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Philip M. Murphy - One of the best experts on this subject based on the ideXlab platform.

  • Chemokine Receptor CX3CR1 mediates skin wound healing by promoting macrophage and fibroblast accumulation and function.
    The Journal of Immunology, 2007
    Co-Authors: Yuko Ishida, Ji-liang Gao, Philip M. Murphy
    Abstract:

    Wounds heal through a highly regulated, self-limited inflammatory response, however, precise inflammatory mediators have not been fully delineated. In this study, we report that in a mouse model of excisional skin wound healing the Chemokine CX3CL1 and its Receptor CX3CR1 were both highly induced at wound sites; CX3CL1 colocalized with macrophages and endothelial cells, whereas CX3CR1 colocalized mainly with macrophages and fibroblasts. Loss of CX3CR1 function delayed wound closure in both CX3CR1 knockout (KO) mice and in wild-type mice infused with anti-CX3CR1-neutralizing Ab. Conversely, transfer of bone marrow from donor wild-type mice, but not from donor CX3CR1 KO mice, restored wound healing to normal in CX3CR1 KO-recipient mice. Direct effects of CX3CR1 disruption at the wound site included marked reduction of macrophages and macrophage products, such as TGF-β1 and vascular endothelial growth factor. Consistent with this, we observed reduced α-smooth muscle actin (a marker for myofibroblasts) and collagen deposition in skin from wounded CX3CR1 KO mice, as well as reduced neovascularization. Together, the data support a molecular model of skin wound repair in which CX3CR1 mediates direct recruitment of bone marrow-derived monocytes/macrophages which release profibrotic and angiogenic mediators.

  • Chemokine Receptor CX3CR1 regulates renal interstitial fibrosis after ischemia-reperfusion injury.
    The American journal of pathology, 2006
    Co-Authors: Kengo Furuichi, Ji-liang Gao, Philip M. Murphy
    Abstract:

    Transient renal ischemia induces both inflammatory and fibrotic processes and is a major cause of acute and chronic renal insufficiency. Study of ischemia-reperfusion injury in gene-targeted mice has identified multiple factors responsible for inflammation, whereas mechanisms underlying fibrosis remain poorly defined. Here we demonstrate by both gene inactivation and target protein blockade that a single Chemokine Receptor subtype, the fractalkine Receptor CX3CR1, is able to reduce both inflammation and fibrosis after ischemia-reperfusion injury in the mouse, leading to partially preserved renal function after injury. The mechanism involves selective effects in the outer medulla, including reduced accumulation of macrophages and reduced expression of the macrophage and platelet-derived fibrogenic protein platelet-derived growth factor-B. CX3CR1 is the first Chemokine Receptor shown to contribute to fibrogenesis in renal ischemia-reperfusion injury.

  • Interleukin (IL)-15 and IL-2 reciprocally regulate expression of the Chemokine Receptor CX3CR1 through selective NFAT1- and NFAT2-dependent mechanisms.
    The Journal of biological chemistry, 2004
    Co-Authors: Jana Barlic, David H Mcdermott, Maya N. Merrell, Jacqueline Gonzales, Laura E. Via, Philip M. Murphy
    Abstract:

    We have recently reported that interleukin (IL)-15 and IL-2, which signal through IL-2Rbetagamma, oppositely regulate expression of the proinflammatory Chemokine Receptor CX3CR1. Here we delineate molecular mechanisms responsible for this paradox. By using a luciferase reporter plasmid, we identified a 433-bp region spanning the major transcriptional start point of human CX3CR1 that, when expressed in human peripheral blood mononuclear cells (PBMCs), possessed strong constitutive promoter activity. IL-2 and IL-15 treatment increased and abolished this activity, respectively, mimicking their effects on endogenous CX3CR1. IL-2 and IL-15 have been reported to also have opposite effects on the immunoregulatory transcription factor NFAT (nuclear factor of activated T cells), and the 433-bp region contains a kappaB-like NFAT site. The effects of IL-15 and IL-2 on both CX3CR1 reporter activity and endogenous CX3CR1 transcription in PBMCs were abolished by the NFAT inhibitors cyclosporin A and VIVIT. Moreover, mutation of the kappaB-like NFAT sequence markedly attenuated IL-2 and IL-15 modulation of CX3CR1 promoter-reporter activity in PBMCs. Furthermore, chromatin immunoprecipitation revealed that IL-15 promoted specific recruitment of NFAT1 but not NFAT2 to the CX3CR1 promoter, whereas IL-2 had the converse effect. This appears to be relevant in vivo because mouse CX3CR1 mRNA was expressed in both PBMCs and splenocytes from NFAT1-/- mice injected with recombinant IL-15 but was undetectable in cells from IL-15-injected NFAT1+/+ BALB/c mice; as predicted, IL-2 up-regulated CX3CR1 in both mouse strains to a similar extent. Thus, by pharmacologic, genetic, and biochemical criteria in vitro and in vivo, our results suggest that IL-15 and IL-2 oppositely regulate CX3CR1 gene expression by differentially recruiting NFAT1 and NFAT2 to a kappaB-like NFAT site within the CX3CR1 promoter. We propose that expression of CX3CR1 and possibly other immunoregulatory genes may be determined in part by the balance of NFAT1 and NFAT2 activity in leukocytes.

  • IL-15 alters expression and function of the Chemokine Receptor CX3CR1 in human NK cells.
    Cellular immunology, 2004
    Co-Authors: Joan M.g. Sechler, Jana Barlic, Jean-charles Grivel, Philip M. Murphy
    Abstract:

    The Chemokine Receptor CX3CR1 is thought to regulate inflammation in part by modulating NK cell adhesion, migration, and killing in response to its ligand CX3CL1 (fractalkine). Recent reports indicate that IL-15, which is essential for development and survival of NK cells, may negatively regulate CX3CR1 expression, however, the effects of the cytokine on human NK cell CX3CR1 expression and function have not been fully delineated. Here, we demonstrate that short term culture in IL-15 decreases surface expression of CX3CR1 on cultured CD56+ cells from human blood resulting in diminished chemotaxis and calcium flux in response to CX3CL1. Cells cultured long term in IL-15 (more than five days) completely lost surface expression as well as mRNA and protein for CX3CR1. The effect was specific since mRNA for CCR5 was increased and mRNA for CXCR4 was unchanged in these cells by IL-15. Thus, exogenous IL-15 is a negative regulator of CX3CR1 expression and function in human CD56+ NK cells. The data imply that the use of IL-15 alone to expand NK cells ex vivo for immunotherapy may produce cells impaired in their ability to traffic to sites of inflammation.

  • IL-15 and IL-2 oppositely regulate expression of the Chemokine Receptor CX3CR1.
    Blood, 2003
    Co-Authors: Jana Barlic, Joan M.g. Sechler, Philip M. Murphy
    Abstract:

    The Chemokine Receptor CX3CR1 (CX3C Chemokine Receptor 1) is expressed in mouse blood on natural killer (NK) cells and on monocytes. Because interleukin-15 (IL-15) is an essential cytokine for NK cell development and maintenance, we hypothesized that it may induce CX3CR1 expression on this cell type. In contrast, we found that in primary mouse bone marrow-derived NK cells IL-15 specifically inhibited CX3CR1 protein and mRNA accumulation, whereas the related cytokine IL-2 did not inhibit but instead increased CX3CR1 expression. Consistent with this finding, intravenous injection of a single dose of recombinant IL-15 into C57BL/6 mice decreased steady-state CX3CR1 levels 24 hours after injection in freshly isolated peripheral blood mononuclear cells (PBMCs), splenocytes, and bone marrow cells, and treatment of mouse PBMCs with IL-15 in vitro inhibited CX3CL1 (ligand for CX3CR1)-induced chemotaxis. These data suggest that IL-15 may be a negative regulator of innate immunity by inhibiting CX3CR1 expression. These data also suggest that IL-15 inhibition of CX3CR1 may subvert potential cell immunotherapy strategies in which IL-15 is used to expand NK cell populations in vivo or ex vivo. Finally, our results provide additional evidence for differential signaling by IL-2 and IL-15, despite usage of common βγc Receptor chains. (Blood. 2003;102:3494-3503)

Christophe Combadière - One of the best experts on this subject based on the ideXlab platform.

  • Pharmacological Inhibition of the Chemokine Receptor, CX3CR1, Reduces Atherosclerosis in Mice
    Arteriosclerosis thrombosis and vascular biology, 2013
    Co-Authors: Lucie Poupel, Alexandre Boissonnas, Patricia Hermand, Karim Dorgham, Elodie Guyon, Constance Auvynet, Flora Saint Charles, Philippe Lesnik, Philippe Deterre, Christophe Combadière
    Abstract:

    Objective—Alterations of the Chemokine Receptor CX3CR1 gene were associated with a reduced risk of myocardial infarction in human and limited atherosclerosis in mice. In this study, we addressed whether CX3CR1 antagonists are potential therapeutic tools to limit acute and chronic inflammatory processes in atherosclerosis. Approach and Results—Treatment with F1, an amino terminus–modified CX3CR1 ligand endowed with CX3CR1 antagonist activity, reduced the extent of atherosclerotic lesions in both Apoe−/− and Ldlr−/− proatherogenic mouse models. Macrophage accumulation in the aortic sinus was reduced in F1-treated Apoe−/− mice but the macrophage density of the lesions was similar in F1-treated and control mice. Both in vitro and in vivo F1 treatment reduced CX3CR1-dependent inflammatory monocyte adhesion, potentially limiting their recruitment. In addition, F1-treated Apoe−/− mice displayed reduced numbers of blood inflammatory monocytes, whereas resident monocyte numbers remained unchanged. Both in vitro an...

  • CX3CR1 reduces Ly6Chigh-monocyte motility within and release from the bone marrow after chemotherapy in mice
    Blood, 2013
    Co-Authors: Sebastien Jacquelin, Lucie Poupel, Patricia Hermand, Karim Dorgham, Elodie Guyon, Philippe Deterre, Christophe Combadière, Fabrice Licata, David A. Hume, Alexandre Boissonnas
    Abstract:

    The Chemokine Receptor CCR2 controls the release of Ly6Chigh monocytes from the bone marrow and their recruitment to sites of inflammation. A second Chemokine Receptor, CX3CR1, is differentially expressed on monocyte subsets. We examined the role of CX3CR1 in monocyte trafficking during the recovery

  • Cutting Edge: Protective Effect of CX3CR1+ Dendritic Cells in a Vaccinia Virus Pulmonary Infection Model
    Journal of immunology (Baltimore Md. : 1950), 2012
    Co-Authors: Olivia Bonduelle, Christophe Combadière, Darragh Duffy, Bernard Verrier, Béhazine Combadière
    Abstract:

    The protective host immune response to viral infections requires both effective innate and adaptive immune responses. Cross-talk between the two responses is coordinated by the Chemokine network and professional APCs such as dendritic cells (DCs). In mice, subpopulations of myeloid DCs in peripheral tissues such as lungs and in blood express CX3CR1 depending on the inflammation state. We thus examined the host response of mice deficient in the Chemokine Receptor CX3CR1 to an intranasal vaccinia virus infection. CX3CR1-deficient mice displayed significantly more severe morbidity and mortality compared with control wild-type mice within 10 d following vaccinia virus infection. CX3CR1 −/− mice had increased viral loads and a reduced T cell response compared with wild-type mice. Finally, an adoptive transfer of CX3CR1 +/+ DCs completely protected CX3CR1 −/− mice to a previously lethal infection. This study therefore opens up the possibility of novel antiviral therapeutics targeting lung DC recruitment.

  • Role of the Chemokine Receptor CX3CR1 in the mobilization of phagocytic retinal microglial cells
    Journal of Neuroimmunology, 2008
    Co-Authors: William Raoul, Nicole Keller, Mathieu P. Rodero, Francine Behar-cohen, Florian Sennlaub, Christophe Combadière
    Abstract:

    We recently showed that subretinal CX3CR1-dependent microglial cell (MC) accumulation may lead to age-related macular degeneration. The fate of MC after engulfing retinal debris is poorly understood. Severe photoReceptor degeneration was observed 40days after exposure to bright light in CX3CR1-deficient but not control mice, and more MCs accumulated in the subretinal space of the former than the latter. To study the fate of subretinal MCs in CX3CR1 competent animals, we used a dystrophic rat model in which abundant subretinal MC accumulation is observed secondary to retinal degeneration. In dystrophic rats, MCs containing rhodopsin or rod outer segment (ROS) debris were found outside the outer retina at sites suggesting choroidal and ciliary egress. In conclusion, our data indicate that MC accumulation at injury sites is independent of CX3CR1 and precedes photoReceptor degeneration. The ectopic presence of rhodopsin-positive MCs suggests that CX3CR1 participates in MC egress from the outer retina.

  • Common CX3CR1 alleles are associated with a reduced risk of headaches.
    Headache, 2008
    Co-Authors: Christophe Combadière, Ophélia Godin, Cécile Vidal, Arnaud Cangialosi, Carole Proust, Christophe Tzourio
    Abstract:

    Objectives.— The aim of this study was to investigate the role of the Chemokine Receptor CX3CR1 in headaches and migraine. Methods.— Distribution of 2 polymorphisms of the Chemokine Receptor CX3CR1 (V249I and T280M) was determined in a population-based sample of 1179 elderly individuals. Results.— Heterozygotes for both CX3CR1 polymorphisms had a reduced risk of recurrent headaches, with an odds ratio (OR) of 0.64 (95% confidence interval [CI] = 0.46-0.90) for the I249 allele and 0.55 (95% CI = 0.38-0.81) for the M280 allele. Haplotype analysis showed that carriers of the rarer CX3CR1 I249-M280 haplotype had a reduced risk of recurrent headaches, with an OR of 0.57 (95% CI = 0.41-0.80, P = .001). This association was seen for both nonmigraine headaches (OR = 0.47, 95% CI = 0.28-0.79, P = .004) and migraine (OR = 0.65, 95% CI = 0.43-0.98, P = .041). Conclusions.— These results need to be replicated but suggest that the Chemokine Receptor CX3CR1 may play a role in recurrent headaches.

Demetrios A. Spandidos - One of the best experts on this subject based on the ideXlab platform.

Steffen Jung - One of the best experts on this subject based on the ideXlab platform.

  • Microglia, seen from the CX3CR1 angle.
    Frontiers in Cellular Neuroscience, 2013
    Co-Authors: Yochai Wolf, Simon Yona, Ki-wook Kim, Steffen Jung
    Abstract:

    Microglial cells in brain and spinal cord are characterized by high expression of the Chemokine Receptor CX3CR1. Expression of the sole CX3CR1 ligand, the membrane-tethered and sheddable Chemokine CX3CL1/fractalkine, is restricted in the brain parenchyma to selected neurons. Here we summarize our current understanding of the physiological role of CX3CR1 for microglia function and the CX3C axis in microglial/neuronal crosstalk in homeostasis and under challenge. Moreover, we will discuss the efforts of our laboratory and others to exploit CX3CR1 promoter activity for the visualization and genetic manipulation of microglia to probe their functional contributions in the central nerve system (CNS) context.

  • CX3CR1+ CD8α+ dendritic cells are a steady-state population related to plasmacytoid dendritic cells
    Proceedings of the National Academy of Sciences of the United States of America, 2010
    Co-Authors: Liat Bar-on, Tal Birnberg, Kanako L. Lewis, Brian T. Edelson, Dunja Bruder, Kai Hildner, Jan Buer, Kenneth M. Murphy, Boris Reizis, Steffen Jung
    Abstract:

    Lymphoid organs are characterized by a complex network of phenotypically distinct dendritic cells (DC) with potentially unique roles in pathogen recognition and immunostimulation. Classical DC (cDC) include two major subsets distinguished in the mouse by the expression of CD8α. Here we describe a subset of CD8α+ DC in lymphoid organs of naive mice characterized by expression of the CX3CR1 Chemokine Receptor. CX3CR1+ CD8α+ DC lack hallmarks of classical CD8α+ DC, including IL-12 secretion, the capacity to cross-present antigen, and their developmental dependence on the transcriptional factor BatF3. Gene-expression profiling showed that CX3CR1+ CD8α+ DC resemble CD8α− cDC. The microarray analysis further revealed a unique plasmacytoid DC (PDC) gene signature of CX3CR1+ CD8α+ DC. A PDC relationship of the cells is supported further by the fact that they harbor characteristic D–J Ig gene rearrangements and that development of CX3CR1+ CD8α+ DC requires E2-2, the critical transcriptional regulator of PDC. Thus, CX3CR1+ CD8α+ DC represent a unique DC subset, related to but distinct from PDC. Collectively, the expression-profiling data of this study refine the resolution of previous DC definitions, sharpen the border of classical CD8α+ and CD8α− DC, and should assist the identification of human counterparts of murine DC subsets.

  • The Chemokine Receptor CX3CR1 mediates homing of MHC class II-positive cells to the normal mouse corneal epithelium.
    Investigative ophthalmology & visual science, 2007
    Co-Authors: Holly R. Chinnery, Steffen Jung, Marc J. Ruitenberg, Giles W. Plant, Eric Pearlman, Paul G. Mcmenamin
    Abstract:

    PURPOSE. Recent investigations have revealed that populations of macrophages and dendritic cells (DCs) are present in the stroma and epithelium of the cornea, although the precise phenotype and distribution are still controversial. CX(3)CR1, the sole Receptor for the Chemokine fractalkine, is expressed by these monocyte-derived cells. Transgenic CX(3)CR1(GFP) mice, in which either one (heterozygous) or both (homozygous) copies of the CX(3)CR1 gene were replaced by enhanced green fluorescent protein (eGFP), were used to characterize monocyte-derived cells in the mouse cornea and to determine whether the expression of this Receptor influences the recruitment of these cells into the normal cornea.

  • the neuronal Chemokine cx3cl1 fractalkine selectively recruits nk cells that modify experimental autoimmune encephalomyelitis within the central nervous system
    The FASEB Journal, 2006
    Co-Authors: Deren Huang, Steffen Jung, Fu Dong Shi, Gary C. Pien, Jintang Wang, Jennifer Weaver, Hans-gustaf Ljunggren, Christine A. Biron, Thais P Salazarmather, Dan R Littman
    Abstract:

    Leukocyte trafficking to the central nervous system (CNS), regulated in part by Chemokines, determines severity of the demyelinating diseases multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). To examine Chemokine Receptor CX3CR1 in EAE, we studied CX3CR1(GFP/GFP) mice, in which CX3CR1 targeting by insertion of Green Fluorescent Protein (GFP) allowed tracking of CX3CR1+ cells in CX3CR1(+/GFP) animals and cells destined to express CX3CR1 in CX3CR1(GFP/GFP) knockouts. NK cells were markedly reduced in the inflamed CNS of CX3CR1-deficient mice with EAE, whereas recruitment of T cells, NKT cells and monocyte/macrophages to the CNS during EAE did not require CX3CR1. Impaired recruitment of NK cells in CX3CR1(GFP/GFP) mice was associated with increased EAE-related mortality, nonremitting spastic paraplegia and hemorrhagic inflammatory lesions. The absence of CD1d did not affect the severity of EAE in CX3CR1(GFP/GFP) mice, arguing against a role for NKT cells. Accumulation of NK cells in livers of wild-type (WT) and CX3CR1(GFP/GFP) mice with cytomegalovirus hepatitis was equivalent, indicating that CX3CL1 mediated chemoattraction of NK cells was relatively specific for the CNS. These results are the first to define a Chemokine that governs NK cell migration to the CNS, and the findings suggest novel therapeutic manipulation of CX3CR1+ NK cells.

  • The neuronal Chemokine CX3CL1/fractalkine selectively recruits NK cells that modify experimental autoimmune encephalomyelitis within the central nervous system
    The FASEB Journal, 2006
    Co-Authors: Deren Huang, Steffen Jung, Fu Dong Shi, Gary C. Pien, Jintang Wang, Thais P. Salazar-mather, Jennifer Weaver, Hans-gustaf Ljunggren, Christine A. Biron
    Abstract:

    Leukocyte trafficking to the central nervous system (CNS), regulated in part by Chemokines, determines severity of the demyelinating diseases multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). To examine Chemokine Receptor CX3CR1 in EAE, we studied CX3CR1(GFP/GFP) mice, in which CX3CR1 targeting by insertion of Green Fluorescent Protein (GFP) allowed tracking of CX3CR1+ cells in CX3CR1(+/GFP) animals and cells destined to express CX3CR1 in CX3CR1(GFP/GFP) knockouts. NK cells were markedly reduced in the inflamed CNS of CX3CR1-deficient mice with EAE, whereas recruitment of T cells, NKT cells and monocyte/macrophages to the CNS during EAE did not require CX3CR1. Impaired recruitment of NK cells in CX3CR1(GFP/GFP) mice was associated with increased EAE-related mortality, nonremitting spastic paraplegia and hemorrhagic inflammatory lesions. The absence of CD1d did not affect the severity of EAE in CX3CR1(GFP/GFP) mice, arguing against a role for NKT cells. Accumulation of NK cells in livers of wild-type (WT) and CX3CR1(GFP/GFP) mice with cytomegalovirus hepatitis was equivalent, indicating that CX3CL1 mediated chemoattraction of NK cells was relatively specific for the CNS. These results are the first to define a Chemokine that governs NK cell migration to the CNS, and the findings suggest novel therapeutic manipulation of CX3CR1+ NK cells.

Virginia Amanatidou - One of the best experts on this subject based on the ideXlab platform.