bosiacka. "Hypoxia Alters the Expression of CC Chemokines and CC Chemokine Receptors in a Tumor–A Literature Review". International Journal of Molecular Sciences 21, nr 16 (6.08.2020): 5647. http://dx.doi.org/10.3390/ijms21165647.
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Hypoxia, i.e., oxygen deficiency condition, is one of the most important factors promoting the growth of tumors. Since its effect on the chemokine system is crucial in understanding the changes in the recruitment of cells to a tumor niche, in this review we have gathered all the available data about the impact of hypoxia on β chemokines. In the introduction, we present the chronic (continuous, non-interrupted) and cycling (intermittent, transient) hypoxia together with the mechanisms of activation of hypoxia inducible factors (HIF-1 and HIF-2) and NF-κB. Then we describe the effect of hypoxia on the expression of chemokines with the CC motif: CCL1, CCL2, CCL3, CCL4, CCL5, CCL7, CCL8, CCL11, CCL13, CCL15, CCL16, CCL17, CCL18, CCL19, CCL20, CCL21, CCL22, CCL24, CCL25, CCL26, CCL27, CCL28 together with CC chemokine receptors: CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, and CCR10. To better understand the effect of hypoxia on neoplastic processes and changes in the expression of the described proteins, we summarize the available data in a table which shows the effect of individual chemokines on angiogenesis, lymphangiogenesis, and recruitment of eosinophils, myeloid-derived suppressor cells (MDSC), regulatory T cells (Treg), and tumor-associated macrophages (TAM) to a tumor niche.
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Princen, Katrien, Sigrid Hatse, Kurt Vermeire, Stefano Aquaro, Erik De Clercq, Lars-Ole Gerlach, Mette Rosenkilde i in. "Inhibition of Human Immunodeficiency Virus Replication by a Dual CCR5/CXCR4 Antagonist". Journal of Virology 78, nr 23 (1.12.2004): 12996–3006. http://dx.doi.org/10.1128/jvi.78.23.12996-13006.2004.
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ABSTRACT Here we report that the N-pyridinylmethyl cyclam analog AMD3451 has antiviral activity against a wide variety of R5, R5/X4, and X4 strains of human immunodeficiency virus type 1 (HIV-1) and HIV-2 (50% inhibitory concentration [IC50] ranging from 1.2 to 26.5 μM) in various T-cell lines, CCR5- or CXCR4-transfected cells, peripheral blood mononuclear cells (PBMCs), and monocytes/macrophages. AMD3451 also inhibited R5, R5/X4, and X4 HIV-1 primary clinical isolates in PBMCs (IC50, 1.8 to 7.3 μM). A PCR-based viral entry assay revealed that AMD3451 blocks R5 and X4 HIV-1 infection at the virus entry stage. AMD3451 dose-dependently inhibited the intracellular Ca2+ signaling induced by the CXCR4 ligand CXCL12 in T-lymphocytic cells and in CXCR4-transfected cells, as well as the Ca2+ flux induced by the CCR5 ligands CCL5, CCL3, and CCL4 in CCR5-transfected cells. The compound did not interfere with chemokine-induced Ca2+ signaling through CCR1, CCR2, CCR3, CCR4, CCR6, CCR9, or CXCR3 and did not induce intracellular Ca2+ signaling by itself at concentrations up to 400 μM. In freshly isolated monocytes, AMD3451 inhibited the Ca2+ flux induced by CXCL12 and CCL4 but not that induced by CCL2, CCL3, CCL5, and CCL7. The CXCL12- and CCL3-induced chemotaxis was also dose-dependently inhibited by AMD3451. Furthermore, AMD3451 inhibited CXCL12- and CCL3L1-induced endocytosis in CXCR4- and CCR5-transfected cells. AMD3451, in contrast to the specific CXCR4 antagonist AMD3100, did not inhibit but enhanced the binding of several anti-CXCR4 monoclonal antibodies (such as clone 12G5) at the cell surface, pointing to a different interaction with CXCR4. AMD3451 is the first low-molecular-weight anti-HIV agent with selective HIV coreceptor, CCR5 and CXCR4, interaction.
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Zvejniece, Laura, Svetlana Kozireva, Zanna Rudevica, Ainars Leonciks, Barbro Ehlin-Henriksson, Elena Kashuba i Irina Kholodnyuk. "Expression of the Chemokine Receptor CCR1 in Burkitt Lymphoma Cell Lines Is Linked to the CD10-Negative Cell Phenotype and Co-Expression of the EBV Latent Genes EBNA2, LMP1, and LMP2". International Journal of Molecular Sciences 23, nr 7 (22.03.2022): 3434. http://dx.doi.org/10.3390/ijms23073434.
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Chemokines and their receptors regulate the migration of immune cells and the dissemination of cancer cells. CCR1, CCR2, CCR3, and CCR5 all belong to a single protein homology cluster and respond to the same inflammatory chemokines. We previously reported that CCR1 and CCR2B are induced upon Epstein-Barr virus (EBV) infection of B cells in vitro. EBV is present in almost all cases of endemic Burkitt lymphoma (BL); however, the contribution of EBV in the pathogenesis of the disease is not fully understood. Here, we analyzed the relation of the expression of CCR1, CCR2, CCR3, and CCR5, the EBV DNA load and expression of EBV latent genes in nine EBV-carrying and four EBV-negative BL cell lines. We revealed that CCR1 is expressed at high mRNA and protein levels in two CD10-negative BL cell lines with co-expression of the EBV latent genes EBNA2, LMP1, and LMP2. Low levels of CCR2 transcripts were found in three BL cell lines. CCR3 and CCR5 transcripts were hardly detectable. Our data suggest that in vivo, CCR1 may be involved in the dissemination of BL cells and in the selection of BL cells with restricted EBV gene expression programs.
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Wenzl, Kerstin, Katharina Troppan, Alexander JA Deutsch, Werner Linkesch, Peter Neumeister i Christine Beham-Schmid. "Distinct Chemokine Receptor Profile In Chronic Lymphocytic Leukaemia and Richter Transformed Diffuse Large B Cell Lymphomas Compared To Germinal Center B Cells and De Novo Diffuse Large B Cell Lymphomas". Blood 122, nr 21 (15.11.2013): 4852. http://dx.doi.org/10.1182/blood.v122.21.4852.4852.
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Abstract Chemokine receptors are G-protein-coupled cell surface receptors, which dissociate upon activation by their ligands and cause downstream signaling. Recently, several studies have revealed the crucial contribution of chemokine receptors and their ligands in normal B-cell differentiation and development of hematopoietic malignancies. The Richter syndrome (RS) represents the clinico-pathologic transformation of chronic lymphocytic leukaemia (CLL) to an aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL). Due to the lack of knowledge on the chemokine receptors in RS, we aimed to investigate their expression profile in Richter syndrome patients. Therefore, we investigated the mRNA expression levels of 18 known chemokine receptors (CCR1-CCR9, CXCR1-CXCR7, XCR1, CX3CR1) by using semi-quantitative real time PCR on seven samples of paired (CLL and transformed DLBCL) RS samples, and six samples of de novo DLBCL, additionally four CLL samples –all of them transformed into DLBCL-, and eight transformed DLBCL samples –all of them originated from CLL- were included. Four samples of peripheral B cells and four samples of germinal center B cells (GCB) served as non-neoplastic controls. 11 out of 18 chemokine receptors were differentially expressed in CLL (RL) and transformed DLBCL originated from CLL (RH) compared to GCBs. RL exhibited an at least 15-fold higher expression of CCR2, CCR4, CCR7, CXCR3, and XCR1, as well as a de novo expression of CCR3, CCR8, CXCR1, CXCR2, and CX3CR1 compared to GCB. Additionally to these chemokine receptors, CCR1 also showed significant higher expression levels comparing GCB and RH samples. Only one chemokine receptor was found to be differentially expressed in our seven paired RS samples: CCR6 showed a trend of up-regulation in CLL components. Interestingly, the transformed DLBCL originated from CLL were characterized by a significant up-regulation of six chemokine receptors (CCR3, CCR7, CXCR1, CXCR3, CXCR4, and CX3CR1) and a down-regulation of CCR5 compared to DLBCL. Our data indicate that the chemokine receptor expression profile of CLL and transformed DLBCL, originated from CLL samples, differs substantially from those of non neoplastic germinal center B cells and de novo DLBCL, suggesting other cellular origin and an impact on more aggressive clinical course of Richter syndrome patients. Hence, these multiple deregulated CC and CXC receptor might serve as useful prognostic tool to separate high malignant Richter syndrome from de novo DLBCL. Disclosures: No relevant conflicts of interest to declare.
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Zhang, Yi-jun, Tatjana Dragic, Yunzhen Cao, Leondios Kostrikis, Douglas S. Kwon, Dan R. Littman, Vineet N. KewalRamani i John P. Moore. "Use of Coreceptors Other Than CCR5 by Non-Syncytium-Inducing Adult and Pediatric Isolates of Human Immunodeficiency Virus Type 1 Is Rare In Vitro". Journal of Virology 72, nr 11 (1.11.1998): 9337–44. http://dx.doi.org/10.1128/jvi.72.11.9337-9344.1998.
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ABSTRACT We have tested a panel of pediatric and adult human immunodeficiency virus type 1 (HIV-1) primary isolates for the ability to employ the following proteins as coreceptors during viral entry: CCR1, CCR2b, CCR3, CCR4, CCR5, CCR8, CXCR4, Bonzo, BOB, GPR1, V28, US28, and APJ. Most non-syncytium-inducing isolates could utilize only CCR5. All syncytium-inducing viruses used CXCR4, some also employed V28, and one (DH123) used CCR8 and APJ as well. A longitudinal series of HIV-1 subtype B isolates from an infected infant and its mother utilized Bonzo efficiently, as well as CCR5. The maternal isolates, which were syncytium inducing, also used CXCR4, CCR8, V28, and APJ.
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Mazur, Grzegorz, Emilia Jaskula, Ilona Kryczek, Dorota Dlubek, Tomasz Wrobel, Aleksandra Butrym, Andrzej Lange i Kazimierz Kuliczkowski. "Gene Expression for Chemokine Receptors Influences Survival of Non-Hodgkin Lymphoma Patients". Blood 116, nr 21 (19.11.2010): 3103. http://dx.doi.org/10.1182/blood.v116.21.3103.3103.
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Abstract Abstract 3103 Non-Hodgkin's lymphoma (nHL) represent heterogenous group of lymphoid malignancies derived from B and T lymphocytes, NK cells or histiocytes. Most of lymphomas are B-cell origin. Lymphoma cells can migrate to other organs and their migration could be linked to chemokines and their receptors. Chemokine receptors are expressed by many cell populations, including lymphoid cells, and their main function is lymphocytes. Chemokine receptors guide lymphocytes homing, chemotaxis, adhesion and interplaying between immunologic system response cells. They are also responsible for cancer metastasis, including also dissemination of Hodgkin's and non-Hodgin's lymphomas. The purpose of the study was to determinate expression of genes coding chemokine receptors: CXCR4, CCR1, CCR2a, CCR2b, CCR3, CCR5, CCR7 and CCR8 in lymphoma lymph nodes comparing to their expression in reactive lymph nodes. We also wanted to analyze the influence of chemokine receptor gene expression on lymphoma patient survival. Methods: Chemokine receptor gene expression was evaluated in 63 lymphoma lymph nodes taken from patients (31 women and 32 men, aged 18–81 years; median age 43 years) at the moment of diagnosis. In 25 samples of reactive lymph nodes (taken from 15 women and 10 men; aged 18–59; median age 32 years) expression of chemokine genes was also studied as a control group. Gene expression of chemokine receptors CXCR4, CCR1, CCR2a, CCR2b, CCR3, CCR5, CCR7 and CCR8 was measured by reverse transcription (RT)-polymerase chain reaction method. Gene expression was estimated in arbitrary units (AU) from 0 to 3 AU points scale. PCR was conducted using primer pairs for CXCR4 (sens GAC CGC TAC CTG GCC ATC, antisens GGC AGC CAA CAG GCG AAGg A, 345 bp), CCR2a (sens GTA TCT CTC GGT GTT CTT CC, antisens TCT AGG CTC CTT CTT TGT CCT G, 271 bp), CCR2b (sens GTA TCT CTC GGT GTT CTT CC, antisens ACC AGC CGA GAC TTC CTG CT, 163 bp) CCR3 (sens TCC TTC TCT CTT CCT ATC AAT, antisens GGC AAT TTT CTG CAT CTA, 312 bp), CCR5 (sens AAT CTT CTT CAT CAT CCT CC, antisens TCT CTG TCA CCT GCA TAG C, 506 bp), CCR7 (sens CTG GTG GTG GCT CTC CTT GT, antisens GCC AGG TTG AGC AGG TAG GT, 271 bp), CCR8 (sens GGT TGG TGC TCA TTG TGG TC, antisens AGT CTA CGC TGG AGG AAC GG, 345 bp). Statistical analysis was performed using the CSS Statistica for Windows (version 7.0) software. Probability values <0.05 were considered statistically significant. Results: There was significantly higher expression of CCR1 and CCR8 gene in lymphoma lymph nodes comparing to controls (p<0.05), while CCR5 and CCR7 gene expression was significantly lower in lymphoma lymph nodes (p<0.05) comparing to reactive lymph nodes. CXCR4, CCR2a, CCR2b, CCR3 expression did not differ between lymphoma and control groups. The patients with higher expression of CCR7 gene had significantly longer survival comparing to those with lower expression (p=0.048). Expression of CCR7 was negatively correlated with IPI (p=0.036, coefficient = -0.32). Higher expression of CCR5 gene was positively correlated with Ki-67 (p=0,016, coefficient = 0.34), stage of disease (p=0.048, coefficient = 0.029) and international prognostic index score - IPI (p=0,047, coefficient = 0.298). We also found positive correlation between CCR8 gene expression and IPI (p=0.039, coefficient = 0.32). Conclusions: Lower expression of CCR7 gene is combined with longer survival of nHL patients. As there are positive correlations between CCR5 expression and Ki-67 proliferation marker and IPI as well as CCR8 and IPI in non-Hodgkin's lymphoma, those receptors can promote tumour progression. Disclosures: No relevant conflicts of interest to declare.
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Tiffany, H. Lee, Ghalib Alkhatib, Christophe Combadiere, Edward A. Berger i Philip M. Murphy. "CC Chemokine Receptors 1 and 3 Are Differentially Regulated by IL-5 During Maturation of Eosinophilic HL-60 Cells". Journal of Immunology 160, nr 3 (1.02.1998): 1385–92. http://dx.doi.org/10.4049/jimmunol.160.3.1385.
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Abstract CC chemokine receptors 1 and 3 (CCR1 and CCR3) are expressed by eosinophils; however, factors regulating their expression and function have not previously been defined. Here we analyze chemokine receptor expression and function during eosinophil differentiation, using the eosinophilic cell line HL-60 clone 15 as a model system. RNA for CCR1, -3, -4, and -5 was not detectable in the parental cells, and the cells did not specifically bind CC chemokines. Cells treated with butyric acid acquired eosinophil characteristics; expressed mRNA for CCR1 and CCR3, but not for CCR4 or CCR5; acquired specific binding sites for macrophage-inflammatory protein-1α and eotaxin (the selective ligands for CCR1 and CCR3, respectively); and exhibited specific calcium flux and chemotaxis responses to macrophage-inflammatory protein-1α, eotaxin, and other known CCR1 and CCR3 agonists. CCR3 was expressed later and at lower levels than CCR1 and could be further induced by IL-5, whereas IL-5 had little or no effect on CCR1 expression. Consistent with the HIV-1 coreceptor activity of CCR3, HL-60 clone 15 cells induced with butyric acid and IL-5 fused with HeLa cells expressing CCR3-tropic HIV-1 envelope glycoproteins, and fusion was blocked specifically by eotaxin or an anti-CCR3 mAb. These data suggest that CCR1 and CCR3 are markers of late eosinophil differentiation that are differentially regulated by IL-5 in this model.
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Ortega Moreno, L., S. Fernández Tomé, M. Chaparro, A. Marin, I. Mora Gutiérrez, C. Santander, M. Baldán, J. Gisbert i D. Bernardo. "P045 Profiling of human circulating dendritic cells and monocytes subsets discriminates type and mucosal status in patients with inflammatory bowel disease". Journal of Crohn's and Colitis 14, Supplement_1 (styczeń 2020): S155—S156. http://dx.doi.org/10.1093/ecco-jcc/jjz203.174.
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Abstract Background Intestinal dendritic cells (DCs) and macrophages govern the mechanisms of immune homeostasis having a role in inflammatory bowel disease (IBD) onset. However, the profile of their circulating precursors (DC and monocytes) in IBD has not been previously described in depth. Our aim was to characterise blood DC and monocyte subsets in healthy controls (HCs) and IBD patients in order to understand their potential implication in IBD pathogenesis. Methods 18 HC and 64 IBD patients were recruited. IBD patients were categorised into Crohn’s disease (CD) and ulcerative colitis (UC), either endoscopically active (aCD and aUC) or quiescent (qCD and qUC), based on the SES-CD or the Mayo index endoscopic subscore. Blood circulating type 1 conventional DC (cDC1), type 2 conventional DC (cDC2), plasmacytoid DC (pDC), classical monocytes, non-classical monocytes and intermediate monocytes were identified by flow cytometry and characterised for the expression of 18 homing and activation markers (β7, CCR1, CCR2, CCR3, CCR5, CCR6, CCR7, CCR9, CCRL1, CD40, CD86, CD137L, CD274 (PD-L1), CLA, CXCR1, CXCR3, ICOSL and HLA-DR). Association between markers and the presence, type or activity of IBD was tested by logistic regression. Discriminant canonical analysis was also performed to classify the patients on their own endoscopy category. Results All groups (HC, aCD, qCD, aUC and qUC) were separated from the others based on the discriminant canonical analyses of the 18 markers applied over all DC and monocytes subsets (Figure 1). Specifically, CCRL1, CCR3 and CCR5 expression on cDC1, CCRL1 on non-classical monocytes and CCR9 and b7 on classical monocytes were highly associated to IBD. CCR3 displayed an odds ratio (OR) of 2.29 along with its 95% confidential interval (CI) between 1.11 and 4.75, showing a strong association with activity in CD; whereas the other markers displayed an inverse association with IBD. Hence, expression of CCRL1 on cDC1 and non-classical monocytes from aUC showed an OR (95% CI) of 0.23 (0.08–0.66) and 0.52 (0.28–0.95), respectively. In the case of qUC, CCR5 on cDC1 and β7 on classical monocytes displayed an OR (95% CI) of 0.10 (0.01–0.83) and 0.56 (0.34–0.90), respectively. CCR9 was inversely associated to qCD with an OR (95% CI) of 0.64 (0.46–0.89) in the classical monocytes subset. Indeed, the same markers (excluding β7) were also associated with IBD when all DC and monocyte subsets were considered at the same time. Conclusion Differences on the expression of migration markers CCR3, CCR5, CCR9, b7 and decoy receptor CCRL1 on circulating DC and monocyte subsets from IBD groups suggest the presence of constitutive migratory differences underlying IBD pathogenesis in CD or UC and its condition (inflamed or non-inflamed).
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Sallusto, Federica, Danielle Lenig, Charles R. Mackay i Antonio Lanzavecchia. "Flexible Programs of Chemokine Receptor Expression on Human Polarized T Helper 1 and 2 Lymphocytes". Journal of Experimental Medicine 187, nr 6 (16.03.1998): 875–83. http://dx.doi.org/10.1084/jem.187.6.875.
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Chemokines and their receptors are important elements for the selective attraction of various subsets of leukocytes. To better understand the selective migration of functional subsets of T cells, chemokine receptor expression was analyzed using monoclonal antibodies, RNase protection assays, and the response to distinct chemokines. Naive T cells expressed only CXC chemokine receptor (CXCR)4, whereas the majority of memory/activated T cells expressed CXCR3, and a small proportion expressed CC chemokine receptor (CCR)3 and CCR5. When polarized T cell lines were analyzed, CXCR3 was found to be expressed at high levels on T helper cell (Th)0s and Th1s and at low levels on Th2s. In contrast, CCR3 and CCR4 were found on Th2s. This was confirmed by functional responses: only Th2s responded with an increase in [Ca2+]i to the CCR3 and CCR4 agonists eotaxin and thymus and activation regulated chemokine (TARC), whereas only Th0s and Th1s responded to low concentrations of the CXCR3 agonists IFN-γ–inducible protein 10 (IP-10) and monokine induced by IFN-γ (Mig). Although CCR5 was expressed on both Th1 and Th2 lines, it was absent in several Th2 clones and its expression was markedly influenced by interleukin 2. Chemokine receptor expression and association with Th1 and Th2 phenotypes was affected by other cytokines present during polarization. Transforming growth factor β inhibited CCR3, but enhanced CCR4 and CCR7 expression, whereas interferon α inhibited CCR3 but upregulated CXCR3 and CCR1. These results demonstrate that chemokine receptors are markers of naive and polarized T cell subsets and suggest that flexible programs of chemokine receptor gene expression may control tissue-specific migration of effector T cells.
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Dragan, Paulina, Matthew Merski, Szymon Wiśniewski, Swapnil Ganesh Sanmukh i Dorota Latek. "Chemokine Receptors—Structure-Based Virtual Screening Assisted by Machine Learning". Pharmaceutics 15, nr 2 (3.02.2023): 516. http://dx.doi.org/10.3390/pharmaceutics15020516.
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Chemokines modulate the immune response by regulating the migration of immune cells. They are also known to participate in such processes as cell–cell adhesion, allograft rejection, and angiogenesis. Chemokines interact with two different subfamilies of G protein-coupled receptors: conventional chemokine receptors and atypical chemokine receptors. Here, we focused on the former one which has been linked to many inflammatory diseases, including: multiple sclerosis, asthma, nephritis, and rheumatoid arthritis. Available crystal and cryo-EM structures and homology models of six chemokine receptors (CCR1 to CCR6) were described and tested in terms of their usefulness in structure-based drug design. As a result of structure-based virtual screening for CCR2 and CCR3, several new active compounds were proposed. Known inhibitors of CCR1 to CCR6, acquired from ChEMBL, were used as training sets for two machine learning algorithms in ligand-based drug design. Performance of LightGBM was compared with a sequential Keras/TensorFlow model of neural network for these diverse datasets. A combination of structure-based virtual screening with machine learning allowed to propose several active ligands for CCR2 and CCR3 with two distinct compounds predicted as CCR3 actives by all three tested methods: Glide, Keras/TensorFlow NN, and LightGBM. In addition, the performance of these three methods in the prediction of the CCR2/CCR3 receptor subtype selectivity was assessed.
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Gomes, Juliana A. S., Lilian M. G. Bahia-Oliveira, Manoel Otávio C. Rocha, Solange C. U. Busek, Mauro M. Teixeira, João Santana Silva i Rodrigo Correa-Oliveira. "Type 1 Chemokine Receptor Expression in Chagas' Disease Correlates with Morbidity in Cardiac Patients". Infection and Immunity 73, nr 12 (grudzień 2005): 7960–66. http://dx.doi.org/10.1128/iai.73.12.7960-7966.2005.
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ABSTRACT Chemokines and chemokine receptors (CKRs) control the migration of leukocytes during the inflammatory process and are important immunological markers of type 1 (CCR5 and CXCR3) and type 2 (CCR3 and CCR4) responses. The coexpression of CKRs (CCR2, CCR3, CCR5, CXCR3, and CXCR4) and intracellular cytokines (interleukin-10 [IL-10], IL-4, tumor necrosis factor alpha [TNF-α], and gamma interferon [IFN-γ]) on T CD4+ and CD8+ peripheral cells from individuals with indeterminate (IND) or cardiac (CARD) clinical forms of Chagas' disease after in vitro stimulation with Trypanosoma cruzi antigens, were evaluated in this study. The percentage of T CD4+ and CD8+ cells coexpressing CCR5 and IFN-γ, CXCR3 and IFN-γ, and CXCR3 and TNF-α were higher in CARD than in IND individuals; on the other hand, the percentage of T CD4+ or CD8+ cells coexpressing CCR3 and IL-10 or coexpressing CCR3 and IL-4 were lower in CARD individuals than in IND individuals. In addition, a significant positive correlation between the expression of CCR5 or CXCR3 and IFN-γ was observed in CARD individuals contrasting with a significant positive correlation between the expression of CCR3 and IL-4 and of CCR3 and IL-10 in IND patients. These results reinforce the hypothesis that a T. cruzi-exacerbated specific type 1 immune response developed by CARD chagasic patients is associated with the development of heart pathology.
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Paula Costa, Guilherme de, Laís Roquete Lopes, Maria Cláudia da Silva, Aline Luciano Horta, Washington Martins Pontes, Cristiane M. Milanezi, Paulo Marcos da Mata Guedes i in. "Doxycycline and Benznidazole Reduce the Profile of Th1, Th2, and Th17 Chemokines and Chemokine Receptors in Cardiac Tissue from ChronicTrypanosoma cruzi-Infected Dogs". Mediators of Inflammation 2016 (2016): 1–11. http://dx.doi.org/10.1155/2016/3694714.
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Chemokines (CKs) and chemokine receptors (CKR) promote leukocyte recruitment into cardiac tissue infected by theTrypanosoma cruzi. This study investigated the long-term treatment with subantimicrobial doses of doxycycline (Dox) in association, or not, with benznidazole (Bz) on the expression of CK and CKR in cardiac tissue. Thirty mongrel dogs were infected, or not, with the Berenice-78 strain ofT. cruziand grouped according their treatments: (i) two months after infection, Dox (50 mg/kg) 2x/day for 12 months; (ii) nine months after infection, Bz (3,5 mg/kg) 2x/day for 60 days; (iii) Dox + Bz; and (iv) vehicle. After 14 months of infection, hearts were excised and processed for qPCR analysis of Th1 (CCL2, CCL3, CCL4, CCL5, CXCL9, and CXCL11), Th2 (CCL1, CCL17, CCL24, and CCL26), Th17 (CCL20) CKs, Th1 (CCR5, CCR6, and CXCR3), and Th2/Th17 (CCR3, CCR4, and CCR8) CKR, as well as IL-17.T. cruziinfection increases CCL1, CCL2, CCL4, CCL5, CCL17, CXCL10, and CCR5 expression in the heart. Dox, Bz, or Dox + Bz treatments cause a reversal of CK and CKR and reduce the expression of CCL20, IL-17, CCR6, and CXCR3. Our data reveal an immune modulatory effect of Dox with Bz, during the chronic phase of infection suggesting a promising therapy for cardiac protection.
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Clemetson, Kenneth J., Jeannine M. Clemetson, Amanda E. I. Proudfoot, Christine A. Power, Marco Baggiolini i Timothy N. C. Wells. "Functional expression of CCR1, CCR3, CCR4, and CXCR4 chemokine receptors on human platelets". Blood 96, nr 13 (15.12.2000): 4046–54. http://dx.doi.org/10.1182/blood.v96.13.4046.
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Abstract Platelets are known to contain platelet factor 4 and β-thromboglobulin, α-chemokines containing the CXC motif, but recent studies extended the range to the β-family characterized by the CC motif, including RANTES and Gro-α. There is also evidence for expression of chemokine receptors CCR4 and CXCR4 in platelets. This study shows that platelets have functional CCR1, CCR3, CCR4, and CXCR4 chemokine receptors. Polymerase chain reaction detected chemokine receptor messenger RNA in platelet RNA. CCR1, CCR3, and especially CCR4 gave strong signals; CXCR1 and CXCR4 were weakly positive. Flow cytometry with specific antibodies showed the presence of a clear signal for CXCR4 and weak signals for CCR1 and CCR3, whereas CXCR1, CXCR2, CXCR3, and CCR5 were all negative. 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. Chemokines specific for these receptors, including monocyte chemotactic protein 1, macrophage inflammatory peptide 1α, eotaxin, RANTES, TARC, macrophage-derived chemokine, and stromal cell–derived factor 1, activate platelets to give Ca++ signals, aggregation, and release of granule contents. Platelet aggregation was dependent on release of adenosine diphosphate (ADP) and its interaction with platelet ADP receptors. Part, but not all, of the Ca++ signal was due to ADP release feeding back to its receptors. Platelet activation also involved heparan or chondroitin sulfate associated with the platelet surface and was inhibited by cleavage of these glycosaminoglycans or by heparin or low molecular weight heparin. These platelet receptors may be involved in inflammatory or allergic responses or in platelet activation in human immunodeficiency virus infection.
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Clemetson, Kenneth J., Jeannine M. Clemetson, Amanda E. I. Proudfoot, Christine A. Power, Marco Baggiolini i Timothy N. C. Wells. "Functional expression of CCR1, CCR3, CCR4, and CXCR4 chemokine receptors on human platelets". Blood 96, nr 13 (15.12.2000): 4046–54. http://dx.doi.org/10.1182/blood.v96.13.4046.h8004046_4046_4054.
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Platelets are known to contain platelet factor 4 and β-thromboglobulin, α-chemokines containing the CXC motif, but recent studies extended the range to the β-family characterized by the CC motif, including RANTES and Gro-α. There is also evidence for expression of chemokine receptors CCR4 and CXCR4 in platelets. This study shows that platelets have functional CCR1, CCR3, CCR4, and CXCR4 chemokine receptors. Polymerase chain reaction detected chemokine receptor messenger RNA in platelet RNA. CCR1, CCR3, and especially CCR4 gave strong signals; CXCR1 and CXCR4 were weakly positive. Flow cytometry with specific antibodies showed the presence of a clear signal for CXCR4 and weak signals for CCR1 and CCR3, whereas CXCR1, CXCR2, CXCR3, and CCR5 were all negative. 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. Chemokines specific for these receptors, including monocyte chemotactic protein 1, macrophage inflammatory peptide 1α, eotaxin, RANTES, TARC, macrophage-derived chemokine, and stromal cell–derived factor 1, activate platelets to give Ca++ signals, aggregation, and release of granule contents. Platelet aggregation was dependent on release of adenosine diphosphate (ADP) and its interaction with platelet ADP receptors. Part, but not all, of the Ca++ signal was due to ADP release feeding back to its receptors. Platelet activation also involved heparan or chondroitin sulfate associated with the platelet surface and was inhibited by cleavage of these glycosaminoglycans or by heparin or low molecular weight heparin. These platelet receptors may be involved in inflammatory or allergic responses or in platelet activation in human immunodeficiency virus infection.
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Kleinhans, Martin, Adrian Tun-Kyi, Michel Gilliet, Marshall E. Kadin, Reinhard Dummer, Günter Burg i Frank O. Nestle. "Functional expression of the eotaxin receptor CCR3 in CD30+ cutaneous T-cell lymphoma". Blood 101, nr 4 (15.02.2003): 1487–93. http://dx.doi.org/10.1182/blood-2002-02-0475.
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Little is known about mechanisms involved in skin-specific homing of cutaneous T-cell lymphoma (CTCL). Chemokine/chemokine receptor interactions have been implicated in the homing of lymphoma cells to various tissue sites. We investigated tissue samples and tumor cell suspensions of patients with CD30+ CTCL (n = 8) and CD30− CTCL (mycosis fungoides, n = 6; Sézary syndrome, n = 6) for expression of the chemokine receptors CCR3, CCR4, and CCR8 and the CCR3 ligands eotaxin/CCL11, monocyte chemoattractant protein 3 (MCP-3)/CCL7, and RANTES (regulated on activation, normal T expressed and secreted)/CCL5. Of 8 CD30+ CTCLs, 7 expressed CCR3, 4 CCR4, and none CCR8. CCR3 expression was not found in skin tissue samples from 12 CD30− CTCLs. Coexpression of CCR3 and CD30 was demonstrated by flow cytometry in tumor cell suspensions. Internalization experiments demonstrated functionality of CCR3 expressed by freshly isolated tumor cells. Actin polymerization as well as migration in response to eotaxin was demonstrated in a CD30+ cutaneous lymphoma cell line. CCR3 ligand eotaxin/CCL11 was detected in lesional skin of CD30+CTCL by immunohistochemistry, preferentially in tumor cells. Eotaxin/CCL11 expression in tumor cells was confirmed by intracellular immunofluorescence. Analysis of cytokine expression pattern of CCR3-bearing infiltrating cells showed a predominance of interleukin-4 (IL-4) but not interferon-γ (IFN-γ) protein expression,1 consistent with a T-helper 2 (Th-2) profile. These results suggest that expression of CCR3 and its ligand eotaxin/CCL11 plays a role in the recruitment and retention of CD30+ malignant T cells to the skin.
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Kim, Chang H., Brent Johnston i Eugene C. Butcher. "Trafficking machinery of NKT cells: shared and differential chemokine receptor expression among Vα24+Vβ11+ NKT cell subsets with distinct cytokine-producing capacity". Blood 100, nr 1 (1.07.2002): 11–16. http://dx.doi.org/10.1182/blood-2001-12-0196.
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Abstract Natural killer T (NKT) cells are important regulators of the immune system, but their trafficking machinery, including expression of chemokine receptors, has been poorly defined. Unlike other conventional T-cell populations, we show that most NKT cells express receptors for extralymphoid tissue or inflammation-related chemokines (CCR2, CCR5, and CXCR3), while few NKT cells express lymphoid tissue–homing chemokine receptors (CCR7 and CXCR5). A population with homing potential for lymph nodes (L selectin+ CCR7+) exists only within a small subset of CD4 NKT cells. We show differential expression of chemokine receptors among NKT cell subsets: CCR4 is mainly expressed by a high cytokine (interleukin-4/interleukin-2)–producing (CD4) NKT subset, while CCR1, CCR6, and CXCR6 are preferentially expressed by the low cytokine-producing CD8 and CD4−CD8− subsets. In line with this, TARC/CCL17 (a CCR4 ligand) induces preferential chemotaxis of the CD4 NKT subset, while chemotactic activities of LARC/CCL20 (a CCR6 ligand) and MIP-1α/CCL3 (a CCR1 ligand) are focused on the CD8 and CD4−CD8− NKT cells. We conclude that, unlike conventional naive, memory, or effector T cells, the entire NKT cell population expresses nonlymphoid tissue homing chemokine receptors, yet NKT cell subsets differ considerably from each other by displaying distinct and reciprocal expression patterns of some chemokine receptors. Our results identify chemokine receptors that are potentially important for trafficking of human blood NKT cell subsets and reveal their function (cytokine production capacity)–dependent differential trafficking potentials.
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Wei, Jin-Hua, Xiao Feng, Zhi-Jian Sun, Pang Cheng, Bin-Fang Ma, Jie Zhao, Yu-Hang Dong, Yuan-Qiang Zhang i Zhen Li. "Different locations of RANTES and its receptors on mouse epididymal spermatozoa". Reproduction, Fertility and Development 28, nr 10 (2016): 1509. http://dx.doi.org/10.1071/rd14231.
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Our previous study showed that the chemokine regulated upon activation normal T-cell expressed and secreted (RANTES) originating from the mouse epididymis bound to the midpiece of luminal spermatozoa. The present study was undertaken to investigate the association between RANTES and epididymal spermatozoa and to determine whether the association is mediated by the RANTES receptors CCR1, CCR3 or CCR5. The use of reverse transcription polymerase chain reaction (RT-PCR), immunohistochemical staining and immunofluorescent staining demonstrated that RANTES secreted by apical and narrow cells of mouse epididymal ducts was associated with luminal spermatozoa. Flow cytometric analysis and immunofluorescent labelling revealed that the association between RANTES and spermatozoa of different regions weakened gradually as the spermatozoa moved along the epididymis. Moreover, CCR1, CCR3 and CCR5 were expressed in epididymal spermatozoa and located on the head of epididymal spermatozoa, while RANTES was generally located at the midpiece. In conclusion, RANTES and its receptors were not in the same sperm location, suggesting that RANTES binding to mouse epididymal spermatozoa is independent of CCR1, CCR3 and CCR5.
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Kim, Chang H., Jeeho Lee i Seung G. Kang. "Developmental and antigen-driven switches in the trafficking receptors of FoxP3+ regulatory T cells (99.2)". Journal of Immunology 178, nr 1_Supplement (1.04.2007): S194. http://dx.doi.org/10.4049/jimmunol.178.supp.99.2.
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Abstract FoxP3+ regulatory T cells play important roles in immune regulation and tolerance. There is an increasing body of evidence that the migration ability of FoxP3+ T cells is important for their regulatory functions at effector tissue sites. We investigated the two different trafficking receptor switches of FoxP3+ T cells occurring in the thymus and secondary lymphoid tissues. The first trafficking receptor switch in the thymus is developmentally programmed: Precursors of FoxP3+ cells undergo the first trafficking receptor switch from CCR8/CCR9 to CXCR4 and then finally to CCR7, generating mostly homogeneous CD62L+CCR7+ FoxP3+ T cells. The recent thymic emigrant CD62L+CCR7+ FoxP3+ T cells are programmed to migrate to secondary lymphoid tissues. The CD62L+CCR7+ FoxP3+ T cells undergo the second switch in trafficking receptors in an antigen-dependent manner. This second switch involves down-regulation of CCR7 and CXCR4 but up-regulation of a number of memory/effector type homing receptors, resulting in generation of heterogeneous FoxP3+ T cell subsets expressing various combinations of trafficking receptors including CCR2, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9 and CXCR5. FoxP3+ cells undergo the second switch to selected non-lymphoid tissue homing receptors at highly accelerated rates. This results in generation of FoxP3+ T cells with unconventionally efficient migratory capacity to major non-lymphoid tissues such as intestinal lamina propria and bone marrow. Importantly, this accelerated switch of FoxP3+ T cells is conserved in both men and mice. The two switches in homing receptors are though to be important for effective distribution and differentiation-dependent effector functions of FoxP3+ regulatory T cells.
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ANDERS, HANS-JOACHIM, VOLKER VIELHAUER, MATTHIAS KRETZLER, CLEMENS D. COHEN, STEPHAN SEGERER, BRUNO LUCKOW, LARS WELLER, HERMANN-JOSEF GRÖNE i DETLEF SCHLÖNDORFF. "Chemokine and Chemokine Receptor Expression during Initiation and Resolution of Immune Complex Glomerulonephritis". Journal of the American Society of Nephrology 12, nr 5 (maj 2001): 919–31. http://dx.doi.org/10.1681/asn.v125919.
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Abstract. Chemokines participate in leukocyte infiltration, which plays a major role in glomerular injury during immune complex glomerulonephritis (IC-GN). Because target cell expression of chemokine receptors (CCR) is thought to mediate leukocyte migration, the expression pattern of chemokines and CCR in a model of IC-GN was examined. The transient course and predominant glomerular pathology of this model allows the examination of both the induction and resolution phases of IC-GN. GN was induced in mice by daily apoferritin injection for 2 wk. Urine samples and kidneys were obtained at 1, 2, and 4 wk. Albuminuria was noted at 2 wk, but resolved after 4 wk. This was associated with glomerular IC deposits and mesangial proliferation. Glomerular macrophage infiltration was prominent at 1 and 2 wk, which resolved at 4 wk. Expression of monocyte chemoattractant protein-1 (MCP-1) and RANTES mRNA was upregulated at week 1 and decreased to control levels at weeks 2 and 4. The expression was localized to glomeruli byin situhybridization and immunohistochemistry. The mRNA of CCR1, CCR2, and CCR5 but not CCR3 or CCR4 were upregulated at week 1 and decreased at weeks 2 and 4. Expression of CCR5 was located to the glomerulus byin situhybridization and quantitative reverse transcription-PCR of isolated glomeruli. In summary, in a model of transient IC-GN, MCP-1 and RANTES and their receptors CCR1, CCR2, and CCR5 are expressed early and are already downregulated at the peak of proteinuria and leukocyte infiltration. Resolution of glomerulonephritis is associated with a return to baseline of chemokine and CCR expression. Therefore, it is concluded that glomerular MCP-1 and RANTES production directs circulating leukocytes that express CCR1, CCR2, and CCR5 into the glomerulus. After initiating GN, MCP-1 and RANTES and their receptors are readily downregulated.
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Agrawal, Lokesh, Christina R. Maxwell, Paul J. Peters, Paul R. Clapham, Sue M. Liu, Charles R. Mackay i David S. Strayer. "Complexity in human immunodeficiency virus type 1 (HIV-1) co-receptor usage: roles of CCR3 and CCR5 in HIV-1 infection of monocyte-derived macrophages and brain microglia". Journal of General Virology 90, nr 3 (1.03.2009): 710–22. http://dx.doi.org/10.1099/vir.0.006205-0.
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CCR3 has been implicated as a co-receptor for human immunodeficiency virus type 1 (HIV-1), particularly in brain microglia cells. We sought to clarify the comparative roles of CCR3 and CCR5 in the central nervous system (CNS) HIV-1 infection and the potential utility of CCR3 as a target for manipulation via gene transfer. To target CCR3, we developed a single-chain antibody (SFv) and an interfering RNA (RNAi), R3-526. Coding sequences for both were cloned into Tag-deleted SV40-dervied vectors, as these vectors transduce brain microglia and monocyte-derived macrophages (MDM) highly efficiently. These anti-CCR3 transgenes were compared to SFv-CCR5, an SFv against CCR5, and RNAi-R5, an RNAi that targets CCR5, for the ability to protect primary human brain microglia and MDM from infection with peripheral and neurotropic strains of HIV-1. Downregulation of CCR3 and CCR5 by these transgenes was independent from one another. Confocal microscopy showed that CCR3 and CCR5 co-localized at the plasma membrane with each other and with CD4. Targeting either CCR5 or CCR3 largely protected both microglia and MDM from infection by many strains of HIV-1. That is, some HIV-1 strains, isolated from either the CNS or periphery, required both CCR3 and CCR5 for optimal productive infection of microglia and MDM. Some HIV-1 strains were relatively purely CCR5-tropic. None was purely CCR3-tropic. Thus, some CNS-tropic strains of HIV-1 utilize CCR5 as a co-receptor but do not need CCR3, while for other isolates both CCR3 and CCR5 may be required.
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Fantuzzi, Laura, Paola Borghi, Veniero Ciolli, George Pavlakis, Filippo Belardelli i Sandra Gessani. "Loss of CCR2 Expression and Functional Response to Monocyte Chemotactic Protein (MCP-1) During the Differentiation of Human Monocytes: Role of Secreted MCP-1 in the Regulation of the Chemotactic Response". Blood 94, nr 3 (1.08.1999): 875–83. http://dx.doi.org/10.1182/blood.v94.3.875.415k28_875_883.
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Human peripheral blood monocytes differentiate into macrophages when cultured in vitro for a few days. In the present study, we investigated the expression of C-C chemokine and CXCR4 receptors in monocytes at different stages of differentiation. Culturing of monocytes for 7 days resulted in a progressive decrease of the mRNA that encodes for CCR2 and CCR3, whereas the expression of mRNA for other chemokine receptors (CCR1, CCR4, CCR5, and CXCR4) was not substantially affected. 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. Furthermore, the biologic response to MCP-1, as measured by intracellular calcium ions increase and chemotactic response, was lost in 7-day–cultured macrophages. 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). The loss of CCR2 expression and the parallel increase of MCP-1 secretion triggered by differentiation may represent a feedback mechanism in the regulation of the chemotactic response of monocytes/macrophages.
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Naif, Hassan M., Shan Li, Mohammed Alali, Andrew Sloane, Lijun Wu, Mark Kelly, Garry Lynch, Andrew Lloyd i Anthony L. Cunningham. "CCR5 Expression Correlates with Susceptibility of Maturing Monocytes to Human Immunodeficiency Virus Type 1 Infection". Journal of Virology 72, nr 1 (1.01.1998): 830–36. http://dx.doi.org/10.1128/jvi.72.1.830-836.1998.
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ABSTRACT The chemokine receptor CCR5 and to a lesser extent CCR3 and CCR2b have been shown to serve as coreceptors for human immunodeficiency virus type 1 (HIV-1) entry into blood- or tissue-derived macrophages. Therefore, we examined the expression of the chemokine receptors CCR1, CCR2b, CCR3, CCR5, and CXCR4 as RNAs or as membrane-expressed antigens in monocytes maturing into macrophages and correlated these results with the susceptibility of macrophages to HIV-1 infection, as measured by their concentrations of extracellular p24 antigen and levels of intracellular HIV DNA by quantitative PCR. There was little change in levels of CCR1, CCR2b, and CCR5 RNAs. CCR3 RNA and surface antigen were undetectable throughout maturation of adherent monocytes over 10 days. CXCR4 RNA and membrane antigen were strongly expressed in newly adherent monocytes, but their levels declined at day 7. The amounts of CCR5 RNA remained stable, but the amounts of CCR5 antigen increased from undetectable to peak levels at day 7 and then declined slightly at day 10. Levels of susceptibility to laboratory (HIV-1BaL) and clinical strains of HIV-1 showed parallel kinetics, peaking at day 7 and then decreasing at days 10 to 14. The concordance of levels of HIV DNA and p24 antigen suggested that the changes in susceptibility with monocyte maturation were at or immediately after entry and correlated well with CCR5 expression and inversely with CXCR4 expression.
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Albright, Andrew V., Joseph T. C. Shieh, Takayuki Itoh, Benhur Lee, David Pleasure, Michael J. O’Connor, Robert W. Doms i Francisco González-Scarano. "Microglia Express CCR5, CXCR4, and CCR3, but of These, CCR5 Is the Principal Coreceptor for Human Immunodeficiency Virus Type 1 Dementia Isolates". Journal of Virology 73, nr 1 (1.01.1999): 205–13. http://dx.doi.org/10.1128/jvi.73.1.205-213.1999.
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ABSTRACT Microglia are the main human immunodeficiency virus (HIV) reservoir in the central nervous system and most likely play a major role in the development of HIV dementia (HIVD). To characterize human adult microglial chemokine receptors, we analyzed the expression and calcium signaling of CCR5, CCR3, and CXCR4 and their roles in HIV entry. Microglia expressed higher levels of CCR5 than of either CCR3 or CXCR4. Of these three chemokine receptors, only CCR5 and CXCR4 were able to transduce a signal in microglia in response to their respective ligands, MIP-1β and SDF-1α, as recorded by single-cell calcium flux experiments. We also found that CCR5 is the predominant coreceptor used for infection of human adult microglia by the HIV type 1 dementia isolates HIV-1DS-br, HIV-1RC-br, and HIV-1YU-2, since the anti-CCR5 antibody 2D7 was able to dramatically inhibit microglial infection by both wild-type and single-round luciferase pseudotype reporter viruses. Anti-CCR3 (7B11) and anti-CXCR4 (12G5) antibodies had little or no effect on infection. Last, we found that virus pseudotyped with the DS-br and RC-br envelopes can infect cells transfected with CD4 in conjunction with the G-protein-coupled receptors APJ, CCR8, and GPR15, which have been previously implicated in HIV entry.
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Yi, Yanjie, Shalini Rana, Julie D. Turner, Nathan Gaddis i Ronald G. Collman. "CXCR-4 Is Expressed by Primary Macrophages and Supports CCR5-Independent Infection by Dual-Tropic but Not T-Tropic Isolates of Human Immunodeficiency Virus Type 1". Journal of Virology 72, nr 1 (1.01.1998): 772–77. http://dx.doi.org/10.1128/jvi.72.1.772-777.1998.
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ABSTRACT Primary macrophages are infected by macrophage (M)-tropic but not T-cell line (T)-tropic human immunodeficiency virus type 1 (HIV-1) strains, and CCR5 and CXCR-4 are the principal cofactors utilized for CD4-mediated entry by M-tropic and T-tropic isolates, respectively. Macrophages from individuals homozygous for an inactivating mutation of CCR5 are resistant to prototype M-tropic strains that depend on CCR5 but are permissive for a dual-tropic isolate, 89.6, that can use both CCR5 and CXCR-4, as well as CCR2b, CCR3, and CCR8. Here we show that 89.6 entry into CCR5-deficient macrophages is blocked by an anti-CXCR-4 antibody and by the CXCR-4-specific chemokine SDF but not by the ligands to CCR2b or CCR3. Reverse transcription-PCR demonstrated expression of CXCR-4 but not CCR3 or CCR8 in macrophages, while CCR2b was variable. Macrophage surface expression of CXCR-4 was confirmed by immunofluorescence staining and flow cytometry. Thus, CXCR-4 is expressed by primary macrophages and functions as a cofactor for entry by dual-tropic but not T-tropic HIV-1 isolates, and macrophage resistance to T-tropic strains does not result from a lack of the T-tropic entry cofactor CXCR-4. Since CXCR-4 on macrophages can be used by some but not other isolates, these results indicate that HIV-1 strains differ in how they utilize chemokine receptors as cofactors for entry and that the ability of a chemokine receptor to mediate HIV-1 entry differs, depending on the cell type in which it is expressed.
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Sørensen, T. L., i F. Sellebjerg. "Selective suppression of chemokine receptor CXCR3 expression by interferon-b1a in multiple sclerosis". Multiple Sclerosis Journal 8, nr 2 (kwiecień 2002): 104–7. http://dx.doi.org/10.1191/1352458502ms781oa.
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We studied the expression of chemokine receptors CCR1, CCR2, CCR3, CCR5, and CXCR3 on CD4 and CD8 positive T cells, and on CD14 positive monocytes in blood from 10 patients with relapsing-remitting multiple sclerosis (MS) at initiation of interferon (IFN)- βtreatment, after 1 month and after 3 months of treatment. It was found that the expression of CXCR3 on CD4+ and CD8+ T cells was significantly reduced after 3 months of treatment. The expression of other receptors was unaltered. Since CXCR3 cells are enriched in cerebrospinal fluid (CSF), and are detected in lesion material in MS this may represent an important mode of action of interferon- βin MS.
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Wise, Emma L., Cécile Duchesnes, Paula C. A. da Fonseca, Rodger A. Allen, Timothy J. Williams i James E. Pease. "Small Molecule Receptor Agonists and Antagonists of CCR3 Provide Insight into Mechanisms of Chemokine Receptor Activation". Journal of Biological Chemistry 282, nr 38 (16.07.2007): 27935–43. http://dx.doi.org/10.1074/jbc.m703255200.
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Chemokine receptor CCR3 is highly expressed by eosinophils and signals in response to binding of the eotaxin family of chemokines, which are up-regulated in allergic disorders. Consequently, CCR3 blockade is of interest as a possible therapeutic approach for the treatment of allergic disease. We have described previously a bispecific antagonist of CCR1 and CCR3 named UCB35625 that was proposed to interact with the transmembrane residues Tyr-41, Tyr-113, and Glu-287 of CCR1, all of which are conserved in CCR3. Here, we show that cells expressing the CCR3 constructs Y113A and E287Q are insensitive to antagonism by UCB35625 and also exhibit impaired chemotaxis in response to CCL11/eotaxin, suggesting that these residues are important for antagonist binding and also receptor activation. Furthermore, mutation of the residue Tyr-113 to alanine was found to turn the antagonist UCB35625 into a CCR3 agonist. Screens of small molecule libraries identified a novel specific agonist of CCR3 named CH0076989. This was able to activate eosinophils and transfectants expressing both wild-type CCR3 and a CCR1–CCR3 chimeric receptor lacking the CCR3 amino terminus, indicating that this region of CCR3 is not required for CH0076989 binding. A direct interaction with the transmembrane helices of CCR3 was supported by mutation of the residues Tyr-41, Tyr-113, and Glu-287 that resulted in complete loss of CH0076989 activity, suggesting that the compound mimics activation by CCL11. We conclude that both agonists and antagonists of CCR3 appear to occupy overlapping sites within the transmembrane helical bundle, suggesting a fine line between agonism and antagonism of chemokine receptors.
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Lee, Benhur, Benjamin J. Doranz, Shalini Rana, Yanji Yi, Mario Mellado, Jose M. R. Frade, Carlos Martinez-A. i in. "Influence of the CCR2-V64I Polymorphism on Human Immunodeficiency Virus Type 1 Coreceptor Activity and on Chemokine Receptor Function of CCR2b, CCR3, CCR5, and CXCR4". Journal of Virology 72, nr 9 (1.09.1998): 7450–58. http://dx.doi.org/10.1128/jvi.72.9.7450-7458.1998.
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ABSTRACT The chemokine receptors CCR5 and CXCR4 are used by human immunodeficiency virus type 1 (HIV-1) in conjunction with CD4 to infect cells. In addition, some virus strains can use alternative chemokine receptors, including CCR2b and CCR3, for infection. A polymorphism inCCR2 (CCR2-V64I) is associated with a 2- to 4-year delay in the progression to AIDS. To investigate the mechanism of this protective effect, we studied the expression of CCR2b and CCR2b-V64I, their chemokine and HIV-1 coreceptor activities, and their effects on the expression and receptor activities of the major HIV-1 coreceptors. CCR2b and CCR2b-V64I were expressed at similar levels, and neither molecule affected the expression or coreceptor activity of CCR3, CCR5, or CXCR4 in cotransfected cell lines. Peripheral blood mononuclear cells (PBMCs) from CCR2-V64I heterozygotes had normal levels of CCR2b and CCR5 but slightly reduced levels of CXCR4. CCR2b and CCR2b-V64I functioned equally well as HIV-1 coreceptors, and CCR2-V64I PBMCs were permissive for HIV-1 infection regardless of viral tropism. The MCP-1-induced calcium mobilization mediated by CCR2b signaling was unaffected by the polymorphism, but MCP-1 signaling mediated by either CCR2b- or CCR2-V64I-encoded receptors resulted in heterologous desensitization (i.e., limiting the signal response of other receptors) of both CCR5 and CXCR4. The heterologous desensitization of CCR5 and CXCR4 signaling by bothCCR2 allele receptor types provides a mechanistic link that might help explain the in vivo effects of CCR2 gene variants on progression to AIDS as well as the reported antiviral activity of natural CCR2 ligands.
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Penton-Rol, Giselle, Nadia Polentarutti, Walter Luini, Alessandro Borsatti, Roberta Mancinelli, Antonio Sica, Silvano Sozzani i Alberto Mantovani. "Selective Inhibition of Expression of the Chemokine Receptor CCR2 in Human Monocytes by IFN-γ". Journal of Immunology 160, nr 8 (15.04.1998): 3869–73. http://dx.doi.org/10.4049/jimmunol.160.8.3869.
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Abstract IFN-γ is a potent activator of mononuclear phagocyte function and promotes the development of Th1 responses. Moreover, it induces and modulates chemokine production in a variety of cell types, including mononuclear phagocytes. In the present study, we examined the effect of IFN-γ on the expression of CC chemokine receptors in human monocytes. IFN-γ selectively and rapidly inhibited expression of the monocyte chemotactic protein (MCP) receptor CCR2 with an ED50 of ∼50 U/ml. The effect was rapid (detectable after 1 h) and reversible. Other chemokine receptors (CCR1, CCR3, CCR4, and CCR5) were not substantially affected, and CXCR4 was reduced. IFN-γ acted in concert with LPS, TNF-α, and IL-1β in inhibiting CCR2 expression. IFN-γ-treated monocytes showed a shorter half-life of CCR2 mRNA compared with untreated cells, whereas the rate of nuclear transcription was unaffected. The inhibition of CCR2 mRNA expression by IFN-γ was associated with a lower number of surface receptors and lower chemotactic responsiveness. Thus, IFN-γ, an inducer of MCP-1 and MCP-3 in mononuclear phagocytes, selectively inhibits expression of the MCP receptor CCR2 in monocytes. These results are consistent with an emerging paradigm of divergent regulation by several agents of chemokine production and receptor expression in monocytes. The inhibition of MCP-1R expression may serve as a means of retaining mononuclear phagocytes at sites of inflammation and as a feedback mechanism in the regulation of recruitment from the blood.
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Hadida, Fabienne, Vincent Vieillard, Brigitte Autran, Ian Clark-Lewis, Marco Baggiolini i Patrice Debré. "HIV-specific T Cell Cytotoxicity Mediated by RANTES Via the Chemokine Receptor CCR3". Journal of Experimental Medicine 188, nr 3 (3.08.1998): 609–14. http://dx.doi.org/10.1084/jem.188.3.609.
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CC chemokines produced by CD8+ T cells are known to act as HIV-suppressive factors. We studied the possible role of these chemokines in HIV-1–specific killing of target cells. We found that the activity of cytotoxic T lymphocytes (CTLs) in CTL lines or freshly isolated peripheral blood mononuclear cells from HIV-1–infected individuals is markedly enhanced by RANTES (regulated on activation, normal T cell expressed and secreted) and virtually abolished by an antibody neutralizing RANTES or the RANTES receptor antagonist RANTES(9-68). Lysis was mediated by CD8+ major histocompatibility complex class I–restricted T cells and was obtained with target cells expressing epitopes of the HIV-1LAI proteins Gag, Pol, Env, and Nef. The cytolytic activity observed in the presence or absence of added RANTES could be abolished by pretreatment of the CTLs with pertussis toxin, indicating that the effect is mediated by a G protein–coupled receptor. The chemokines monocyte chemotactic protein (MCP)-3, MCP-4, and eotaxin acted like RANTES, whereas macrophage inflammatory protein (MIP)-1α, MIP-1β, MCP-1, and stromal cell–derived factor 1 were inactive, suggesting a role for the eotaxin receptor, CCR3, and ruling out the involvement of CCR1, CCR2, CCR5, and CXCR4. CTL activity was abrogated by an antibody that blocks CCR3, further indicating that specific lysis is triggered via this chemokine receptor. These observations reveal a novel mechanism for the induction of HIV-1–specific cytotoxicity that depends on RANTES acting via CCR3.
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Rabin, Ronald L., Matthew K. Park, Fang Liao, Ruth Swofford, David Stephany i Joshua M. Farber. "Chemokine Receptor Responses on T Cells Are Achieved Through Regulation of Both Receptor Expression and Signaling". Journal of Immunology 162, nr 7 (1.04.1999): 3840–50. http://dx.doi.org/10.4049/jimmunol.162.7.3840.
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Abstract To address the issues of redundancy and specificity of chemokines and their receptors in lymphocyte biology, we investigated the expression of CC chemokine receptors CCR1, CCR2, CCR3, CCR5, CXCR3, and CXCR4 and responses to their ligands on memory and naive, CD4 and CD8 human T cells, both freshly isolated and after short term activation in vitro. Activation through CD3 for 3 days had the most dramatic effects on the expression of CXCR3, which was up-regulated and functional on all T cell populations including naive CD4 cells. In contrast, the effects of short term activation on expression of other chemokine receptors was modest, and expression of CCR2, CCR3, and CCR5 on CD4 cells was restricted to memory subsets. In general, patterns of chemotaxis in the resting cells and calcium responses in the activated cells corresponded to the patterns of receptor expression among T cell subsets. In contrast, the pattern of calcium signaling among subsets of freshly isolated cells did not show a simple correlation with receptor expression, so the propensity to produce a global rise in the intracellular calcium concentration differed among the various receptors within a given T cell subset and for an individual receptor depending on the cell where it was expressed. Our data suggest that individual chemokine receptors and their ligands function on T cells at different stages of T cell activation/differentiation, with CXCR3 of particular importance on newly activated cells, and demonstrate T cell subset-specific and activation state-specific responses to chemokines that are achieved by regulating receptor signaling as well as receptor expression.
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Aasa-Chapman, Marlén M. I., Craig R. Seymour, Ian Williams i Áine McKnight. "Novel Envelope Determinants for CCR3 Use by Human Immunodeficiency Virus". Journal of Virology 80, nr 21 (1.11.2006): 10884–89. http://dx.doi.org/10.1128/jvi.01030-06.
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ABSTRACT Human immunodeficiency virus type 1 can generally use CCR3 and CCR5 for cell entry. We show that envelopes with novel phenotypes arise during “coreceptor switch”: one loses the ability to use CCR3 (R5-only phenotype), and another gains use of CXCR4 in addition to CCR5 and CCR3 (R3/R5/X4-using phenotype). The envelope determinants for CCR3 use mapped to three amino acids. One, N356 in conserved region 3, is a potential glycosylation site and has not previously been associated with coreceptor use. The other two, R440 and N448 in conserved region 4, are proximal to but distinct from residues already identified as being important for CCR5 binding.
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González-Arriagada, Wilfredo A., Carlos Lozano-Burgos, Rodrigo Zúñiga-Moreta, Paulina González-Díaz i Ricardo D. Coletta. "Clinicopathological significance of chemokine receptor (CCR1, CCR3, CCR4, CCR5, CCR7 and CXCR4) expression in head and neck squamous cell carcinomas". Journal of Oral Pathology & Medicine 47, nr 8 (8.06.2018): 755–63. http://dx.doi.org/10.1111/jop.12736.
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Yamaguchi, Mio, Kiyoshi Takagi, Koki Narita, Yasuhiro Miki, Yoshiaki Onodera, Minoru Miyashita, Hironobu Sasano i Takashi Suzuki. "Stromal CCL5 Promotes Breast Cancer Progression by Interacting with CCR3 in Tumor Cells". International Journal of Molecular Sciences 22, nr 4 (15.02.2021): 1918. http://dx.doi.org/10.3390/ijms22041918.
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Chemokines secreted from stromal cells have important roles for interactions with carcinoma cells and regulating tumor progression. C-C motif chemokine ligand (CCL) 5 is expressed in various types of stromal cells and associated with tumor progression, interacting with C-C chemokine receptor (CCR) 1, 3 and 5 expressed in tumor cells. However, the expression on CCL5 and its receptors have so far not been well-examined in human breast carcinoma tissues. We therefore immunolocalized CCL5, as well as CCR1, 3 and 5, in 111 human breast carcinoma tissues and correlated them with clinicopathological characteristics. Stromal CCL5 immunoreactivity was significantly correlated with the aggressive phenotype of breast carcinomas. Importantly, this tendency was observed especially in the CCR3-positive group. Furthermore, the risk of recurrence was significantly higher in the patients with breast carcinomas positive for CCL5 and CCR3 but negative for CCR1 and CCR5, as compared with other patients. In summary, the CCL5-CCR3 axis might contribute to a worse prognosis in breast cancer patients, and these findings will contribute to a better understanding of the significance of the CCL5/CCRs axis in breast carcinoma microenvironment.
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van Aalst, Evan, Jotham Koneri i Benjamin J. Wylie. "In Silico Identification of Cholesterol Binding Motifs in the Chemokine Receptor CCR3". Membranes 11, nr 8 (28.07.2021): 570. http://dx.doi.org/10.3390/membranes11080570.
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CC motif chemokine receptor 3 (CCR3) is a Class A G protein-coupled receptor (GPCR) mainly responsible for the cellular trafficking of eosinophils. As such, it plays key roles in inflammatory conditions, such as asthma and arthritis, and the metastasis of many deadly forms of cancer. However, little is known about how CCR3 functionally interacts with its bilayer environment. Here, we investigate cholesterol binding sites in silico through Coarse-Grained Molecular Dynamics (MD) and Pylipid analysis using an extensively validated homology model based on the crystal structure of CCR5. These simulations identified several cholesterol binding sites containing Cholesterol Recognition/Interaction Amino Acid Consensus motif (CRAC) and its inversion CARC motifs in CCR3. One such site, a CARC site in TM1, in conjunction with aliphatic residues in TM7, emerged as a candidate for future investigation based on the cholesterol residency time within the binding pocket. This site forms the core of a cholesterol binding site previously observed in computational studies of CCR2 and CCR5. Most importantly, these cholesterol binding sites are conserved in other chemokine receptors and may provide clues to cholesterol regulation mechanisms in this subfamily of Class A GPCRs.
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BANAS, BERNHARD, BRUNO LUCKOW, MARCUS MÖLLER, CHRISTIANE KLIER, PETER J. NELSON, ERIK SCHADDE, MANFRED BRIGL i in. "Chemokine and Chemokine Receptor Expression in a Novel Human Mesangial Cell Line". Journal of the American Society of Nephrology 10, nr 11 (listopad 1999): 2314–22. http://dx.doi.org/10.1681/asn.v10112314.
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Abstract. Chemokines are thought to play a pivotal role in mediating the selective migration of leukocytes into sites of tissue injury. The local production of chemokines by mesangial cells (MC) has been linked to inflammatory processes within the glomerulus. To study the chemokine biology of human MC, an immortalized human MC line was generated and then chemokine and chemokine receptor expression was examined in response to various proinflammatory stimuli. The results show that human MC have a specific and limited repertoire of chemokine expression. The stimulus-specific regulation of the chemokines monocyte chemoattractant protein-1 (MCP-1), regulated upon activation, normal T cell expressed and secreted (RANTES), interleukin-8 (IL-8), and IP-10 was demonstrated using RNase protection assays. Transcripts for the chemokines MIP-1α, MIP-1β, I-309, or lymphotactin could not be detected. The expression of CC chemokine receptors was investigated by reverse transcription-PCR and RNase protection assays. MC stimulated with interferon-γ (IFN-γ) expressed mRNA for the chemokine receptor CCR1. The expression could be further increased by activating the cells with a combination of tumor necrosis factor-α (TNF-α), IL-1β, and IFN-γ. Under these conditions, no mRNA for CCR2, CCR3, CCR4, CCR5, or CCR8 was detected. A comparison of the immortalized human mesangial cells with primary cells showed identical expression patterns of chemokine receptors. To demonstrate functional activity of chemokine receptors expressed by human MC, chemotaxis assays were performed. MC stimulated with a combination of TNF-α, IL-1β, and IFN-γ, but not unstimulated MC, migrated toward a RANTES gradient. Eotaxin did not enhance the migratory activity of human MC. In summary, a novel human mesangial cell line was established and the pattern of chemokine expression was examined. For the first time, the inducible expression of functionally active CCR1 by human MC was shown.
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Lloyd, Clare M., Tracy Delaney, Trang Nguyen, Jane Tian, Carlos Martinez-A, Anthony J. Coyle i Jose-Carlos Gutierrez-Ramos. "Cc Chemokine Receptor (Ccr)3/Eotaxin Is Followed by Ccr4/Monocyte-Derived Chemokine in Mediating Pulmonary T Helper Lymphocyte Type 2 Recruitment after Serial Antigen Challenge in Vivo". Journal of Experimental Medicine 191, nr 2 (17.01.2000): 265–74. http://dx.doi.org/10.1084/jem.191.2.265.
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Isolated peripheral blood CD4 cells from allergic individuals express CC chemokine receptor (CCR)3 and CCR4 after expansion in vitro. In addition, human T helper type 2 (Th2) cells polarized in vitro selectively express CCR3 and CCR4 at certain stages of activation/differentiation and respond preferentially to the ligands eotaxin and monocyte-derived chemokine (MDC). However, controversy arises when the in vivo significance of this distinct expression is discussed. To address the functional role of CCR3/eotaxin and CCR4/MDC during the in vivo recruitment of Th2 cells, we have transferred effector Th cells into naive mice to induce allergic airway disease. Tracking of these cells after repeated antigen challenge has established that both CCR3/eotaxin and CCR4/MDC axes contribute to the recruitment of Th2 cells to the lung, demonstrating the in vivo relevance of the expression of these receptors on Th2 cells. We have shown that involvement of the CCR3/eotaxin pathway is confined to early stages of the response in vivo, whereas repeated antigen stimulation results in the predominant use of the CCR4/MDC pathway. We propose that effector Th2 cells respond to both CCR3/eotaxin and CCR4/MDC pathways initially, but that a progressive increase in CCR4-positive cells results in the predominance of the CCR4/MDC axis in the long-term recruitment of Th2 cells in vivo.
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Bjerregaard, Thomas, Marie Krogh Nielsen, Christopher Rue Molbech, Yousif Subhi i Torben Lykke Sørensen. "Treatment failure in neovascular age-related macular degeneration is associated with a complex chemokine receptor profile". BMJ Open Ophthalmology 4, nr 1 (lipiec 2019): e000307. http://dx.doi.org/10.1136/bmjophth-2019-000307.
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ObjectiveTo investigate if chemokine expression patterns on leucocyte subsets influence the short-term anatomical treatment response of intravitreal antivascular endothelial growth factor therapy against neovascular age-related macular degeneration (AMD).Methods and analysisThis study was conducted as a prospective observational cohort study of 79 patients with neovascular AMD. We used optical coherence tomography to quantify central retinal thickness (CRT) and to evaluate the presence of intraretinal and subretinal fluids in treatment-naive patients at baseline and after loading dose. Anatomical response was categorised into either good responders (complete regression of fluid or a reduction of >75% in CRT), partial responders (reduction of 0%–75% in CRT) or non-responders (increase of CRT). Expression levels of chemokine receptors (CCR1, CCR2, CCR3, CCR5, CXCR3 and CX3CR1) were measured on leucocyte subsets (monocytes, CD4 +T cells, and CD8 +T cells) using flow cytometry. Finally, we explored potential correlation patterns of chemokine expression between the leucocyte subsets using group-specific correlation networks.ResultsNon-responders had higher CCR1 expression on monocytes (p=0.016) and lower CCR3 expression on CD8+ T cells (p=0.037). Correlation network analyses of chemokine receptor expression patterns on leucocyte subsets revealed intergroup differences.ConclusionShort-term anatomical treatment response in neovascular AMD varies according to the leucocyte subset chemokine expression pattern, which confirms that immune dysfunction is a complex issue in AMD. Our results suggest that focusing on chemokines may be a relevant approach towards personalised treatment in neovascular AMD.
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Bonecchi, Raffaella, Nadia Polentarutti, Walter Luini, Alessandro Borsatti, Sergio Bernasconi, Massimo Locati, Christine Power i in. "Up-Regulation of CCR1 and CCR3 and Induction of Chemotaxis to CC Chemokines by IFN-γ in Human Neutrophils". Journal of Immunology 162, nr 1 (1.01.1999): 474–79. http://dx.doi.org/10.4049/jimmunol.162.1.474.
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Abstract Human neutrophils (polymorphonuclear leukocytes; PMN) respond to some CXC chemokines but do not migrate to CC chemokines. Recent work has shown that chemokine receptors can be modulated by inflammatory cytokines. In this study, the effect of IFN-γ, a prototypic Th1 cytokine, on chemokine receptor expression in PMN was investigated. IFN-γ caused a rapid (∼1 h) and concentration-dependent increase of CCR1 and CCR3 mRNA. The expression of CCR2, CCR5, and CXCR1–4 was not augmented. IFN-γ-treated PMN, but not control cells, expressed specific binding sites for labeled monocyte-chemotactic protein (MCP)-3 and migrated to macrophage-inflammatory protein (MIP)-1α, RANTES, MCP-3, MIP-5/HCC2, and eotaxin. 7B11, a mAb for CCR3, inhibited the chemotactic response of IFN-γ-treated PMN to eotaxin, and aminoxypentane-RANTES blocked PMN migration to RANTES. These results suggest that the selectivity of certain chemokines for their target cells may be altered by cytokines produced within an inflammatory context. Since PMN may play a role in orienting immunity toward Th1 responses, it is possible to speculate that IFN-γ not only promotes Th1 differentiation directly, but also reorients the functional significance of Th2 effector cytokines by broadening the spectrum of their action to include PMN.
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Ayehunie, Seyoum, Eduardo A. Garcia-Zepeda, James A. Hoxie, Richard Horuk, Thomas S. Kupper, Andrew D. Luster i Ruth M. Ruprecht. "Human Immunodeficiency Virus-1 Entry Into Purified Blood Dendritic Cells Through CC and CXC Chemokine Coreceptors". Blood 90, nr 4 (15.08.1997): 1379–86. http://dx.doi.org/10.1182/blood.v90.4.1379.
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Abstract Blood dendritic cells (DC) are susceptible to both macrophage (M) and T-cell line (T) tropic human immunodeficiency virus type 1. The CC chemokines RANTES, macrophage inflammatory protein-1α (MIP-1α), MIP-1β, eotaxin, and, to a lesser extent, monocyte chemoattractant protein-1 (MCP-1) and MCP-4 blocked entry of M-tropic virus into blood DC. The CXC chemokine, SDF-1, a fusin (CXCR4 chemokine receptor) ligand, and an antifusin antibody inhibited DC entry by T-tropic virus. Purified blood DC contained CCR1, CCR2, CCR3, and CCR5 as well as the CXCR4 chemokine receptor RNA transcripts and high levels of fusin on the cell surface. The coexpression of multiple chemokine receptors offers a molecular mechanism to explain the permissiveness of DC for both M- and T-tropic viruses.
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Ayehunie, Seyoum, Eduardo A. Garcia-Zepeda, James A. Hoxie, Richard Horuk, Thomas S. Kupper, Andrew D. Luster i Ruth M. Ruprecht. "Human Immunodeficiency Virus-1 Entry Into Purified Blood Dendritic Cells Through CC and CXC Chemokine Coreceptors". Blood 90, nr 4 (15.08.1997): 1379–86. http://dx.doi.org/10.1182/blood.v90.4.1379.1379_1379_1386.
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Blood dendritic cells (DC) are susceptible to both macrophage (M) and T-cell line (T) tropic human immunodeficiency virus type 1. The CC chemokines RANTES, macrophage inflammatory protein-1α (MIP-1α), MIP-1β, eotaxin, and, to a lesser extent, monocyte chemoattractant protein-1 (MCP-1) and MCP-4 blocked entry of M-tropic virus into blood DC. The CXC chemokine, SDF-1, a fusin (CXCR4 chemokine receptor) ligand, and an antifusin antibody inhibited DC entry by T-tropic virus. Purified blood DC contained CCR1, CCR2, CCR3, and CCR5 as well as the CXCR4 chemokine receptor RNA transcripts and high levels of fusin on the cell surface. The coexpression of multiple chemokine receptors offers a molecular mechanism to explain the permissiveness of DC for both M- and T-tropic viruses.
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Ren, Han-Yun, Meng Wang, Xiang-Juan Ma, Yu-Jun Dong, Zhi-Xiang Qiu i Wei Liu. "Differential Regulation Of Chemokine Receptor Expressions On T Lymphocyte Subsets In Healthy Donors After Mobilization With Rhg-CSF and Its Correlation With Acute GvHD". Blood 122, nr 21 (15.11.2013): 3296. http://dx.doi.org/10.1182/blood.v122.21.3296.3296.
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Abstract Introduction This study is aimed to investigate chemokine receptors (CCR5, CCR6, CCR7, CCR9, CXCR3 and CCR2) expression on T cell subsets in healthy donors after mobilization with recombinant human granulocyte colony-stimulating factor (rhG-CSF) and analyze its correlation with acute graft-versus-host disease (aGVHD) and to understand the possible mechanisms underlying rhG-CSF-induced immune tolerance. Methods Sixty-eight healthy donor and their recipient pairs of family donor allogeneic hematopoietic stem cell transplantation (allo-HSCT) were included in this study. The expressions of chemokine receptors on CD4+ and CD8+ T cells in the peripheral blood (PB) before and after mobilization was detected using flow cytometry (FCM) respectively. Six chemokine receptors (CCR2, CCR5, CCR6, CCR7, CCR9 and CXCR3) were detected on T cell subsets in all the donors, and CCR5 and CCR7 were detected only in eighteen of all the donors. The expressions of chemokine receptor before and after mobilization was compared and its correlation with II-IV aGVHD were analyzed. Results After rhG-CSF mobilization, the expression of CCR9 on CD4+ T cells and CCR7 on CD8+ T cells were significantly upregulated compared with that before mobilization (p<0.05). However, the mean value of CCR5, CCR6 and CXCR3 expression on CD4+ and CD8+ T cell subsets in PB after mobilization didn’t differ significantly compared with that before mobilization(p>0.10). However, different individuals showed apparent inconsistencies. According to the changes of chemokine receptor expression on CD4+ and CD8+ T cell subsets, the evaluable donors and their relevant recipients were divided into the down-regulated group and the non-down-regulated (unchanged or up-regulated ) group. The incidence of grade II to IV aGVHD in the two groups were compared in their corresponding recipients. In the univariate analysis, mismatched HLA (p=0.046), down-regulation of CCR7 expression on donor CD4+ T cell subsets (p=0.010), unchangeableness or up-regulation of CCR5 expression on donor CD4+ T cell subsets (p=0.032) and CCR6 down-regulation on donor CD8+ T cells (p=0.045) were risk factors for recipients to develop II-IV aGVHD. In the multivariate analysis, down-regulation of CCR7 expression on donor CD4+ T cells after rhG-CSF was independent risk factor for II-IV aGVHD [RR=3.5, 95% CI (1.3-9.4), p=0.012], while CCR5 down-regulation on CD4+ T cells could reduce the incidence of II-IV aGVHD [RR=0.3, 95% CI (0.1-0.8), p=0.031]. Conclusions rhG-CSF mobilization could lead to differential regulation of chemokine receptors expression on T cell subsets, which might cause different effects on the migration of T cells in vivo, and decrease T cells trafficking towards GVHD target organs, and thus reduce the incidence of aGVHD after transplantation. Disclosures: No relevant conflicts of interest to declare.
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Stenstad, Hanna, Anna Ericsson, Bengt Johansson-Lindbom, Marcus Svensson, Jan Marsal, Matthias Mack, Dominic Picarella i in. "Gut-associated lymphoid tissue–primed CD4+ T cells display CCR9-dependent and -independent homing to the small intestine". Blood 107, nr 9 (1.05.2006): 3447–54. http://dx.doi.org/10.1182/blood-2005-07-2860.
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CD4+ T-cell entry to the intestinal mucosa is central to the generation of mucosal immunity as well as chronic intestinal inflammation, yet the mechanisms regulating this process remain poorly defined. Here we show that murine small intestinal CD4+ lamina propria lymphocytes express a heterogeneous but restricted array of chemokine receptors including CCR5, CCR6, CCR9, CXCR3, and CXCR6. CD4+ T-cell receptor transgenic OT-II cells activated in mesenteric lymph nodes acquired a distinct chemokine receptor profile, including expression of CCR6, CCR9, and CXCR3 that was only partially reproduced in vitro after priming with mesenteric lymph node dendritic cells. A subset of these effector CD4+ T cells, expressing CD69 and α4β7, entered the intestinal lamina propria and the majority of these cells expressed CCR9. CCR9–/– OT-II cells were disadvantaged in their ability to localize to the intestinal lamina propria; however, they were readily detected at this site and expressed α4β7, but little CCR2, CCR5, CCR6, CCR8, CCR10, CXCR3, or CXCR6. Thus, whereas CD4+ T cells activated in gut-associated lymphoid tissue express a restricted chemokine receptor profile, including CCR9, targeting both CCR9-dependent and CCR9-independent entry mechanisms is likely to be important to maximally inhibit accumulation of these cells within the small intestinal mucosa.
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Sand, Kristoffer E., Astrid Olsnes Kittang i Øystein Bruserud. "Circulating T Cells Derived From Patients with Low Risk Myelodysplastic Syndromes Show Altered Chemokine Receptor Expression". Blood 116, nr 21 (19.11.2010): 4018. http://dx.doi.org/10.1182/blood.v116.21.4018.4018.
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Abstract Abstract 4018 Several T cell abnormalities have been described in myelodysplastic syndromes (MDS), and such abnormalities may become important for identification of patients who will benefit from T cell targeting immunosuppressive treatment. Chemokine receptor repertoires are important in the regulation of both T cell migration and function and may therefore be important in the development of MDS. Materials and Methods: The chemokine receptor expression by circulating T cells were investigated by multicolor flow cytometry for patients with newly diagnosed low risk MDS (N=16) and for healthy controls (N=18). CD3+CD8+ and CD3+CD8- cells were examined for expression of CCR2-7, CXCR3-4 and CX3CR1 (only 7 unselected patients examined for CX3CR1 expression). CCR6 and CXCR4 expression was also investigated for specific T cell subsets defined by CD62L and CD45RA expression (naïve, central memory, effector memory and terminal effector). CX3CR1 expression was stratified for CD8+ and CD8- subpopulations according to high, low and negative expression of CCR5. Results: Chemokine receptor profiles showed several differences between low risk MDS patients and controls. Total CD8+ T cells from MDS patients showed increased expression of CCR3 (p=0.005) and decreased expression of CCR7 and CCR4 (p=0.023 and p=0.036 respectively), whereas the CD8- T cells from MDS patients showed increased expression of CX3CR1 (p=0.043). In contrast, CCR6 expression was increased only by CD8+ central memory T cells (p=0.044). Finally, CD8+CCR5- and CD8-CCR5high cells from MDS patients showed increased expression of CX3CR1 compared with the controls (p=0.011 and p=0.049). Discussion: CCR7 is mainly expressed by central memory and naïve T cells whereas CX3CR1 is especially expressed by cytotoxic effector lymphocytes independent of the lymphocyte subclass (i.e. CD4, CD8, delta/gamma and NK cells). The observed changes are in line with a shift from naïve/central memory to effector/effector memory dominance, especially in the CD8+ population. A similar shift has been described previously using CD45RA and CD62L (Zou et al, Leukemia 2009). Our median values are in line with such a shift. CCR6 expression is associated with IL17 production both for CD8+ and CD4+cells, and increased levels of circulating CD4+ IL17 producing cells in low risk MDS have been described. Conclusions: The chemokine receptor profiles of circulating T cells differ between low risk MDS patients and healthy controls, especially for the CD8+ T cell subset. These differences may be important for T cell trafficking and disease development, and they may reflect a shift from naïve to effector/effector memory cell dominance in low risk MDS. Disclosures: No relevant conflicts of interest to declare.
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Uhl, Barbara, Katharina T. Prochazka, Katrin Pansy, Kerstin Wenzl, Johanna Strobl, Claudia Baumgartner, Marta M. Szmyra i in. "Distinct Chemokine Receptor Expression Profiles in De Novo DLBCL, Transformed Follicular Lymphoma, Richter’s Trans-Formed DLBCL and Germinal Center B-Cells". International Journal of Molecular Sciences 23, nr 14 (17.07.2022): 7874. http://dx.doi.org/10.3390/ijms23147874.
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Chemokine receptors and their ligands have been identified as playing an important role in the development of diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, and Richter syndrome (RS). Our aim was to investigate the different expression profiles in de novo DLBCL, transformed follicular lymphoma (tFL), and RS. Here, we profiled the mRNA expression levels of 18 chemokine receptors (CCR1–CCR9, CXCR1–CXCR7, CX3CR1 and XCR1) using RQ-PCR, as well as immunohistochemistry of seven chemokine receptors (CCR1, CCR4–CCR8 and CXCR2) in RS, de novo DLBCL, and tFL biopsy-derived tissues. Tonsil-derived germinal center B-cells (GC-B) served as non-neoplastic controls. The chemokine receptor expression profiles of de novo DLBCL and tFL substantially differed from those of GC-B, with at least 5-fold higher expression of 15 out of the 18 investigated chemokine receptors (CCR1–CCR9, CXCR1, CXCR2, CXCR6, CXCR7, CX3CR1 and XCR1) in these lymphoma subtypes. Interestingly, the de novo DLBCL and tFL exhibited at least 22-fold higher expression of CCR1, CCR5, CCR8, and CXCR6 compared with RS, whereas no significant difference in chemokine receptor expression profile was detected when comparing de novo DLBCL with tFL. Furthermore, in de novo DLBCL and tFLs, a high expression of CCR7 was associated with a poor overall survival in our study cohort, as well as in an independent patient cohort. Our data indicate that the chemokine receptor expression profile of RS differs substantially from that of de novo DLBCL and tFL. Thus, these multiple dysregulated chemokine receptors could represent novel clinical markers as diagnostic and prognostic tools. Moreover, this study highlights the relevance of chemokine signaling crosstalk in the tumor microenvironment of aggressive lymphomas.
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Pawlik, Katarzyna, Katarzyna Ciapała, Agata Ciechanowska, Klaudia Kwiatkowski i Joanna Mika. "Pharmacological Evidence of the Important Roles of CCR1 and CCR3 and Their Endogenous Ligands CCL2/7/8 in Hypersensitivity Based on a Murine Model of Neuropathic Pain". Cells 12, nr 1 (26.12.2022): 98. http://dx.doi.org/10.3390/cells12010098.
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Neuropathic pain treatment remains a challenging issue because the therapies currently used in the clinic are not sufficiently effective. Moreover, the mechanism of neuropathy is still not entirely understood; however, much evidence indicates that chemokines are important factors in the initial and late phases of neuropathic pain. To date, the roles of CCR1, CCR3 and their endogenous ligands have not been extensively studied; therefore, they have become the subject of our research. In the present comprehensive behavioral and biochemical study, we detected significant time-dependent and long-lasting increases in the mRNA levels of CCR1 and/or CCR3 ligands, such as CCL2/3/4/5/6/7/8/9, in the murine spinal cord after chronic constriction injury of the sciatic nerve, and these increases were accompanied by changes in the levels of microglial/macrophage, astrocyte and neutrophil cell markers. ELISA results suggested that endogenous ligands of CCR1 and CCR3 are involved in the development (CCL2/3/5/7/8/9) and persistence (CCL2/7/8) of neuropathic pain. Moreover, intrathecal injection of CCL2/3/5/7/8/9 confirmed their possible strong influence on mechanical and thermal hypersensitivity development. Importantly, inhibition of CCL2/7/8 production and CCR1 and CCR3 blockade by selective/dual antagonists effectively reduced neuropathic pain-like behavior. The obtained data suggest that CCL2/7/8/CCR1 and CCL7/8/CCR3 signaling are important in the modulation of neuropathic pain in mice and that these chemokines and their receptors may be interesting targets for future investigations.
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Simmons, Graham, Jacqueline D. Reeves, Áine McKnight, Nathalie Dejucq, Sam Hibbitts, Christine A. Power, Emma Aarons i in. "CXCR4 as a Functional Coreceptor for Human Immunodeficiency Virus Type 1 Infection of Primary Macrophages". Journal of Virology 72, nr 10 (1.10.1998): 8453–57. http://dx.doi.org/10.1128/jvi.72.10.8453-8457.1998.
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ABSTRACT The coreceptors used by primary syncytium-inducing (SI) human immunodeficiency virus type 1 isolates for infection of primary macrophages were investigated. SI strains using only CXCR4 replicated equally well in macrophages with or without CCR5 and were inhibited by several different ligands for CXCR4 including SDF-1 and bicyclam derivative AMD3100. SI strains that used a broad range of coreceptors including CCR3, CCR5, CCR8, CXCR4, and BONZO infected CCR5-deficient macrophages about 10-fold less efficiently than CCR5+macrophages. Moreover, AMD3100 blocked infection of CCR5-negative macrophages by these strains. Our results therefore demonstrate that CXCR4, as well as CCR5, is used for infection of primary macrophages but provide no evidence for the use of alternative coreceptors.
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Davies, Faith E., Mona H. Al Rayes, J. Anthony Child, Gareth J. Morgan i Andrew C. Rawstron. "The Bone Marrow Microenvironment Influences the Differential Chemokine Receptor Expression of Normal and Neoplastic Plasma Cells." Blood 104, nr 11 (16.11.2004): 2353. http://dx.doi.org/10.1182/blood.v104.11.2353.2353.
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Abstract The expression of cytokines and chemokines are under control of several factors, including the bone marrow (BM) microenvironment. The aim of this work was to study the chemokine receptor expression on normal and neoplastic PCs and to investigate the relationship between the BM microenvironment and plasma cell behaviour. The study included 20 patients with reactive disorders or normal BM, 20 individuals with MGUS (monoclonal gammopathy of undetermined significance) and 19 patients with multiple myeloma at presentation. A large panel of chemokine receptor-specific antibodies directed against CCR1, CCR2, CCR3, CCR5, CCR6, CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 was characterized employing a four-colour flow cytometry approach. We demonstrate that normal and myeloma PCs have a specific chemokine receptor profile expressing 7/10 of the receptors studied. CCR2, CCR6, and CXCR1 showed decreased expression on myeloma PCs in comparison to normal PCs (average 3.3, 1.5 and 1.8-fold difference in expression level respectively). In contrast CXCR4 was upregulated on myeloma PCs on average 2.2-fold in comparison to normal PCs. There was no significant difference in expression between normal (CD19+) and neoplastic (CD19−) PCs from the same bone marrow environment in MGUS patients with respect to CCR6, CXCR1 and CXCR4. In contrast there was a significant difference in expression of CCR2 between CD19+ and CD19− PCs from the same BM (P=0.002). The level of expression on CD19− PCs was on average 1.6-fold lower than on their CD19+ counterparts (range 1.1 6.8-fold lower). In conclusion these data demonstrate that normal and myeloma PCs have a specific chemokine receptor profile. Myeloma PCs have a reduced level of some chemokine receptors compared to normal PCs which may account for their abnormal localization within the BM. Differences in expression of CXCR1, CXCR4, and CCR6 are not specific to the neoplastic process, as both normal and neoplastic plasma cells from the same marrow in MGUS patients show corresponding levels of expression. It is probable that feedback loops between neoplastic plasma cells and bone marrow stroma also influence normal plasma cell expression of these chemokine receptors. However, differences in CCR2 expression are not influenced by the marrow microenvironment, therefore downregulation of CCR2 expression is either a function of the neoplastic process or of the stage of differentiation of the originating neoplastic cell. Interfering with chemokines and their receptors which are related to the malignant transformation, particularly CCR2, may prove useful as adjunct to chemotherapy approaches.
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Buri, Caroline, Meike Körner, Patrik Schärli, Daniel Cefai, Mariagrazia Uguccioni, Christoph Mueller, Jean A. Laissue i Luca Mazzucchelli. "CC chemokines and the receptors CCR3 and CCR5 are differentially expressed in the nonneoplastic leukocytic infiltrates of Hodgkin disease". Blood 97, nr 6 (15.03.2001): 1543–48. http://dx.doi.org/10.1182/blood.v97.6.1543.
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Lymph nodes with Hodgkin disease (HD) harbor few neoplastic cells in a marked leukocytic infiltrate. Since chemokines are likely to be involved in the recruitment of these leukocytes, the expression of potentially relevant chemokines and chemokine receptors were studied in lymph nodes from 24 patients with HD and in 5 control lymph nodes. The expression of regulated on activation, normal T cell expressed and secreted (RANTES), monocyte chemotactic protein (MCP)–1, macrophage inflammatory protein (MIP)–1α, and MIP-1β was analyzed by in situ hybridization and that of CCR3 and CCR5 by immunohistochemistry and flow cytometry. It was found that, overall, the expression of all 4 chemokines was markedly enhanced, but the cellular source was different. RANTES was expressed almost exclusively by T cells whereas the expression of MCP-1, MIP-1α, and MIP-1β was confined largely to macrophages. In control lymph nodes, chemokine expression was low, with the exception of MIP-1α in macrophages. CCR3 and CCR5 were highly expressed in T cells of HD involved but not of control lymph nodes. CCR3 was equally distributed in CD4+ and CD8+ cells, but CCR5 was associated largely with CD4+ cells. In HD lymph nodes, CCR3 and CCR5 were also expressed in B cells, which normally do not express these receptors. All these chemokines and receptors studied, by contrast, were absent in the neoplastic cells. It was concluded that chemokines are involved in the formation of the HD nonneoplastic leukocytic infiltrate. Expression of CCR3 and CCR5 appears to be characteristic of HD, but the roles of these receptors' up-regulation for the disease process remain unclear.
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Ghorpade, Anuja, Meng Qi Xia, Bradley T. Hyman, Yuri Persidsky, Adeline Nukuna, Paul Bock, Myhanh Che, Jenae Limoges, Howard E. Gendelman i Charles R. Mackay. "Role of the β-Chemokine Receptors CCR3 and CCR5 in Human Immunodeficiency Virus Type 1 Infection of Monocytes and Microglia". Journal of Virology 72, nr 4 (1.04.1998): 3351–61. http://dx.doi.org/10.1128/jvi.72.4.3351-3361.1998.
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ABSTRACT Human immunodeficiency virus type 1 (HIV-1) infection in mononuclear phagocyte lineage cells (monocytes, macrophages, and microglia) is a critical component in the pathogenesis of viral infection. Viral replication in macrophages serves as a reservoir, a site of dissemination, and an instigator for neurological sequelae during HIV-1 disease. Recent studies demonstrated that chemokine receptors are necessary coreceptors for HIV-1 entry which determine viral tropism for different cell types. To investigate the relative contribution of the β-chemokine receptors CCR3 and CCR5 to viral infection of mononuclear phagocytes we utilized a panel of macrophage-tropic HIV-1 strains (from blood and brain tissue) to infect highly purified populations of monocytes and microglia. Antibodies to CD4 (OKT4A) abrogated HIV-1 infection. The β chemokines and antibodies to CCR3 failed to affect viral infection of both macrophage cell types. Antibodies to CCR5 (3A9) prevented monocyte infection but only slowed HIV replication in microglia. Thus, CCR5, not CCR3, is an essential receptor for HIV-1 infection of monocytes. Microglia express both CCR5 and CCR3, but antibodies to them fail to inhibit viral entry, suggesting the presence of other chemokine receptors for infection of these cells. These studies demonstrate the importance of mononuclear phagocyte heterogeneity in establishing HIV-1 infection and persistence.
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Worgall, Stefan, Ruth Connor, Robert J. Kaner, Elizabeth Fenamore, Kristine Sheridan, Ravi Singh i Ronald G. Crystal. "Expression and Use of Human Immunodeficiency Virus Type 1 Coreceptors by Human Alveolar Macrophages". Journal of Virology 73, nr 7 (1.07.1999): 5865–74. http://dx.doi.org/10.1128/jvi.73.7.5865-5874.1999.
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ABSTRACT Human immunodeficiency virus type 1 (HIV-1) requires, in addition to CD4, coreceptors of the CC or CXC chemokine families for productive infection of T cells and cells of the monocyte-macrophage lineage. Based on the hypothesis that coreceptor expression on alveolar macrophages (AM) may influence HIV-1 infection of AM in the lung, this study analyzes the expression and utilization of HIV-1 coreceptors on AM of healthy individuals. AM were productively infected with five different primary isolates of HIV-1. Levels of surface expression of CCR5, CXCR4, and CD4 were low compared to those of blood monocytes, but CCR3 was not detectable. mRNA for CCR5, CXCR4, CCR2, and CCR3 were all detectable, but to varying degrees and with variability among donors. Expression of CCR5, CXCR4, and CCR2 mRNA was downregulated following stimulation with lipopolysaccharide (LPS). In contrast, secretion of the chemokines RANTES, MIP-1α, and MIP-1β was upregulated with LPS stimulation. Interestingly, HIV-1 replication was diminished following LPS stimulation. Infection of AM with HIV-1 in the presence of the CC chemokines demonstrated blocking of infection. Together, these studies demonstrate that AM can be infected by a variety of primary HIV-1 isolates, AM express a variety of chemokine receptors, the dominant coreceptor used for HIV entry into AM is CCR5, the expression of these receptors is dependent on the state of activation of AM, and the ability of HIV-1 to infect AM may be modulated by expression of the chemokine receptors and by chemokines per se.