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1
Korbecki, Jan, Klaudyna Kojder, Katarzyna Barczak, Donata Simińska, Izabela Gutowska, Dariusz Chlubek, and 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, no. 16 (August 6, 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, et al. "Inhibition of Human Immunodeficiency Virus Replication by a Dual CCR5/CXCR4 Antagonist." Journal of Virology 78, no. 23 (December 1, 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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Zhang, Yi-jun, Tatjana Dragic, Yunzhen Cao, Leondios Kostrikis, Douglas S. Kwon, Dan R. Littman, Vineet N. KewalRamani, and 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, no. 11 (November 1, 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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Taylor, James R., Katherine C. Kimbrell, Robert Scoggins, Marie Delaney, Lijun Wu, and David Camerini. "Expression and Function of Chemokine Receptors on Human Thymocytes: Implications for Infection by Human Immunodeficiency Virus Type 1." Journal of Virology 75, no. 18 (September 15, 2001): 8752–60. http://dx.doi.org/10.1128/jvi.75.18.8752-8760.2001.
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ABSTRACT The presence or absence of the receptor CD4 and the coreceptors CCR5 and CXCR4 restrict the cell tropism of human immunodeficiency virus type 1 (HIV-1). Despite the importance of thymic infection by HIV-1, conflicting reports regarding the expression of HIV-1 coreceptors on human thymocytes have not been resolved. We assayed the expression and function of the major HIV-1 coreceptors, CCR5 and CXCR4, as well as CCR4 and CCR7 as controls, on human thymocytes. We detected CCR5 on 2.5% of thymocytes, CXCR4 on 53% of the cells, and CCR4 on 16% and CCR7 on 11% of human thymocytes. Moreover, infection by R5 HIV-1 did not significantly induce expression of CCR5. We found that two widely used anti-CCR5 monoclonal antibodies cross-reacted with CCR8, which may account for discrepancies among published reports of CCR5 expression on primary cells. This cross-reactivity could be eliminated by deletion of amino acids 2 through 4 of CCR8. Chemotaxis assays showed that SDF-1, which binds CXCR4; MDC, which binds CCR4; and ELC, which binds CCR7, mediated significant chemotaxis of thymocytes. In contrast, MIP-1β, whose receptor is CCR5, did not induce significant chemotaxis. Our results indicate that CXCR4, CCR4, CCR7, and their chemokine ligands may be involved in thymocyte migration during development in the thymus. CCR5 and its ligands, however, are likely not involved in these processes. Furthermore, the pattern of CCR5 and CXCR4 expression that we found may explain the greater susceptibility of human thymocytes to infection by HIV-1 isolates capable of using CXCR4 in cell entry compared to those that use only CCR5.
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Mazur, Grzegorz, Emilia Jaskula, Ilona Kryczek, Dorota Dlubek, Tomasz Wrobel, Aleksandra Butrym, Andrzej Lange, and Kazimierz Kuliczkowski. "Gene Expression for Chemokine Receptors Influences Survival of Non-Hodgkin Lymphoma Patients." Blood 116, no. 21 (November 19, 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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Ren, Han-Yun, Meng Wang, Xiang-Juan Ma, Yu-Jun Dong, Zhi-Xiang Qiu, and 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, no. 21 (November 15, 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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Kim, Chang H., Jeeho Lee, and Seung G. Kang. "Developmental and antigen-driven switches in the trafficking receptors of FoxP3+ regulatory T cells (99.2)." Journal of Immunology 178, no. 1_Supplement (April 1, 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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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, et al. "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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Zvejniece, Laura, Svetlana Kozireva, Zanna Rudevica, Ainars Leonciks, Barbro Ehlin-Henriksson, Elena Kashuba, and 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, no. 7 (March 22, 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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Catusse, Julie, Chris M. Parry, David R. Dewin, and Ursula A. Gompels. "Inhibition of HIV-1 infection by viral chemokine U83A via high-affinity CCR5 interactions that block human chemokine-induced leukocyte chemotaxis and receptor internalization." Blood 109, no. 9 (January 5, 2007): 3633–39. http://dx.doi.org/10.1182/blood-2006-08-042622.
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AbstractHIV-1 strains use C-C-chemokine receptor 5, CCR5, as a coreceptor for host transmission. Human CCR5 chemokine ligands inhibit binding and infection, whereas CCR5 mutations also inhibit infection by preventing surface expression, resulting in delayed progression to AIDS. Here, we describe a human herpesvirus 6 (HHV-6A) chemokine, U83A, which binds CCR5 with higher affinity than human chemokines, displacing their binding and leading to inhibition of chemotaxis of human leukocytes. Similarly, U83A inhibits infection by HIV-1 strains which use CCR5, but not the CXCR4, coreceptor. Unlike human CCR5 chemokine ligands which induce rapid CCR5 internalization mediated via clathrin, treatment with U83A prevents internalization. A spliced truncated U83A isoform, U83A-N, also binds CCR5 albeit with lower affinity, and this correlates with lower HIV-1 infection inhibition, whereas further truncation abolishes binding and any inhibition. Confocal microscopy confirms CCR5 internalization inhibition by U83A treatment, whereas labeled transferrin uptake shows that endocytosis via clathrin is unaltered. Previous results show that, although U83A-N is an antagonist, U83A is an agonist for CCR1, CCR4, CCR6, and CCR8 present on immune effector and antigen-presenting cells and here also shown for CCR5. Thus, U83A could act as a novel inhibitor of HIV-1 infection while also stimulating local immunity to the virus.
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Ortega Moreno, L., S. Fernández Tomé, M. Chaparro, A. Marin, I. Mora Gutiérrez, C. Santander, M. Baldán, J. Gisbert, and 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 (January 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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Stenstad, Hanna, Anna Ericsson, Bengt Johansson-Lindbom, Marcus Svensson, Jan Marsal, Matthias Mack, Dominic Picarella, et al. "Gut-associated lymphoid tissue–primed CD4+ T cells display CCR9-dependent and -independent homing to the small intestine." Blood 107, no. 9 (May 1, 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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Wenzl, Kerstin, Katharina Troppan, Alexander JA Deutsch, Werner Linkesch, Peter Neumeister, and 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, no. 21 (November 15, 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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ANDERS, HANS-JOACHIM, VOLKER VIELHAUER, MATTHIAS KRETZLER, CLEMENS D. COHEN, STEPHAN SEGERER, BRUNO LUCKOW, LARS WELLER, HERMANN-JOSEF GRÖNE, and DETLEF SCHLÖNDORFF. "Chemokine and Chemokine Receptor Expression during Initiation and Resolution of Immune Complex Glomerulonephritis." Journal of the American Society of Nephrology 12, no. 5 (May 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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Fox, James M., Elisa Letellier, Christopher J. Oliphant, and Nathalie Signoret. "TLR2-dependent pathway of heterologous down-modulation for the CC chemokine receptors 1, 2, and 5 in human blood monocytes." Blood 117, no. 6 (February 10, 2011): 1851–60. http://dx.doi.org/10.1182/blood-2010-05-287474.
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Abstract During innate immune responses, the inflammatory CC chemokine receptors CCR1, CCR2, and CCR5 mediate the recruitment of blood monocytes to infected tissues by promoting cell migration in response to chemokines CCL2-5. Toll-like receptors also play an essential role, allowing pathogen recognition by the recruited monocytes. Here, we demonstrate that Toll-like receptor 2 (TLR2) stimulation by lipoteichoic acid (LTA) from Staphylococcus aureus leads to gradual down-modulation of CCR1, CCR2, and CCR5 from the plasma membrane of human blood-isolated monocytes and inhibits chemotaxis. Interestingly, LTA does not promote rapid desensitization of chemokine-mediated calcium responses. We found that the TLR2 crosstalk with chemokine receptors is not dependent on the Toll/interleukin-1 receptor domain-containing adaptor protein, but instead involves phospholipase C, the small G protein Rac1, and is phorbol ester sensitive. Activation of this pathway by LTA lead to β-arrestin–mediated endocytosis of Ser349-phosphorylated CCR5 into recycling endosomes, as does CCL5 treatment. However, LTA-induced internalization of CCR5 is a slower process associated with phospholipase C–mediated and phorbol ester–sensitive phosphorylation. Overall, our data indicate that TLR2 negatively regulates CCR1, CCR2, and CCR5 on human blood monocytes by activating the machinery used to support chemokine-dependent down-modulation and provide a molecular mechanism for inhibiting monocyte migration after pathogen recognition.
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Kim, Chang H., Brent Johnston, and 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, no. 1 (July 1, 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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Zilio, Serena, Silvio Bicciato, Donald Weed, and Paolo Serafini. "CCR1 and CCR5 mediate cancer-induced myelopoiesis and differentiation of myeloid cells in the tumor." Journal for ImmunoTherapy of Cancer 10, no. 1 (January 2022): e003131. http://dx.doi.org/10.1136/jitc-2021-003131.
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BackgroundCancer-induced ‘emergency’ myelopoiesis plays a key role in tumor progression by inducing the accumulation of myeloid cells with a suppressive phenotype peripherally and in the tumor. Chemokine receptors (CCRs) and, in particular, CCR1, CCR2, CCR5, and CCR7 are emerging as key regulators of myeloid cell trafficking and function but their precise role has not been completely clarified yet because of the signal redundancy, integration, and promiscuity of chemokines and of the expression of these CCRs on other leukocyte subsets.MethodsWe used the 4PD nanoparticle for the in vivo targeted silencing of CCR1, CCR2, CCR5, and/or CCR7 in the myeloid cells of tumor bearing mice to evaluate the effect of treatments on tumor growth, myeloid cell trafficking and polarization. We used flow and image cytometry and functional assays to monitor changes in the tumor microenvironment and depletion experiments and immune deficient mice to determine the role of Ly6G+cells during tumor progression. We further evaluated in vitro the impact of chemokine receptor inhibition and tumor derived factors on myeloid cell differentiation from mouse and human hematopoietic stem and precursors cells (HSPCs) using flow cytometry, transcriptome analysis, cytokines beads arrays, functional assays, and mice deficient for CCR1 or CCR5.Results4PD-mediated in vivo silencing of CCR1 and CCR5 on myeloid cells and myeloid precursors was necessary and sufficient to inhibit tumor progression. Functional studies indicated that this antitumor effect was not mediated by alteration of myeloid cell chemotaxes but rather by the repolarization of polymorphonuclear myeloid-derived suppressor cells (MDSCs) into tumoricidal neutrophils. Transcriptome functional and cytokine analysis indicated that tumor derived factors induced CCL3 and CCL4 in HSPCs that, through the autocrine engagement of CCR1 and CCR5, induced HSPCs differentiation in MDSCs. These finding were confirmed across mice with different genetic backgrounds and using HSPCs from umbilical cord blood and peripheral blood of patients with cancer.ConclusionsOur data support the notion that CCR1 and CCR5 and their ligands are a master immunological hub activated by several tumor derived factors. Activation of this pathway is necessary for the differentiation of MDSCs and protumoral macrophages.
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Soto-Rodriguez, Guadalupe, Juan-Antonio Gonzalez-Barrios, Daniel Martinez-Fong, Victor-Manuel Blanco-Alvarez, Jose R. Eguibar, Araceli Ugarte, Francisco Martinez-Perez, et al. "Analysis of Chemokines and Receptors Expression Profile in the Myelin MutantTaiepRat." Oxidative Medicine and Cellular Longevity 2015 (2015): 1–8. http://dx.doi.org/10.1155/2015/397310.
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Taieprat has a failure in myelination and remyelination processes leading to a state of hypomyelination throughout its life. Chemokines, which are known to play a role in inflammation, are also involved in the remyelination process. We aimed to demonstrate that remyelination-stimulating factors are altered in the brainstem of 1- and 6-month-oldtaieprats. We used a Rat RT2Profiler PCR Array to assess mRNA expression of 84 genes coding for cytokines, chemokines, and their receptors. We also evaluated protein levels of CCL2, CCR1, CCR2, CCL5, CCR5, CCR8, CXCL1, CXCR2, CXCR4, FGF2, and VEGFA by ELISA. Sprague-Dawley rats were used as a control. PCR Array procedure showed that proinflammatory cytokines were not upregulated in thetaieprat. In contrast, some mRNA levels of beta and alpha chemokines were upregulated in 1-month-old rats, but CXCR4 was downregulated at their 6 months of age. ELISA results showed that CXCL1, CCL2, CCR2, CCR5, CCR8, and CXCR4 protein levels were decreased in brainstem at the age of 6 months. These results suggest the presence of a chronic neuroinflammation process with deficiency of remyelination-stimulating factors (CXCL1, CXCR2, and CXCR4), which might account for the demyelination in thetaieprat.
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Sullivan, Nicole L., Christopher S. Eickhoff, Olivia K. Giddings, Daniel F. Hoft, and Thomas E. Lane. "CCR5 is not required for mucosal protection against Trypanosoma cruzi (39.28)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 39.28. http://dx.doi.org/10.4049/jimmunol.182.supp.39.28.
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Abstract Trypanosoma cruzi is an intracellular obligate parasite and the causative agent of Chagas disease. Previous work has shown that the chemokine receptor CCR5 plays a role in systemic responses against T. cruzi. We evaluated whether CCR5 plays a critical role in mucosal protection against natural oral and conjunctival challenges. Memory-immune CCR5-/- and wild-type C57BL/6 mice were generated by repeated infectious challenges with sublethal doses of insect-derived metacyclic trypomastigotes. Similar IgA, IgG and IFN-γ responses were detected in the spleen in both memory-immune and primary infected wild-type and CCR5-/- mice. More importantly, protection was evaluated in memory-immune mice via real-time PCR and limiting dilution assay for parasite outgrowth. CCR5-/- memory-immune mice developed equivalent levels of protection against both oral and conjunctival mucosal challenges. Preliminary studies from the stomachs of CCR5-/- memory-immune mice showed an increase in the transcript levels of CCL5 as compared to memory-immune wild-type mice. Overall, it appears that CCR5 does not play a critical role in the control of parasite replication and immune responses at sites of initial mucosal infection with T. cruzi. However, CCL5 signaling through CCR1 and/or CCR3 may compensate for the absence of CCR5.
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Abid, Shariq, Elisabeth Marcos, Aurélien Parpaleix, Valérie Amsellem, Marielle Breau, Amal Houssaini, Nora Vienney, et al. "CCR2/CCR5-mediated macrophage–smooth muscle cell crosstalk in pulmonary hypertension." European Respiratory Journal 54, no. 4 (July 18, 2019): 1802308. http://dx.doi.org/10.1183/13993003.02308-2018.
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Macrophages are major players in the pathogenesis of pulmonary arterial hypertension (PAH).To investigate whether lung macrophages and pulmonary-artery smooth muscle cells (PASMCs) collaborate to stimulate PASMC growth and whether the CCL2-CCR2 and CCL5-CCR5 pathways inhibited macrophage–PASMC interactions and PAH development, we used human CCR5-knock-in mice and PASMCs from patients with PAH and controls.Conditioned media from murine M1 or M2 macrophages stimulated PASMC growth. This effect was markedly amplified with conditioned media from M2 macrophage/PASMC co-cultures. CCR2, CCR5, CCL2 and CCL5 were upregulated in macrophage/PASMC co-cultures. Compared to inhibiting either receptor, dual CCR2 and CCR5 inhibition more strongly attenuated the growth-promoting effect of conditioned media from M2-macrophage/PASMC co-cultures. Deleting either CCR2 or CCR5 in macrophages or PASMCs attenuated the growth response. In mice with hypoxia- or SUGEN/hypoxia-induced PH, targeting both CCR2 and CCR5 prevented or reversed PH more efficiently than targeting either receptor alone. Patients with PAH exhibited CCR2 and CCR5 upregulation in PASMCs and perivascular macrophages compared to controls. The PASMC growth-promoting effect of conditioned media from M2-macrophage/PASMC co-cultures was greater when PASMCs from PAH patients were used in the co-cultures or as the target cells and was dependent on CCR2 and CCR5. PASMC migration toward M2-macrophages was greater with PASMCs from PAH patients and was attenuated by blocking CCR2 and CCR5.CCR2 and CCR5 are required for collaboration between macrophages and PASMCs to initiate and amplify PASMC migration and proliferation during PAH development. Dual targeting of CCR2 and CCR5 may hold promise for treating human PAH.
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Raghu, Harini, Christin M. Lepus, Qian Wang, Heidi H. Wong, Nithya Lingampalli, Francesca Oliviero, Leonardo Punzi, et al. "CCL2/CCR2, but not CCL5/CCR5, mediates monocyte recruitment, inflammation and cartilage destruction in osteoarthritis." Annals of the Rheumatic Diseases 76, no. 5 (December 13, 2016): 914–22. http://dx.doi.org/10.1136/annrheumdis-2016-210426.
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ObjectivesWhile various monocyte chemokine systems are increased in expression in osteoarthritis (OA), the hierarchy of chemokines and chemokine receptors in mediating monocyte/macrophage recruitment to the OA joint remains poorly defined. Here, we investigated the relative contributions of the CCL2/CCR2 versus CCL5/CCR5 chemokine axes in OA pathogenesis.MethodsCcl2-, Ccr2-, Ccl5- and Ccr5-deficient and control mice were subjected to destabilisation of medial meniscus surgery to induce OA. The pharmacological utility of blocking CCL2/CCR2 signalling in mouse OA was investigated using bindarit, a CCL2 synthesis inhibitor, and RS-504393, a CCR2 antagonist. Levels of monocyte chemoattractants in synovial tissues and fluids from patients with joint injuries without OA and those with established OA were investigated using a combination of microarray analyses, multiplexed cytokine assays and immunostains.ResultsMice lacking CCL2 or CCR2, but not CCL5 or CCR5, were protected against OA with a concomitant reduction in local monocyte/macrophage numbers in their joints. In synovial fluids from patients with OA, levels of CCR2 ligands (CCL2, CCL7 and CCL8) but not CCR5 ligands (CCL3, CCL4 and CCL5) were elevated. We found that CCR2+ cells are abundant in human OA synovium and that CCR2+ macrophages line, invade and are associated with the erosion of OA cartilage. Further, blockade of CCL2/CCR2 signalling markedly attenuated macrophage accumulation, synovitis and cartilage damage in mouse OA.ConclusionsOur findings demonstrate that monocytes recruited via CCL2/CCR2, rather than by CCL5/CCR5, propagate inflammation and tissue damage in OA. Selective targeting of the CCL2/CCR2 system represents a promising therapeutic approach for OA.
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Uhl, Barbara, Katharina T. Prochazka, Katrin Pansy, Kerstin Wenzl, Johanna Strobl, Claudia Baumgartner, Marta M. Szmyra, et al. "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, no. 14 (July 17, 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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Deutsch, Alexander J. A., Ariane Aigelsreiter, Elisabeth Steinbauer, Werner Linkesch, Christine Beham-Schmid, Helmut Schaider, and Peter Neumeister. "Chemokine Receptor Expression Profile in the Model of Parotid MALT Lymphomagenesis: De Novo Expression of CXCR6." Blood 110, no. 11 (November 16, 2007): 2622. http://dx.doi.org/10.1182/blood.v110.11.2622.2622.
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Abstract Chemokine receptors mediate migration and activation of lymphocytes through binding of their ligands. Several recent studies have revealed important contributions of chemokine receptors and their ligands to the development and progression/dissemination of hematopoietic neoplasms. Strong expression of CXCR5 and its ligand BCA-1 was detected in transformed B cells in H. pylori positive gastric MALT lymphoma. Because the knowledge of chemokine receptor expression in parotid MALT lymphoma is limited, we performed a comprehensive study on tissue samples of parotid glands (P), parotid glands affected by Sjoegren Syndrome (SS), parotid MALT lymphoma (MALT) and extranodal diffuse large B cell lymphoma (eDLBCL). By investigating the expression of all 19 known chemokine receptor at mRNA levels by real time PCR using a semi quantitative approach and of 3 chemokine receptors (CCR1, CCR5 and CXCR6) at protein levels we propose a model of MALT lymphoma that the development from a non neoplastic event to Sjoegren Syndrome or malignant transformation is accompanied by significant deregulations in the chemokine receptor expression profile: in the development of SS CCR5 was 783 times up regulated and CCR6, CCR8 and CCR10 mRNAs were de novo expressed; in the progression process of SS to parotid MALT CCR7, CXCR3, CXCR4, CXCR5, CXCR6, CX3CR1 and XCR1 were de novo expressed and CCR10 lost its expression; during the transformation of MALT to eDLBCL, CCR1, CCR8 and CXCR3 were 13 times down regulated and CX3CR1 and XCR1 lost their expression. Expression of CCR1, CCR5 and CXCR6 were confirmed by immunohistochemistry. The present results support a model of a stepwise progression of parotid MALT lymphoma from a non neoplastic event to Sjoegren Syndrome and finally overt MALT lymphoma guided by differentially expressed chemokine receptors and their ligands.
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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, and Rodrigo Correa-Oliveira. "Type 1 Chemokine Receptor Expression in Chagas' Disease Correlates with Morbidity in Cardiac Patients." Infection and Immunity 73, no. 12 (December 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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Barroso-González, Jonathan, Nabil El Jaber-Vazdekis, Laura García-Expósito, José-David Machado, Rafael Zárate, Ángel G. Ravelo, Ana Estévez-Braun, and Agustín Valenzuela-Fernández. "The Lupane-type Triterpene 30-Oxo-calenduladiol Is a CCR5 Antagonist with Anti-HIV-1 and Anti-chemotactic Activities." Journal of Biological Chemistry 284, no. 24 (April 22, 2009): 16609–20. http://dx.doi.org/10.1074/jbc.m109.005835.
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The existence of drug-resistant human immunodeficiency virus (HIV) viruses in patients receiving antiretroviral treatment urgently requires the characterization and development of new antiretroviral drugs designed to inhibit resistant viruses and to complement the existing antiretroviral strategies against AIDS. We assayed several natural or semi-synthetic lupane-type pentacyclic triterpenes in their ability to inhibit HIV-1 infection in permissive cells. We observed that the 30-oxo-calenduladiol triterpene, compound 1, specifically impaired R5-tropic HIV-1 envelope-mediated viral infection and cell fusion in permissive cells, without affecting X4-tropic virus. This lupane derivative competed for the binding of a specific anti-CCR5 monoclonal antibody or the natural CCL5 chemokine to the CCR5 viral coreceptor with high affinity. 30-Oxo-calenduladiol seems not to interact with the CD4 antigen, the main HIV receptor, or the CXCR4 viral coreceptor. Our results suggest that compound 1 is a specific CCR5 antagonist, because it binds to the CCR5 receptor without triggering cell signaling or receptor internalization, and inhibits RANTES (regulated on activation normal T cell expressed and secreted)-mediated CCR5 internalization, intracellular calcium mobilization, and cell chemotaxis. Furthermore, compound 1 appeared not to interact with β-chemokine receptors CCR1, CCR2b, CCR3, or CCR4. Thereby, the 30-oxo-calenduladiol-associated anti-HIV-1 activity against R5-tropic virus appears to rely on the selective occupancy of the CCR5 receptor to inhibit CCR5-mediated HIV-1 infection. Therefore, it is plausible that the chemical structure of 30-oxo-calenduladiol or other related dihydroxylated lupane-type triterpenes could represent a good model to develop more potent anti-HIV-1 molecules to inhibit viral infection by interfering with early fusion and entry steps in the HIV life cycle.
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Sallusto, Federica, Danielle Lenig, Charles R. Mackay, and Antonio Lanzavecchia. "Flexible Programs of Chemokine Receptor Expression on Human Polarized T Helper 1 and 2 Lymphocytes." Journal of Experimental Medicine 187, no. 6 (March 16, 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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Korbecki, Jan, Szymon Grochans, Izabela Gutowska, Katarzyna Barczak, and Irena Baranowska-Bosiacka. "CC Chemokines in a Tumor: A Review of Pro-Cancer and Anti-Cancer Properties of Receptors CCR5, CCR6, CCR7, CCR8, CCR9, and CCR10 Ligands." International Journal of Molecular Sciences 21, no. 20 (October 15, 2020): 7619. http://dx.doi.org/10.3390/ijms21207619.
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CC chemokines (or β-chemokines) are 28 chemotactic cytokines with an N-terminal CC domain that play an important role in immune system cells, such as CD4+ and CD8+ lymphocytes, dendritic cells, eosinophils, macrophages, monocytes, and NK cells, as well in neoplasia. In this review, we discuss human CC motif chemokine ligands: CCL1, CCL3, CCL4, CCL5, CCL18, CCL19, CCL20, CCL21, CCL25, CCL27, and CCL28 (CC motif chemokine receptor CCR5, CCR6, CCR7, CCR8, CCR9, and CCR10 ligands). We present their functioning in human physiology and in neoplasia, including their role in the proliferation, apoptosis resistance, drug resistance, migration, and invasion of cancer cells. We discuss the significance of chemokine receptors in organ-specific metastasis, as well as the influence of each chemokine on the recruitment of various cells to the tumor niche, such as cancer-associated fibroblasts (CAF), Kupffer cells, myeloid-derived suppressor cells (MDSC), osteoclasts, tumor-associated macrophages (TAM), tumor-infiltrating lymphocytes (TIL), and regulatory T cells (Treg). Finally, we show how the effect of the chemokines on vascular endothelial cells and lymphatic endothelial cells leads to angiogenesis and lymphangiogenesis.
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VIELHAUER, VOLKER, HANS-JOACHIM ANDERS, MATTHIAS MACK, JOSEF CIHAK, FRANK STRUTZ, MANFRED STANGASSINGER, BRUNO LUCKOW, HERMANN-JOSEF GRÖNE, and DETLEF SCHLÖNDORFF. "Obstructive Nephropathy in the Mouse: Progressive Fibrosis Correlates with Tubulointerstitial Chemokine Expression and Accumulation of CC Chemokine Receptor 2- and 5-Positive Leukocytes." Journal of the American Society of Nephrology 12, no. 6 (June 2001): 1173–87. http://dx.doi.org/10.1681/asn.v1261173.
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Abstract. The infiltration of leukocytes plays a major role in mediating tubulointerstitial inflammation and fibrosis in chronic renal disease. CC chemokines participate in leukocyte migration and infiltration into inflamed renal tissue. Because CC chemokine-directed leukocyte migration is mediated by target cell expression of a group of CC chemokine receptors, this study examined the expression of CC chemokines and their receptors during initiation of tubulointerstitial fibrosis after unilateral ureteral obstruction in C57BL/6 mice. Obstructed kidneys developed hydronephrosis, tubular cell damage, interstitial inflammation, and fibrosis. From days 2 to 10, a progressive interstitial influx of F4/80+ macrophages and CD3+ lymphocytes occurred (macrophages, 4-fold; lymphocytes, 20-fold at day 10, compared with contralateral control kidneys). In parallel, the number of activated fibroblast-specific protein 1+ fibroblasts and interstitial collagen IV accumulation increased from days 2 to 10. The mRNA expression of CC chemokines (predominantly monocyte chemoattractant protein-1 [MCP-1]/CCL2, RANTES/CCL5) and their receptors CCR1, CCR2, CCR5 increased progressively from days 2 to 10. Byin situhybridization, a prominent interstitial mRNA expression of MCP-1 and RANTES and their receptors CCR2 and CCR5 localized to interstitial mononuclear cell infiltrates. MCP-1 and RANTES expression was also seen in tubular epithelial cells. Fluorescence-activated cell sorter analysis of single-cell suspensions from obstructed kidneys revealed a prominent expression of CCR2 and CCR5 by infiltrating macrophages, whereas most lymphocytes expressed CCR5 only. These data demonstrate an increased expression of MCP-1/CCL2 and RANTES/CCL5 at sites of tubulointerstitial damage and progressive fibrosis during unilateral ureteral obstruction that correlates with simultaneous accumulation of interstitial macrophages and T lymphocytes expressing the respective surface receptors CCR2 and CCR5. The chemokine receptor—mediated leukocyte influx into the tubulointerstitium could offer a new potential target for therapeutic intervention in progressive renal tubulointerstitial fibrosis.
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Clark, D. J., J. Catusse, A. Stacey, P. Borrow, and U. A. Gompels. "Activation of CCR2+ human proinflammatory monocytes by human herpesvirus-6B chemokine N-terminal peptide." Journal of General Virology 94, no. 7 (July 1, 2013): 1624–35. http://dx.doi.org/10.1099/vir.0.050153-0.
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Human monocytes expressing CCR2 with CD14 and CD16 can mediate antigen presentation, and promote inflammation, brain infiltration and immunosenescence. Recently identified roles are in human immunodeficiency virus infection, tuberculosis and parasitic disease. Human herpesvirus 6B (HHV-6B) encodes a chemokine, U83B, which is monospecific for CCR2, and is distinct from the related HHV-6A U83A, which activates CCR1, CCR4, CCR5, CCR6 and CCR8 on immune effector cells and dendritic cells. These differences could alter leukocyte-subset recruitment for latent/lytic replication and associated neuroinflammatory pathology. Therefore, cellular interactions between U83A and U83B could help dictate potential tropism differences between these viruses. U83A specificity is maintained in the 38-residue N-terminal spliced-truncated form. Here, we sought to determine the basis for the chemokine receptor specificity differences and identify possible applications. To do this we first analysed variation in a natural host population in sub-Saharan Africa where both viruses are equally prevalent and compared these to global strains. Analyses of U83 N-terminal variation in 112 HHV-6A and HHV-6B infections identified 6/38 U83A or U83B-specific residues. We also identified a unique single U83A-specific substitution in one U83B sequence, ‘U83BA’. Next, the variation effects were tested by deriving N-terminal (NT) 17-mer peptides and assaying activation of ex vivo human leukocytes, the natural host and cellular target. Chemotaxis of CCR2+ leukocytes was potently induced by U83B-NT, but not U83BA-NT or U83A-NT. Analyses of the U83B-NT activated population identified migrated CCR2+, but not CCR5+, leukocytes. The U83BA-NT asparagine-lysine14 substitution disrupted activity, thus defining CCR2 specificity and acting as a main determinant for HHV-6A/B differences in cellular interactions. A flow-cytometry-based shape-change assay was designed, and used to provide further evidence that U83B-NT could activate CCR2+CD14+CD16+ monocytes. This defines a potential antiviral target for HHV-6A/B disease and novel peptide immunomodulator for proinflammatory monocytes.
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Kramp, Birgit K., Remco T. A. Megens, Alisina Sarabi, Sabine Winkler, Delia Projahn, Christian Weber, Rory R. Koenen, and Philipp von Hundelshausen. "Exchange of extracellular domains of CCR1 and CCR5 reveals confined functions in CCL5-mediated cell recruitment." Thrombosis and Haemostasis 110, no. 10 (2013): 795–806. http://dx.doi.org/10.1160/th13-05-0420.
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SummaryThe chemokine CCL5 recruits monocytes into inflamed tissues by triggering primarily CCR1-mediated arrest on endothelial cells, whereas subsequent spreading is dominated by CCR5. The CCL5-induced arrest can be enhanced by heteromer formation with CXCL4. To identify mechanisms for receptor-specific functions, we employed CCL5 mutants and transfectants expressing receptor chimeras carrying transposed extracellular regions. Mutation of the basic 50s cluster of CCL5, a coordinative site for CCL5 surface presentation, reduced CCR5- but not CCR1-mediated arrest and transmigration. Impaired arrest was restored by exchanging the CCR5-N-terminus for that of CCR1, which supported arrest even without the 50s cluster, whereas mutation of the basic 40s cluster essential for proteoglycan binding of CCL5 could not be rescued. The enhancement of CCL5-induced arrest by CXCL4 was mediated by CCR1 requiring its third extracellular loop. The domain exchanges did not affect formation and co-localisation of receptor dimers, indicating a sensing role of the third extracellular loop for hetero-oligomers in an arrest microenvironment. Our data identify confined targetable regions of CCR1 specialised to facilitate CCL5-induced arrest and enhanced responsiveness to the CXCL4-CCL5 heteromer.Note: The review process for this manuscript was fully handled by G. Y. H. Lip, Editor in Chief.
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Zernecke, Alma, Elisa A. Liehn, Ji-Liang Gao, William A. Kuziel, Philip M. Murphy, and Christian Weber. "Deficiency in CCR5 but not CCR1 protects against neointima formation in atherosclerosis-prone mice: involvement of IL-10." Blood 107, no. 11 (June 1, 2006): 4240–43. http://dx.doi.org/10.1182/blood-2005-09-3922.
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AbstractThe chemokine RANTES has been implicated in neointimal hyperplasia after arterial injury. We analyzed the differential role of the RANTES receptors CCR1 and CCR5 by genetic deletion in apolipoprotein E–deficient mice. Deficiency in CCR5 significantly reduced neointimal area after arterial wire injury, associated with a decrease in macrophages, CD3+ T lymphocytes, and CCR2+ cells. In contrast, CCR1 deficiency did not affect neointimal area or cell content. Deletion of CCR5 entailed an up-regulation of the anti-inflammatory cytokine interleukin 10 (IL-10) in neointimal smooth muscle cells, and its antibody blockade reversed effects in CCR5–/– mice. Conversely, proinflammatory interferon γ was increased in the neointima of CCR1–/– mice, and its blockade unmasked a reduction in macrophage recruitment. Our data indicate that CCR5 is more crucial than CCR1 for neointimal plaque formation, and that its attenuation in CCR5–/– mice is due to an atheroprotective immune response involving IL-10. This harbors important implications for targeting chemokine receptors in vascular remodeling.
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Wang, Meng, Han-Yun Ren, Yu-Jun Dong, Ze-Yin Liang, Zhi-Xiang Qiu, Wei Liu, and Li-Hong Wang. "Association Of Chemokine Receptor CCR5, CCR6 and CCR7 Expressions On T Lymphocyte Subsets In Recipients After Allo-HSCT With Acute GvHD." Blood 122, no. 21 (November 15, 2013): 4596. http://dx.doi.org/10.1182/blood.v122.21.4596.4596.
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Introduction To study the correlation of chemokine receptors expression on T lymphocyte subsets in recipients after allogeneic hematopoietic stem cell transplantation (allo-HSCT) with acute graft-versus-host disease (acute GVHD). Methods Forty-four recipients of family donor allogeneic hematopoietic stem cell transplantation were included in this study. According to the severity of acute GVHD, the recipients were divided into Grade II-IV acute GVHD group (n=16) and Grade 0-I acute GVHD group (n=28). Additionally,fifty healthy donors were also included in this study as the control group (n=50). The expression of chemokine receptors (CCR2,CCR5,CCR6,CCR7,CCR9 and CXCR3) on CD4+ and CD8+T cells in the peripheral blood after transplantation were detected using flow cytometry (FCM) respectively. The differences of the chemokine receptors expression between each group were compared. Results In both Grade 0-I acute GVHD group (on the 30th day after transplantation) and Grade II-IV acute GVHD group (at the peak of GVHD), CCR5 expression was significantly higher than that in the control group (p<0.01), and the expression of CCR7 was significantly lower than that in the control group (p<0.01). However, compared with the Grade 0-I acute GVHD group, the Grade II-IV acute GVHD group showed lower CD4+/CD8+ cell ratio (0.36 ± 0.30 vs 0.76 ± 0.61, p=0.003), higher CD4+CCR5+ ratio (65.20 ± 20.17% vs 50.82 ± 28.59%, p=0.048), decreased expression of CCR6 and CCR7 on CD4+ T cells (17.02 ± 12.43% vs 34.69 ± 18.58%, p=0.006; 20.28 ± 4.37% vs 25.45 ± 10.47%, p=0.025). Conclusions Chemokine receptors on T cell subsets are involved in the pathogenesis of acute GVHD. Expression of chemokine receptors can be used as a powerful marker for early diagnosis and differential diagnosis of acute GVHD. And targeting chemokine receptors might be the new direction of prevention and treatment of acute GVHD. Disclosures: No relevant conflicts of interest to declare.
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Mirandola, Leonardo, Maurizio Chiriva-Internati, Everardo Cobos, Yuefei Yu, Jose A. Figueroa, Silvia Garavelli, Michela Colombo, et al. "Chemokine receptors as novel targets of the oncogene Notch1 in acute lymphoblastic leukemia." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 7060. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.7060.
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7060 Background: Malignant cells from different cancers express different profiles of chemokine receptors (CKR). Their presence may influence site-specific spread of tumor cells, by enabling them to respond to chemokine gradient, and may increase cell sensibility to chemokine mediated proliferative and anti-apoptotic stimuli. Notch ability to positively regulate CKR has been reported: stimulation of Pax5-/- pre-B cells with the Notch ligand Delta-1 results in induction of transcripts for CCR4, CCR8 and CXCR 6; the Delta-1-dependent regulation of Langerhans cell development includes induction of CCR6 expression resulting in the activation of chemotactic response to MIP-1a; Notch controls CCR7 signaling a regulator of CNS infiltration in T-acute lymphoblastic leukemia (T-ALL). Methods: This work aims to explore the correlation between the activation of the Notch oncogenic pathway in T-ALL and multiple myeloma (MM) cells and the aberrant expression CKR. Human T-ALL cell lines were treated with the Notch activation inhibitor, DAPT, or with a potent inhibitor of the Notch target, C-MYC, and evaluated the expression and functions of CCR9, CCR5, and CXCR4. Results: Treatment of human T-ALL and MM cell lines with pharmacologic inhibitors of Notch receptor activation produced a significant reduction of CCR9, CCR5 and CXCR4 expression, at both mRNA and protein levels. Results were confirmed by chemotaxis and survival assays. We identified the product of C-MYC gene as a possible mediator of Notch effect in regulating CKR networks in T-ALL and MM. Conclusions: These results suggest that Notch receptors play a previously unknown role in cancer progression and metastasis, by maintaining the expression levels of CKR. In conclusion, the identification of the potential axis Notch/CKR could have a prognostic value and provide the rationale for a tailored approach, since both Notch and CKR are targeted by emerging drugs.
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Parween, Farhat, Noshin Kathuria, Hongwei Zhang, and Joshua M. Farber. "CCR2 mediates transendothelial migration of human pathogenic Th17 cells." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 117.23. http://dx.doi.org/10.4049/jimmunol.202.supp.117.23.
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Abstract Leukocyte extravasation is characterized by rolling and arrest on the endothelium followed by transendothelial migration (TEM). Leukocyte arrest and TEM typically require chemokines and their receptors. Previously, we showed that CD4+CCR5+CCR2+ T cells are highly differentiated, readily activated memory cells in human blood that exhibit diverse effector capabilities. We and others have also shown that CCR6 is the signature chemokine receptor for Th17 cells. Here we describe studies of the migratory capabilities and effector profiles of CD4+CCR6+CCR2+ as compared with CD4+CCR6+CCR2− and CD4+CCR6−CCR2− effector-memory T cells from human blood. Using flow chamber assays with TNFa-activated human umbilical vein endothelial cells, we found that among the CCR6+ cells, only the CCR2+ subset was able to cross the endothelial monolayer efficiently. We found that CCR6 and CCR5 were important for arrest whereas CCR2 was critical for subsequent TEM. Our RNA-Seq data and intracellular staining data of ex vivo activated T cells showed that the CCR6+CCR2+ cells were distinguished by their expression not only of the cytokines typical of Th17-cells, but also of cytokines, including IFNg and GM-CSF, and transcription factors characteristic of the pathogenic Th17 cells that mediate tissue injury in mouse models of autoimmune disease. Taken together, our studies suggest that chemokine receptors on memory Th cells play non-redundant roles in the egress from blood, that providing T cells with a combination of CCR6 CCR5 and CCR2 could enhance their trafficking into tissue, and that, on the other hand, blocking CCR2 alone could prevent the extravasation of pathogenic Th17 cells and potentially diminish tissue damage in Th17-cell driven disease.
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Owen, Sherry M., Dennis Ellenberger, Mark Rayfield, Stefan Wiktor, Philippe Michel, Michael H. Grieco, Feng Gao, Beatrice H. Hahn, and Renu B. Lal. "Genetically Divergent Strains of Human Immunodeficiency Virus Type 2 Use Multiple Coreceptors for Viral Entry." Journal of Virology 72, no. 7 (July 1, 1998): 5425–32. http://dx.doi.org/10.1128/jvi.72.7.5425-5432.1998.
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ABSTRACT Several members of the seven-transmembrane chemokine receptor family have been shown to serve, with CD4, as coreceptors for entry by human immunodeficiency virus type 1 (HIV-1). While coreceptor usage by HIV-1 primary isolates has been studied by several groups, there is only limited information available concerning coreceptor usage by primary HIV-2 isolates. In this study, we have analyzed coreceptor usage of 15 primary HIV-2 isolates, using lymphocytes from a donor with nonfunctional CCR5 (CCR5 −/−; homozygous 32-bp deletion). Based on the infections of PBMCs, seven of these primary isolates had an absolute requirement for CCR5 expression, whereas the remaining eight exhibited a broader coreceptor usage. All CCR5-requiring isolates were non-syncytium inducing, whereas isolates utilizing multiple coreceptors were syncytium inducing. Blocking experiments using known ligands for chemokine receptors provided indirect evidence for additional coreceptor utilization by primary HIV-2 isolates. Analysis of GHOST4 cell lines expressing various chemokine receptors (CCR1, CCR2b, CCR3, CCR4, CCR5, CXCR4, BONZO, and BOB) further defined specific coreceptor usage of primary HIV-2 isolates. The receptors used included CXCR4, CCR1-5, and the recently described receptors BONZO and BOB. However, the efficiency at which the coreceptors were utilized varied greatly among the various isolates. Analysis of V3 envelope sequences revealed no specific motif that correlated with coreceptor usage. Our data demonstrate that primary HIV-2 isolates are capable of using a broad range of coreceptors for productive infection in vitro. Additionally, our data suggest that expanded coreceptor usage by HIV-2 may correlate with disease progression.
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Lee, Benhur, Benjamin J. Doranz, Shalini Rana, Yanji Yi, Mario Mellado, Jose M. R. Frade, Carlos Martinez-A., et al. "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, no. 9 (September 1, 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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Yamaguchi, Mio, Kiyoshi Takagi, Koki Narita, Yasuhiro Miki, Yoshiaki Onodera, Minoru Miyashita, Hironobu Sasano, and Takashi Suzuki. "Stromal CCL5 Promotes Breast Cancer Progression by Interacting with CCR3 in Tumor Cells." International Journal of Molecular Sciences 22, no. 4 (February 15, 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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Ogilvie, Patricia, Giuseppe Bardi, Ian Clark-Lewis, Marco Baggiolini, and Mariagrazia Uguccioni. "Eotaxin is a natural antagonist for CCR2 and an agonist for CCR5." Blood 97, no. 7 (April 1, 2001): 1920–24. http://dx.doi.org/10.1182/blood.v97.7.1920.
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Abstract Eotaxin is a potent inducer of eosinophil chemotaxis and was considered as a selective ligand of the CC chemokine receptor 3 (CCR3), which is expressed on eosinophils, basophils, and Th2 lymphocytes. This study shows that eotaxin also interacts with CCR2 and CCR5 and can, thus, affect the responses of monocytes, which express both receptors. In human monocytes pretreatment with eotaxin decreased responsiveness to MCP-1, a selective ligand for CCR2, as well as to RANTES and MIP-1β, which bind to CCR5. Similar effects were obtained with transfected cells expressing CCR2 or CCR5, but here a difference became apparent: Eotaxin triggered CCR5 at a concentration of 100 nM but not CCR2 even at 1 μM, suggesting an antagonistic effect on this receptor. In agreement with this observation, eotaxin induced internalization of CCR5 but not of CCR2 in human monocytes and transfected cells. Binding studies showed that eotaxin displaces125 I-MCP-1 from monocytes in a concentration-dependent manner, and functional experiments showed that eotaxin inhibits MCP-1-induced chemotaxis and enzyme release. The results demonstrate that eotaxin is a CCR5 agonist and a CCR2 antagonist. The present findings suggest a role of eotaxin in the fine-tuning of cellular responses occurring at sites of allergic inflammation, in which both MCP-1 and eotaxin are produced.
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Naif, Hassan M., Shan Li, Mohammed Alali, Andrew Sloane, Lijun Wu, Mark Kelly, Garry Lynch, Andrew Lloyd, and Anthony L. Cunningham. "CCR5 Expression Correlates with Susceptibility of Maturing Monocytes to Human Immunodeficiency Virus Type 1 Infection." Journal of Virology 72, no. 1 (January 1, 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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Simmons, Graham, Jacqueline D. Reeves, Áine McKnight, Nathalie Dejucq, Sam Hibbitts, Christine A. Power, Emma Aarons, et al. "CXCR4 as a Functional Coreceptor for Human Immunodeficiency Virus Type 1 Infection of Primary Macrophages." Journal of Virology 72, no. 10 (October 1, 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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Wei, Jin-Hua, Xiao Feng, Zhi-Jian Sun, Pang Cheng, Bin-Fang Ma, Jie Zhao, Yu-Hang Dong, Yuan-Qiang Zhang, and Zhen Li. "Different locations of RANTES and its receptors on mouse epididymal spermatozoa." Reproduction, Fertility and Development 28, no. 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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Hartley, Oliver, Karim Dorgham, Danielle Perez-Bercoff, Fabrice Cerini, Anouk Heimann, Hubert Gaertner, Robin E. Offord, Gianfranco Pancino, Patrice Debré, and Guy Gorochov. "Human Immunodeficiency Virus Type 1 Entry Inhibitors Selected on Living Cells from a Library of Phage Chemokines." Journal of Virology 77, no. 12 (June 15, 2003): 6637–44. http://dx.doi.org/10.1128/jvi.77.12.6637-6644.2003.
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ABSTRACT The chemokine receptors CCR5 and CXCR4 are promising non-virus-encoded targets for human immunodeficiency virus (HIV) therapy. We describe a selection procedure to isolate mutant forms of RANTES (CCL5) with antiviral activity considerably in excess of that of the native chemokine. The phage-displayed library of randomly mutated and N-terminally extended variants was screened by using live CCR5-expressing cells, and two of the selected mutants, P1 and P2, were further characterized. Both were significantly more potent HIV inhibitors than RANTES, with P2 being the most active (50% inhibitory concentration of 600 pM in a viral coat-mediated cell fusion assay, complete protection of target cells against primary HIV type 1 strains at a concentration of 10 nM). P2 resembles AOP-RANTES in that it is a superagonist of CCR5 and potently induces receptor sequestration. P1, while less potent than P2, has the advantage of significantly reduced signaling activity via CCR5 (30% of that of RANTES). Additionally, both P1 and P2 exhibit not only significantly increased affinity for CCR5 but also enhanced receptor selectivity, retaining only trace levels of signaling activity via CCR1 and CCR3. The phage chemokine approach that was successfully applied here could be adapted to other chemokine-chemokine receptor systems and used to further improve the first-generation mutants reported in this paper.
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Tiffany, H. Lee, Ghalib Alkhatib, Christophe Combadiere, Edward A. Berger, and 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, no. 3 (February 1, 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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Kohlmeier, Alison, Lisa Haddad, Richard Haaland, Davis Lupo, Igho Ofotokun, Clyde Hart, and Jacob E. Kohlmeier. "Distinct migratory phenotypes of luminal CD4 T cell subsets in the female genital tract." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 136.11. http://dx.doi.org/10.4049/jimmunol.196.supp.136.11.
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Abstract The trafficking and retention of T cells in the genital mucosa provides a means of protection against many invading pathogens, yet this process is poorly understood. We measured six chemokine receptors and integrins important for T cell trafficking into peripheral sites on both resident (TRM: CCR7lo and CD69+) and recirculating (TRCM: CCR7hi CD69−) memory CD4 T cells localized at the luminal surface of the genital tract from healthy women to characterize migratory phenotypes under steady state conditions. Compared to memory CD4 T cells from blood, total memory CD4 T cells from the lumen expressed an increased frequency of CCR5, CCR6, CX3CR1, and α4β7, with no significant difference in CCR9 and CXCR3. Comparing luminal TRM and TRCM, we observed the TRCM subset expressed increased CCR6, CXCR3, and CX3CR1, with no difference in CCR5, α4β7, and CCR9. The increased frequency of CCR5+ cells among luminal TRM and TRCM suggested that CCR5 may regulate the trafficking on memory CD4 T cells to this site. Using a dual adoptive transfer mouse model, we observed that CCR5-deficient CD4 T cells were significantly impaired in their ability to migrate to the luminal surface of the genital tract under steady state conditions, but showed no defect in migration to other mucosal sites such as the gut and lung. These data reveal that TRCM express a broader migratory phenotype compared to luminal TRM, which may enable their ability to perform immune surveillance at multiple peripheral sites. Furthermore, the increased frequency of CCR5+ TRM and TRCM at the luminal surface and the defective trafficking of CCR5-deficient cells to this site suggests that CCR5 is required for the establishment of both TRM and TRCM CD4 subsets at the surface of the genital mucosa.
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Segerer, Stephan, and Peter J. Nelson. "Chemokines in Renal Diseases." Scientific World JOURNAL 5 (2005): 835–44. http://dx.doi.org/10.1100/tsw.2005.105.
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The chemokines, members of a large family of chemotactic cytokines, act as directional cues for sorting inflammatory cell subsets to sites of inflammation or lymphoid microenvironments. In addition to their effects on migration, chemokines can also activate effector function in leukocytes and are involved in cell proliferation and angiogenesis. Therefore, it is not surprising that chemokines play important roles in a wide range of human diseases, including genetic immunodeficiencies, infections, autoimmune diseases, and malignant tumors. In this report, we have reviewed recent developments (since mid 2003) in chemokines in renal diseases. In animal models, chemokines are produced at the site of injury, leading to inflammatory cell recruitment. The therapeutic impact of the blockade of CCR1, CCR2, CCR4, CCR5, or the corresponding ligands has been further studied in various renal disease models. Recent studies on the role of the chemokine receptors in human diseases have demonstrated the expression of CXCR1, CXCR3, CCR2, and CCR5 on different subsets of inflammatory cells. The number of CCR5- and CXCR3-positive interstitial infiltrating cells (mainly T cells) correlates with renal function and proteinuria in glomerular diseases. Polymorphisms of chemokines and chemokine receptors are of impact on renal disease courses and allograft survival. Chemokine receptor blockade has approached clinical applications in nonrenal diseases and awaits the application in patients with kidney diseases.
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Yi, Yanjie, Shalini Rana, Julie D. Turner, Nathan Gaddis, and 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, no. 1 (January 1, 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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Fantuzzi, Laura, Paola Borghi, Veniero Ciolli, George Pavlakis, Filippo Belardelli, and 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, no. 3 (August 1, 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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Albright, Andrew V., Joseph T. C. Shieh, Takayuki Itoh, Benhur Lee, David Pleasure, Michael J. O’Connor, Robert W. Doms, and 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, no. 1 (January 1, 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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Farber, Joshua M., Kaimei Song, Hongwei H. Zhang, Ronald L. Rabin, Brenna J. Hill, Irini Sereti, Calman Prussin, Richard M. Siegel, Daniel C. Douek, and Mario Roederer. "CCR2 identifies first responders among human CD4+ memory T cells: long-lived, apoptosis-resistant, antigen-responsive cells with enhanced migration potential, a low threshold for activation, and immediate effector capabilities (85.5)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S119. http://dx.doi.org/10.4049/jimmunol.178.supp.85.5.
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Abstract The persistence and roles of memory T cells with effector capability have been questioned. We analyzed human memory CD4+ T cells from peripheral blood defined by their expression of chemokine receptors CCR5 and CCR2, the principal subsets being CCR5−CCR2−, CCR5+CCR2−, and CCR5+CCR2+. CCR2+ cells co-expressed the most chemokine receptor types (up to six) and migrated to the greatest number of chemokines, followed by CCR5+CCR2− cells. Numbers of T cell receptor gene excision circles were CCR5−CCR2− > CCR5+CCR2− > CCR5+CCR2+. The CCR2+ cells were those most readily activated through TCR but showed reduced proliferative potential, were enriched in cells responding to a remote immunogen, secreted high levels of effector cytokines, and were resistant to apoptosis. By contrast, the CCR5+CCR2− population was enriched in recently activated/cycling cells and Treg, and was more susceptible to apoptosis. The data suggest that patterns of CCR5 and CCR2 expression separate effector- vs. memory-cell enriched CD4+ subsets, and that CCR2 marks highly differentiated, long-lived memory cells with effector capabilities. The data also suggest co-ordination among a memory cell’s position on a unidirectional pathway of differentiation, ability to be recruited into tissue, and threshold for activation/effector function, with the most chemokine-responsive cells being best equipped as first responders in a recall response.
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Sand, Kristoffer E., Astrid Olsnes Kittang, and Øystein Bruserud. "Circulating T Cells Derived From Patients with Low Risk Myelodysplastic Syndromes Show Altered Chemokine Receptor Expression." Blood 116, no. 21 (November 19, 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.