The Experts below are selected from a list of 18795 Experts worldwide ranked by ideXlab platform
Ji Ming Wang - One of the best experts on this subject based on the ideXlab platform.
-
signal relay by cc Chemokine Receptor 2 CCR2 and formylpeptide Receptor 2 fpr2 in the recruitment of monocyte derived dendritic cells in allergic airway inflammation
Journal of Biological Chemistry, 2013Co-Authors: Keqiang Chen, Mingyong Liu, Ying Liu, Chunyan Wang, Teizo Yoshimura, Wanghua Gong, Lino Tessarollo, Ji Ming WangAbstract:Chemoattractant Receptors regulate leukocyte accumulation at sites of inflammation. In allergic airway inflammation, although a Chemokine Receptor CCR2 was implicated in mediating monocyte-derived dendritic cell (DC) recruitment into the lung, we previously also discovered reduced accumulation of DCs in the inflamed lung in mice deficient in formylpeptide Receptor Fpr2 (Fpr2−/−). We therefore investigated the role of Fpr2 in the trafficking of monocyte-derived DCs in allergic airway inflammation in cooperation with CCR2. We report that in allergic airway inflammation, CCR2 mediated the recruitment of monocyte-derived DCs to the perivascular region, and Fpr2 was required for further migration of the cells into the bronchiolar area. We additionally found that the bronchoalveolar lavage liquid from mice with airway inflammation contained both the CCR2 ligand CCL2 and an Fpr2 agonist CRAMP. Furthermore, similar to Fpr2−/− mice, in the inflamed airway of CRAMP−/− mice, DC trafficking into the peribronchiolar areas was diminished. Our study demonstrates that the interaction of CCR2 and Fpr2 with their endogenous ligands sequentially mediates the trafficking of DCs within the inflamed lung. Background: Chemoattractant Receptor Fpr2 interacts with host-derived agonists and mediates leukocyte trafficking. Results: In the lung of allergic inflammation, Chemokine Receptor CCR2 elicits accumulation of monocyte-derived DC in perivascular region, but Fpr2 is critical for cell trafficking to peribronchiolar area. Conclusion: CCR2 and Fpr2 sequentially guide DC trafficking in inflamed lung. Significance: DC trafficking is controlled by multiple chemoattractant Receptors, which are potential therapeutic targets.
-
signal relay by cc Chemokine Receptor 2 CCR2 and formylpeptide Receptor 2 fpr2 in the recruitment of monocyte derived dendritic cells in allergic airway inflammation
Journal of Biological Chemistry, 2013Co-Authors: Keqiang Chen, Mingyong Liu, Ying Liu, Chunyan Wang, Teizo Yoshimura, Wanghua Gong, Lino Tessarollo, Ji Ming WangAbstract:Abstract Chemoattractant Receptors regulate leukocyte accumulation at sites of inflammation. In allergic airway inflammation, although a Chemokine Receptor CCR2 was implicated in mediating monocyte-derived dendritic cell (DC) recruitment into the lung, we previously also discovered reduced accumulation of DCs in the inflamed lung in mice deficient in formylpeptide Receptor Fpr2 (Fpr2−/−). We therefore investigated the role of Fpr2 in the trafficking of monocyte-derived DCs in allergic airway inflammation in cooperation with CCR2. We report that in allergic airway inflammation, CCR2 mediated the recruitment of monocyte-derived DCs to the perivascular region, and Fpr2 was required for further migration of the cells into the bronchiolar area. We additionally found that the bronchoalveolar lavage liquid from mice with airway inflammation contained both the CCR2 ligand CCL2 and an Fpr2 agonist CRAMP. Furthermore, similar to Fpr2−/− mice, in the inflamed airway of CRAMP−/− mice, DC trafficking into the peribronchiolar areas was diminished. Our study demonstrates that the interaction of CCR2 and Fpr2 with their endogenous ligands sequentially mediates the trafficking of DCs within the inflamed lung.
Alain Creange - One of the best experts on this subject based on the ideXlab platform.
-
monocyte chemoattractant protein 1 and Chemokine Receptor CCR2 productions in guillain barre syndrome and experimental autoimmune neuritis
Journal of Neuroimmunology, 2003Co-Authors: David Orlikowski, Anne Plonquet, Francoise Poron, Jean Claude Raphael, Tarek Sharshar, Benedicte Chazaud, Riccardo Gherardi, Patrick Maison, Alain CreangeAbstract:Abstract Infiltration of activated lymphocytes and monocytes is a key phenomenon in the pathogenesis of Guillain–Barre syndrome (GBS) and experimental autoimmune neuritis (EAN). To investigate the role of Chemokines, we determined the blood and nerve tissue expression of monocyte chemoattractant protein 1 (MCP-1), a major chemoattractant of monocytes and activated lymphocytes, and its Receptor CCR2 in GBS and EAN. MCP-1 circulating levels (ng/ml) in GBS were increased at the time of progression, peaked at the time of plateau and normalized with recovery. MCP-1 circulating levels were the highest in the most disabled patients. The number of circulating CCR2 positive cells was lower in patients with GBS than in healthy subjects ( p
-
monocyte chemoattractant protein 1 and Chemokine Receptor CCR2 productions in guillain barre syndrome and experimental autoimmune neuritis
Journal of Neuroimmunology, 2003Co-Authors: David Orlikowski, Anne Plonquet, Francoise Poron, Jean Claude Raphael, Tarek Sharshar, Benedicte Chazaud, Riccardo Gherardi, Patrick Maison, Alain CreangeAbstract:Infiltration of activated lymphocytes and monocytes is a key phenomenon in the pathogenesis of Guillain-Barre syndrome (GBS) and experimental autoimmune neuritis (EAN). To investigate the role of Chemokines, we determined the blood and nerve tissue expression of monocyte chemoattractant protein 1 (MCP-1), a major chemoattractant of monocytes and activated lymphocytes, and its Receptor CCR2 in GBS and EAN. MCP-1 circulating levels (ng/ml) in GBS were increased at the time of progression, peaked at the time of plateau and normalized with recovery. MCP-1 circulating levels were the highest in the most disabled patients. The number of circulating CCR2 positive cells was lower in patients with GBS than in healthy subjects (p<0.004). In GBS, MCP-1 expression was observed in epineurial and endoneurial vessels, on infiltrating cells, Schwann cells and in the endoneurial extracellular matrix. Some CCR2 positive cells were observed in nerve biopsies of GBS patients. In EAN, a slight positivity for MCP-1 was observed in the sciatic nerve. There was no circulating CCR2 positive cells. However, at the time of plateau, a conspicuous infiltration of CCR2 positive cells was observed in the sciatic nerve that was no longer observed at the time of recovery. These results suggest that MCP-1 and CCR2 may participate to the recruitment of circulating mononuclear cells in nerve tissue in EAN and GBS.
William A Kuziel - One of the best experts on this subject based on the ideXlab platform.
-
cerebral malaria for the development of experimental Chemokine Receptor CCR2 is not essential
2014Co-Authors: Matthias Mack, William A Kuziel, Elodie Belnoue, Fabio T M Costa, Francoise Gonnet, I Landau, Nico Van Rooijen, Ana M VigarioAbstract:ANKA induces cerebral malaria in susceptible mice. Brain-sequesteredCD8 T cells are responsible for this pathology. We have evaluated the role of CCR2, a Chemokine Receptorexpressed on CD8 T cells. Infected CCR2-deficient mice were as susceptible to cerebral malaria as wild-typemice were, and CD8 T-cell migration to the brain was not abolished.
-
Chemokine Receptor CCR2 but not ccr5 or ccr6 mediates the increase in pulmonary dendritic cells during allergic airway inflammation
Journal of Immunology, 2007Co-Authors: Lander Robays, William A Kuziel, Tania Maes, Serge Lebecque, Sergio A Lira, Guy Brusselle, Guy Joos, Karim V VermaelenAbstract:Increased numbers of pulmonary dendritic cells (DCs) are recruited to the lungs during allergic airway inflammation and contribute to the maintenance of the inflammatory immune response. The Chemokine Receptors that directly control DC accumulation into the lungs are largely unknown. To explore this issue, we generated mixed bone marrow chimeric mice containing both wild-type and knockout cells for a given Chemokine Receptor. After induction of allergic airway inflammation, we specifically tracked and compared Chemokine Receptor knockout vs wild-type DC populations through various lung compartments. Using this approach, we show that CCR2, but not CCR5 or CCR6, directly controls the accumulation of DCs into allergic lungs. Furthermore, the size of inflammatory monocyte populations in peripheral blood was strikingly CCR2 dependent, suggesting that CCR2 primarily mediates the release of monocytic DC precursors into the bloodstream.
-
The complex role of the Chemokine Receptor CCR2 in collagen-induced arthritis: implications for therapeutic targeting of CCR2 in rheumatoid arthritis
Journal of Molecular Medicine, 2005Co-Authors: Marlon P. Quinones, William A Kuziel, Matthias Mack, Carlos A. Estrada, Yogeshwar Kalkonde, Sunil K. Ahuja, Seema S. AhujaAbstract:CCR2 has been widely considered as a potential therapeutic target for autoimmune disease, particularly rheumatoid arthritis, and various CCR2 blocking agents have been developed, some of which have entered clinical trials. In this review, we examine the relevant information regarding the role of CCR2, and to a lesser extent of the closely related Chemokine Receptor CCR5, in the immunopathogenesis of collagen-induced arthritis, an animal model of rheumatoid arthritis. Experimental evidence showing that CIA is accelerated and exacerbated when CCR2 is genetically inactivated (knockout mice) or blocked with specific antibodies warrant additional investigations before the relevance of the findings in rodent models can be applied to human patients with RA.
-
Chemokine Receptor CCR2 involvement in skeletal muscle regeneration
The FASEB Journal, 2005Co-Authors: Gordon L Warren, William A Kuziel, Tracy Hulderman, Dawn Mishra, Xin Gao, Lyndell Millecchia, Laura Ofarrell, Petia P SimeonovaAbstract:SPECIFIC AIMSWe hypothesized that signaling through CCR2, a major Receptor for monocyte chemoattractant protein-1 MCP-1 (CCL2), affects degeneration/regeneration after skeletal muscle injury via indirect and direct effects on muscle precursor cells. We characterized localization of CCR2 in regenerating muscle [freeze-injured mouse tibialis anterior (TA) muscle] and compared cellular/molecular characteristics of skeletal muscle regeneration in CCR2-deficient vs. wild-type (WT) mice.PRINCIPAL FINDINGS1. CCR2 cellular localization in injured skeletal muscleTo determine whether expression of CCR2 is localized to macrophages and/or muscle precursor cells in injured muscle, we conducted double immunostaining for CCR2 and Mac-3, a marker of activated monocytes/macrophages, or myogenin, a marker of activated and differentiating muscle precursor cells. CCR2 was found to be localized to the membrane of cells expressing cytoplasmic localized Mac-3 (Fig. 1⤻ A) or nuclear localized myogenin (Fig. 1B⤻ ), demonstrating ...
-
expression of the Chemokine Receptor CCR2 on immature b cells negatively regulates their cytoskeletal rearrangement and migration
Blood, 2004Co-Authors: Liat Flaishon, William A Kuziel, Shirly Beckerherman, Gili Hart, Yoram Levo, Idit ShacharAbstract:Immature B cells are targeted to specific areas in the spleen, where a fraction of these cells receive signals that induce them to mature and participate in the immune response. In this study, we show that the C-C Chemokine Receptor 2 (CCR2) is transcribed in immature B cells, while its message is dramatically down-regulated at the mature stage. CCR2-deficient cells exhibit up-regulation of Chemokine-induced actin polymerization, migration, and homing to the lymph nodes of immature B cells. In addition, we demonstrate that control of homing by CCR2 is mediated by its ligand, CCL2/JE, which is secreted by B cells and down-regulates the stromal derived factor-1 (SDF-1) signaling cascade. Thus, this study describes an additional, previously uncharacterized, role for CCR2 and its ligand as negative regulators of the homing of immature B cells.
Martin J Stone - One of the best experts on this subject based on the ideXlab platform.
-
phosphoproteomic characterization of the signaling network resulting from activation of the Chemokine Receptor CCR2
Journal of Biological Chemistry, 2020Co-Authors: Cheng Huang, Simon R Foster, Anup Shah, Oded Kleifeld, Meritxell Canals, Ralf B Schittenhelm, Martin J StoneAbstract:Leukocyte recruitment is a universal feature of tissue inflammation and regulated by the interactions of Chemokines with their G protein-coupled Receptors. Activation of CC Chemokine Receptor 2 (CCR2) by its cognate Chemokine ligands, including CC Chemokine ligand 2 (CCL2), plays a central role in recruitment of monocytes in several inflammatory diseases. In this study, we used phosphoproteomics to conduct an unbiased characterization of the signaling network resulting from CCL2 activation of CCR2. Using data-independent acquisition MS analysis, we quantified both the proteome and phosphoproteome in FlpIn-HEK293T cells stably expressing CCR2 at six time points after activation with CCL2. Differential expression analysis identified 699 significantly regulated phosphorylation sites on 441 proteins. As expected, many of these proteins are known to participate in canonical signal transduction pathways and in the regulation of actin cytoskeleton dynamics, including numerous guanine nucleotide exchange factors and GTPase-activating proteins. Moreover, we identified regulated phosphorylation sites in numerous proteins that function in the nucleus, including several constituents of the nuclear pore complex. The results of this study provide an unprecedented level of detail of CCR2 signaling and identify potential targets for regulation of CCR2 function.
-
phosphate modulates Receptor sulfotyrosine recognition by the Chemokine monocyte chemoattractant protein 1 mcp 1 ccl2
Organic and Biomolecular Chemistry, 2015Co-Authors: Justin P Ludeman, Cheng Huang, Richard J Payne, Brendan L Wilkinson, Mahdieh Nazarirobati, Martin J StoneAbstract:Tyrosine sulfation is a widespread post-translational modification that mediates the interactions of secreted and membrane-associated proteins in such varied biological processes as peptide hormone action, adhesion, blood coagulation, complement activation and regulation of leukocyte trafficking. Due to the heterogeneous nature of tyrosine sulfation, detailed biochemical and biophysical studies of tyrosine sulfation rely on homogenous, synthetic sulfopeptides. Here we describe the synthesis of a fluorescent sulfopeptide (FL-R2D) derived from the Chemokine Receptor CCR2 and the application of FL-R2D in direct and competitive fluorescence anisotropy assays that enable the efficient measurement of binding affinities between sulfopeptides and their binding proteins. Using these assays, we have found that the binding of the Chemokine monocyte chemoattractant protein-1 (MCP-1) to sulfated peptides derived from the Chemokine Receptor CCR2 is highly dependent on the assay buffer. In particular, phosphate buffer at close to physiological concentrations competes with the Receptor sulfopeptide by binding to the sulfopeptide binding pocket on the Chemokine surface. Thus, physiological phosphate may modulate the Receptor binding selectivity of Chemokines.
-
tyrosine sulfation of Chemokine Receptor CCR2 enhances interactions with both monomeric and dimeric forms of the Chemokine monocyte chemoattractant protein 1 mcp 1
Journal of Biological Chemistry, 2013Co-Authors: Justin P Ludeman, Richard J Payne, Meritxell Canals, Deni Taleski, Jamie Wedderburn, Pam Hall, Stephen J Butler, Arthur Christopoulos, Michael J Hickey, Martin J StoneAbstract:Abstract Chemokine Receptors are commonly post-translationally sulfated on tyrosine residues in their N-terminal regions, the initial site of binding to Chemokine ligands. We have investigated the effect of tyrosine sulfation of the Chemokine Receptor CCR2 on its interactions with the Chemokine monocyte chemoattractant protein-1 (MCP-1/CCL2). Inhibition of CCR2 sulfation, by growth of expressing cells in the presence of sodium chlorate, significantly reduced the potency for MCP-1 activation of CCR2. MCP-1 exists in equilibrium between monomeric and dimeric forms. The obligate monomeric mutant MCP-1(P8A) was similar to wild type MCP-1 in its ability to induce leukocyte recruitment in vivo, whereas the obligate dimeric mutant MCP-1 (T10C) was less effective at inducing leukocyte recruitment in vivo. In 2D NMR experiments, sulfated peptides derived from the N-terminal region of CCR2 bound to both the monomeric and dimeric forms of wild type MCP-1 and shifted the equilibrium to favour the monomeric form. Similarly, MCP-1(P8A) bound more tightly than MCP-1(T10C) to the CCR2-derived sulfopeptides. NMR chemical shift mapping using the MCP-1 mutants showed that the sulfated N-terminal region of CCR2 binds to the same region (N-loop and β3-strand) of both monomeric and dimeric MCP-1 but that binding to the dimeric form also influences the environment of Chemokine N-terminal residues, which are involved in dimer formation. We conclude that interaction with the sulfated N-terminus of CCR2 destabilises the dimerization interface of inactive dimeric MCP-1, thus inducing dissociation to the active monomeric state.
Kevin D G Pfleger - One of the best experts on this subject based on the ideXlab platform.
-
the molecular structure and role of ccl2 mcp 1 and c c Chemokine Receptor CCR2 in skeletal biology and diseases
Journal of Cellular Physiology, 2021Co-Authors: Kevin D G Pfleger, Sipin Zhu, Mei Liu, Samuel Bennett, Ziyi WangAbstract:Monocyte chemoattractant protein-1, also called Chemokine (C-C motif) ligand 2 (CCL2) or small inducible cytokine A2, is an inflammatory mediator capable of recruiting monocytes, memory T cells, and dendritic cells. CCL2 is a member of the CC Chemokine superfamily, which binds to its Receptor, C-C motif Chemokine Receptor-2 (CCR2), for the induction of chemotactic activity and an increase of calcium influx. It exerts multiple effects on a variety of cells, including monocytes, macrophages, osteoclasts, basophils, and endothelial cells, and is involved in a diverse range of diseases. This review discusses the molecular structure and role of CCL2 and CCR2 in skeletal biology and disease. Molecular structure analyses reveal that CCL2 shares a conserved C-C motif; however, it has only limited sequence homology with other CCL family members. Likewise, CCR2, as a member of the G-protein-coupled seven-transmembrane Receptor superfamily, shares conserved cysteine residues, but exhibits very limited sequence homology with other CCR family members. In the skeletal system, the expression of CCL2 is regulated by a variety of factors, such as parathyroid hormone/parathyroid hormone-related peptide, interleukin 1b, tumor necrosis factor-α and transforming growth factor-beta, RANKL, and mechanical forces. The interaction of CCL2 and CCR2 activates several signaling cascades, including PI3K/Akt/ERK/NF-κB, PI3K/MAPKs, and JAK/STAT-1/STAT-3. Understanding the role of CCL2 and CCR2 will facilitate the development of novel therapies for skeletal disorders, including rheumatoid arthritis, osteolysis and other inflammatory diseases related to abnormal chemotaxis.
-
key determinants of selective binding and activation by the monocyte chemoattractant proteins at the Chemokine Receptor CCR2
Science Signaling, 2017Co-Authors: Zil E Huma, Julie Sanchez, Herman D Lim, Jessica L Bridgford, Cheng Huang, Bradyn J Parker, Jiann G Pazhamalil, Benjamin T Porebski, Kevin D G PflegerAbstract:Chemokines and their Receptors collectively orchestrate the trafficking of leukocytes in normal immune function and inflammatory diseases. Different Chemokines can induce distinct responses at the same Receptor. In comparison to monocyte chemoattractant protein-1 (MCP-1; also known as CCL2), the Chemokines MCP-2 (CCL8) and MCP-3 (CCL7) are partial agonists of their shared Receptor CCR2, a key regulator of the trafficking of monocytes and macrophages that contribute to the pathology of atherosclerosis, obesity, and type 2 diabetes. Through experiments with chimeras of MCP-1 and MCP-3, we identified the Chemokine amino-terminal region as being the primary determinant of both the binding and signaling selectivity of these two Chemokines at CCR2. Analysis of CCR2 mutants showed that the Chemokine amino terminus interacts with the major subpocket in the transmembrane helical bundle of CCR2, which is distinct from the interactions of some other Chemokines with the minor subpockets of their Receptors. These results suggest the major subpocket as a target for the development of small-molecule inhibitors of CCR2.