Philip M Murphy

National Institute of Allergy and Infectious Diseases, 베서스다, Maryland, United States

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Publications (147)1244.16 Total impact

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    ABSTRACT: Atypical chemokine receptor 1 (Ackr1; previously known as the Duffy antigen receptor for chemokines or Darc) is thought to regulate acute inflammatory responses in part by scavenging inflammatory CC and CXC chemokines; however, evidence for a role in chronic inflammation has been lacking. Here we investigated the role of Ackr1 in chronic inflammation, in particular in the setting of atherogenesis, using the apolipoprotein E-deficient (ApoE(-/-)) mouse model. Ackr1(-/-)ApoE(-/-) and Ackr1(+/+)ApoE(-/-) littermates were obtained by crossing ApoE(-/-) mice and Ackr1(-/-) mice on a C57BL/6J background. Ackr1 (+/+)ApoE(-/-)mice fed a Western diet upregulated Ackr1 expression in the aorta and had markedly increased atherosclerotic lesion size compared with Ackr1(-/-)ApoE(-/-) mice. This difference was observed in both the whole aorta and the aortic root in both early and late stages of the model. Ackr1 deficiency did not affect serum cholesterol levels or macrophage, collagen or smooth muscle cell content in atherosclerotic plaques, but significantly reduced the expression of Ccl2 and Cxcl1 in the whole aorta of ApoE(-/-) mice. In addition, Ackr1 deficiency resulted in a modest decrease in inflammatory mononuclear phagocyte content in aorta and blood in the model. Ackr1 deficiency appears to be protective in the ApoE knockout model of atherogenesis, but is associated with only modest changes in cytokine and chemokine expression as well as T cell subset frequency and inflammatory macrophage content. Published by Oxford University Press on behalf of the European Society of Cardiology 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.
    Cardiovascular Research 04/2015; DOI:10.1093/cvr/cvv124 · 5.81 Impact Factor
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    ABSTRACT: AMD3100 (plerixafor), is a specific CXCR4 antagonist approved by the FDA for mobilizing hematopoietic stem cells from bone marrow to blood for transplantation in cancer. AMD3100 also mobilizes most mature leukocyte subsets to blood; however, their source and trafficking potential have not been fully delineated. Here, we show that a single injection of AMD3100 10 mg/kg into C57Bl/6 mice rapidly mobilizes (peak ∼ 2.5 hours) the same leukocyte subsets to blood as in humans. Using this model, we found that AMD3100 mobilization of neutrophils, lymphocytes and monocytes to blood isn't reduced by splenectomy or by blockade of lymphocyte egress from lymph node with FTY720, but is coupled to i) reduced content of each of these cell types in the bone marrow; ii) reduced T-cell numbers in thymuses; iii) increased lymphocytes in lymph nodes; and iv) increased neutrophil and monocyte content in the lung. Direct intrathymic labeling showed that AMD3100 selectively mobilizes naïve thymic CD4(+) and CD8(+) T cells to blood. Finally, AMD3100-induced neutrophil mobilization to blood did not reduce neutrophil trafficking to thioglycollate-inflamed peritoneum. Thus, AMD3100 redistributes lymphocytes, monocytes and neutrophils from primary immune organs to secondary immune organs, peripheral tissues and blood, without compromising neutrophil trafficking to inflamed sites. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 03/2015; DOI:10.1002/eji.201445245 · 4.52 Impact Factor
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    ABSTRACT: Chromothripsis is a catastrophic cellular event recently described in cancer in which chromosomes undergo massive deletion and rearrangement. Here, we report a case in which chromothripsis spontaneously cured a patient with WHIM syndrome, an autosomal dominant combined immunodeficiency disease caused by gain-of-function mutation of the chemokine receptor CXCR4. In this patient, deletion of the disease allele, CXCR4(R334X), as well as 163 other genes from one copy of chromosome 2 occurred in a hematopoietic stem cell (HSC) that repopulated the myeloid but not the lymphoid lineage. In competitive mouse bone marrow (BM) transplantation experiments, Cxcr4 haploinsufficiency was sufficient to confer a strong long-term engraftment advantage of donor BM over BM from either wild-type or WHIM syndrome model mice, suggesting a potential mechanism for the patient's cure. Our findings suggest that partial inactivation of CXCR4 may have general utility as a strategy to promote HSC engraftment in transplantation. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell 02/2015; DOI:10.1016/j.cell.2015.01.014 · 33.12 Impact Factor
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    ABSTRACT: Atypical Chemokine Receptor 1 (ACKR1), previously known as Duffy Antigen Receptor for Chemokines, stands out among chemokine receptors for high selective expression on cerebellar Purkinje neurons. Although ACKR1 ligands activate Purkinje cells in vitro, evidence for ACKR1 regulation of brain function in vivo is lacking. Here we demonstrate that Ackr1 (-/-) mice have markedly impaired balance and ataxia on a rotating rod and increased tremor when injected with harmaline, which induces whole-body tremor by activating Purkinje cells. Ackr1 (-/-) mice also exhibited impaired exploratory behavior, increased anxiety-like behavior and frequent episodes of marked hypoactivity under low-stress conditions. Surprisingly, Ackr1 (+/-) had similar behavioral abnormalities, indicating pronounced haploinsufficiency. The behavioral phenotype of Ackr1 (-/-) mice was the opposite of mouse models of cerebellar degeneration, and the defects persisted when Ackr1 was deficient only on non-hematopoietic cells. Together, the results suggest that normal motor function and behavior may partly depend on negative regulation of Purkinje cell activity by Ackr1.
    Behavior Genetics 07/2014; 44(5). DOI:10.1007/s10519-014-9665-7 · 2.84 Impact Factor
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  • Nature Immunology 02/2014; 15(3):207-8. DOI:10.1038/ni.2812 · 24.97 Impact Factor
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    ABSTRACT: WHIM syndrome is a rare immunodeficiency disorder caused by gain-of-function mutations in the G protein-coupled chemokine receptor CXCR4. The CXCR4 antagonist plerixafor, which is FDA-approved for stem cell mobilization in cancer and administered for that indication at 0.24 mg/kg, has been shown in short-term (1-2 week) Phase 1 dose escalation studies to correct neutropenia and other cytopenias in WHIM syndrome; however, long-term safety and long-term hematologic and clinical efficacy data are lacking. Here we report results from the first long-term clinical trial of plerixafor in any disease, in which three adults with WHIM syndrome self-injected 0.01-0.02 mg/kg (4-8% of the FDA-approved dose) subcutaneously twice daily for 6 months. Circulating leukocytes were durably increased throughout the trial in all patients, and this was associated with fewer infections and improvement in warts in combination with imiquimod; however immunoglobulin levels and specific vaccine responses were not fully restored. No drug-associated side effects were observed. These results provide preliminary evidence for the safety and clinical efficacy of long-term, low-dose plerixafor in WHIM syndrome, and support its continued study as mechanism-based therapy in this disease. The ClinicalTrials.gov identifier for this study is NCT00967785.
    Blood 02/2014; 123(15). DOI:10.1182/blood-2013-09-527226 · 9.78 Impact Factor
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    ABSTRACT: Sixteen years ago, the Nomenclature Committee of the International Union of Pharmacology approved a system for naming human seven-transmembrane (7TM) G protein-coupled chemokine receptors, the large family of leukocyte chemoattractant receptors that regulates immune system development and function, in large part by mediating leukocyte trafficking. This was announced in Pharmacological Reviews in a major overview of the first decade of research in this field [Murphy PM, Baggiolini M, Charo IF, Hébert CA, Horuk R, Matsushima K, Miller LH, Oppenheim JJ, and Power CA (2000) Pharmacol Rev 52:145-176]. Since then, several new receptors have been discovered, and major advances have been made for the others in many areas, including structural biology, signal transduction mechanisms, biology, and pharmacology. New and diverse roles have been identified in infection, immunity, inflammation, development, cancer, and other areas. The first two drugs acting at chemokine receptors have been approved by the U.S. Food and Drug Administration (FDA), maraviroc targeting CCR5 in human immunodeficiency virus (HIV)/AIDS, and plerixafor targeting CXCR4 for stem cell mobilization for transplantation in cancer, and other candidates are now undergoing pivotal clinical trials for diverse disease indications. In addition, a subfamily of atypical chemokine receptors has emerged that may signal through arrestins instead of G proteins to act as chemokine scavengers, and many microbial and invertebrate G protein-coupled chemokine receptors and soluble chemokine-binding proteins have been described. Here, we review this extended family of chemokine receptors and chemokine-binding proteins at the basic, translational, and clinical levels, including an update on drug development. We also introduce a new nomenclature for atypical chemokine receptors with the stem ACKR (atypical chemokine receptor) approved by the Nomenclature Committee of the International Union of Pharmacology and the Human Genome Nomenclature Committee.
    Pharmacological reviews 01/2014; 66(1):1-79. DOI:10.1124/pr.113.007724 · 18.55 Impact Factor
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    ABSTRACT: Systemic Candida albicans infection causes high morbidity and mortality and is associated with neutropenia; however, the roles of other innate immune cells in pathogenesis are poorly defined. Here, using a mouse model of systemic candidiasis, we found that resident macrophages accumulated in the kidney, the main target organ of infection, and formed direct contacts with the fungus in vivo mainly within the first few hours after infection. Macrophage accumulation and contact with Candida were both markedly reduced in mice lacking chemokine receptor CX3CR1, which was found almost exclusively on resident macrophages in uninfected kidneys. Infected Cx3cr1-/- mice uniformly succumbed to Candida-induced renal failure, but exhibited clearance of the fungus in all other organs tested. Renal macrophage deficiency in infected Cx3cr1-/- mice was due to reduced macrophage survival, not impaired proliferation, trafficking, or differentiation. In humans, the dysfunctional CX3CR1 allele CX3CR1-M280 was associated with increased risk of systemic candidiasis. Together, these data indicate that CX3CR1-mediated renal resident macrophage survival is a critical innate mechanism of early fungal control that influences host survival in systemic candidiasis.
    The Journal of clinical investigation 11/2013; DOI:10.1172/JCI71307 · 13.77 Impact Factor
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    ABSTRACT: Shifts in commensal microbiota composition are emerging as a hallmark of gastrointestinal inflammation. In particular, outgrowth of γ-proteobacteria has been linked to the etiology of inflammatory bowel disease and the pathologic consequences of infections. Here we show that following acute Toxoplasma gondii gastrointestinal infection of mice, control of commensal outgrowth is a highly coordinated process involving both the host response and microbial signals. Notably, neutrophil emigration to the intestinal lumen results in the generation of organized intraluminal structures that encapsulate commensals and limit their contact with the epithelium. Formation of these luminal casts depends on the high-affinity N-formyl peptide receptor, Fpr1. Consequently, after infection, mice deficient in Fpr1 display increased microbial translocation, poor commensal containment, and increased mortality. Altogether, our study describes a mechanism by which the host rapidly contains commensal pathobiont outgrowth during infection. Further, these results reveal Fpr1 as a major mediator of host commensal interaction during dysbiosis.
    Cell host & microbe 09/2013; 14(3):318-28. DOI:10.1016/j.chom.2013.08.003 · 12.19 Impact Factor
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    ABSTRACT: Saint Louis polyomavirus (STLPyV) was recently discovered in human feces. Using random-primed rolling circle amplification combined with deep sequencing, we have found a divergent variant of STLPyV in a sanitized human skin wart specimen. The result strongly suggests that STLPyV directly infects humans and is not simply a dietary contaminant.
    Genome Announcements 08/2013; 1(5). DOI:10.1128/genomeA.00812-13
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    ABSTRACT: Epidermodysplasia verruciformis is a rare genodermatosis characterized by abnormal susceptibility to infection with specific human papillomavirus serotypes. Epidermodysplasia verruciformis is a genetically heterogeneous disease, and autosomal recessive and X-linked inheritance patterns have been reported. Nonsense mutations in the genes EVER1 and EVER2 have been identified in over 75% of cases. We present epidermodysplasia verruciformis in a father and a son with typical histologic and clinical findings that occur in the absence of mutations in EVER1 or EVER2. Epidermodysplasia verruciformis in this father/son pair in a nonconsanguinous pedigree is consistent with autosomal dominant inheritance. This is the first report of autosomal dominant transmission of epidermodysplasia verruciformis, providing further evidence of the genetic heterogeneity of epidermodysplasia verruciformis.
    Pediatric Dermatology 08/2013; 26(3):306-10. DOI:10.1111/j.1525-1470.2008.00853.x · 1.52 Impact Factor
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    ABSTRACT: Commensal bacteria and their products provide beneficial effects to the mammalian gut by stimulating epithelial cell turnover and enhancing wound healing, without activating overt inflammation. We hypothesized that N-formylpeptide receptors, which bind bacterial N-formylpeptides and are expressed by intestinal epithelial cells, may contribute to these processes. Here we report that formylpeptide receptor-2 (FPR2), which we show is expressed on the apical and lateral membranes of colonic crypt epithelial cells, mediates N-formylpeptide-dependent epithelial cell proliferation and renewal. Colonic epithelial cells in FPR2-deficient mice displayed defects in commensal bacterium-dependent homeostasis as shown by the absence of responses to N-formylpeptide stimulation, shortened colonic crypts, reduced acute inflammatory responses to dextran sulfate sodium (DSS) challenge, delayed mucosal restoration after injury, and increased azoxymethane-induced tumorigenesis. These results indicate that FPR2 is critical in mediating homeostasis, inflammation, and epithelial repair processes in the colon.
    The Journal of clinical investigation 03/2013; 123(4). DOI:10.1172/JCI65569 · 13.77 Impact Factor
  • Wuzhou Wan, Philip M Murphy
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    ABSTRACT: Atherosclerosis is a chronic inflammatory and metabolic disorder affecting large- and medium-sized arteries, and the leading cause of mortality worldwide. The pathogenesis of atherosclerosis involves accumulation of lipids and leukocytes in the intima of blood vessel walls creating plaque. How leukocytes accumulate in plaque remains poorly understood; however, chemokines acting at specific G protein-coupled receptors appear to be important. Studies using knockout mice suggest that chemokine receptor signaling may either promote or inhibit atherogenesis, depending on the receptor. These proof of concept studies have spurred efforts to develop drugs targeting the chemokine system in atherosclerosis, and several have shown beneficial effects in animal models. This study will review key discoveries in basic and translational research in this area.
    Archivum Immunologiae et Therapiae Experimentalis 12/2012; 61(1). DOI:10.1007/s00005-012-0202-1 · 2.82 Impact Factor
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    ABSTRACT: AIMS: Recent evidence suggests that both Ccr7 and its ligands, Ccl19 and Ccl21, are present in mouse and human atherosclerotic plaques; however, the role of Ccr7 in atherogenesis is still controversial. Here, we addressed this question by using the classic apolipoprotein E-deficient (ApoE-/-) mouse model of atherosclerosis.Methods and ResultsCcr7-/-ApoE-/- double knockout mice were generated and maintained on a high-fat Western diet for 8 weeks to induce atherosclerosis. Ccr7-/-ApoE-/- mice showed an ~80% increase in atherosclerotic lesion size in the whole aorta and a two-fold increase in the aortic root compared to Ccr7+/+ApoE-/- mice. Ccr7-/-ApoE-/- mice had increased T cells in the blood, bone marrow and spleen, as well as in atherosclerotic lesions. Competitive repopulation experiments revealed that T cells from Ccr7-/-ApoE-/- mice migrated poorly into lymph nodes but better into mouse aortas. Transplantation of bone marrow from Ccr7-/-ApoE-/- mice into lethally irradiated Ccr7+/+ApoE-/- mice resulted in ~60% more atherosclerotic lesions compared to Ccr7+/+ApoE-/- donor bone marrow, suggesting that exacerbation was mediated by a Ccr7(+) bone marrow-derived cell(s). Furthermore, in Ccr7-/-ApoE-/- mice the serum level of IL-12 was markedly increased while the level of TGF-β (Transforming Growth Factor beta) was significantly decreased, suggesting an imbalance of T cell responses in these mice. CONCLUSION: Our data suggest that genetic deletion of Ccr7 exacerbates atherosclerosis by increasing T cell accumulation in atherosclerotic lesions.
    Cardiovascular Research 11/2012; 97(3). DOI:10.1093/cvr/cvs349 · 5.81 Impact Factor
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    ABSTRACT: Listeria monocytogenes (Listeria) causes opportunistic infection in immunocompromised hosts with high mortality. Resistance to Listeria depends on immune responses and recruitment of neutrophils of the immune system into infected sites is an early and critical step. Mouse neutrophils express two G protein-coupled formylpeptide receptor subtypes Fpr1 and Fpr2 that recognize bacterial and host-derived chemotactic molecules including Listeria peptides for cell migration and activation. Here we report deficiency in Fprs exacerbated the severity of the infection and increased the mortality of infected mice. The mechanism involved impaired early neutrophil recruitment to the liver with Fpr1 and Fpr2 being sole receptors for neutrophils to sense Listeria chemoattractant signals and for production of bactericidal superoxide. Thus, Fprs are essential sentinels to guide the first wave of neutrophil infiltration in the liver of Listeria-infected mice for effective elimination of the invading pathogen.
    Scientific Reports 11/2012; 2:786. DOI:10.1038/srep00786 · 5.08 Impact Factor
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    ABSTRACT: Nine polyomavirus (PyV) species are known to productively infect humans. The circular DNA genomes of PyVs are readily detectable using rolling circle amplification (RCA). RCA-based analysis of condyloma specimens from a patient with warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome demonstrated the presence of a tenth apparently human-tropic polyomavirus species, which we name HPyV10.
    Journal of Virology 10/2012; 86(19):10887. DOI:10.1128/JVI.01690-12 · 4.65 Impact Factor
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    ABSTRACT: Formyl peptide receptor 1 (FPR1) is a G protein-coupled chemoattractant receptor expressed mainly on leukocytes. Surprisingly, aging Fpr1(-/-) mice develop spontaneous lens degeneration without inflammation or infection (J-L. Gao et al., manuscript in preparation). Therefore, we hypothesized that FPR1 is functionally expressed directly on lens epithelial cells, the only cell type in the lens. Consistent with this, the human fetal lens epithelial cell line FHL 124 expressed FPR1 mRNA, and was strongly FPR1 protein positive by Western blot and FACS. Competition binding using FPR1 ligands fNLFNYK, fMLF and peptide W revealed the same profile for FHL 124 cells, neutrophils and FPR1-transfected HEK 293 cells. Saturation binding with fluorescent fNLFNYK-Fl revealed ~2500 specific binding sites on FHL-124 cells (K(D)~0.5 nM), versus ~40,000 sites on neutrophils (K(D)=3.2 nM). Moreover, fMLF induced pertussis toxin-sensitive Ca(2+) flux in FHL 124 cells, consistent with classic G(i)-mediated FPR1 signaling. FHL 124 cell FPR1 was atypical in that it resisted agonist-induced internalization. Expression of FPR1 was additionally supported by detection of the intact full-length open reading frame in sequenced cDNA from FHL 124 cells. Thus, FHL 124 cells express functional FPR1, which is consistent with a direct functional role for FPR1 in the lens, as suggested by the phenotype of Fpr1 knockout mice.
    Journal of Biological Chemistry 09/2012; DOI:10.1074/jbc.M112.411181 · 4.60 Impact Factor
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    Sunny C Yung, Philip M Murphy
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    ABSTRACT: Chemokines are best known for their classic leukocyte chemotactic activity, which is critical for directing the immune response to sites of infection and injury. However, recent studies have suggested that at least some chemokines may also interfere with infectious agents directly. Antimicrobial chemokines tend to contain amphipathic alpha helical secondary structure, and broad-spectrum activity against both Gram-positive and Gram negative bacteria, as well as fungi. Conversely, several bacteria have been identified that possess mechanisms for specifically blocking the antimicrobial activities of chemokines. Although the precise mechanisms by which chemokines and microbes disarm one another in vitro remain unknown, there is now emerging evidence in vivo that such interactions may be biologically significant. More research will be needed to determine whether chemokines with direct antimicrobial activity may be translated into a novel class of antibiotics.
    Frontiers in Immunology 09/2012; 3:276. DOI:10.3389/fimmu.2012.00276
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    ABSTRACT: Neutrophils are first responders rapidly mobilized to inflammatory sites by a tightly regulated, non-redundant hierarchy of chemoattractants. These chemoattractants engage neutrophil cell surface receptors triggering heterotrimeric G-protein Gα(i) subunits to exchange GDP for GTP. By limiting the duration that Gα(i) subunits remain GTP-bound, RGS proteins modulate chemoattractant receptor signaling. Here, we show that neutrophils with a genomic knock-in of a mutation that disables RGS protein-Gα(i2) interactions accumulate in the bone marrow and mobilize poorly to inflammatory sites. These defects are attributable to enhanced sensitivity to background signals, prolonged chemoattractant receptor signaling, and inappropriate CXCR2 downregulation. Intravital imaging revealed a failure of the mutant neutrophils to accumulate at and stabilize sites of sterile inflammation. Furthermore, these mice could not control a non-lethal Staphylococcus aureus infection. Neutrophil RGS proteins establish a threshold for Gα(i) activation helping to coordinate desensitization mechanisms. Their loss renders neutrophils functionally incompetent.
    Molecular and Cellular Biology 09/2012; DOI:10.1128/MCB.00651-12 · 5.04 Impact Factor

Publication Stats

11k Citations
1,244.16 Total Impact Points

Institutions

  • 1992–2015
    • National Institute of Allergy and Infectious Diseases
      • • Laboratory of Immunoregulation
      • • Laboratory of Parasitic Diseases (LPD)
      베서스다, Maryland, United States
  • 1998–2013
    • National Institutes of Health
      • • Section on Cellular Signaling
      • • Laboratory of Cellular and Molecular Immunology
      • • Laboratory of Host Defenses
      Maryland, United States
  • 2012
    • National Institute of Allergy and Infectious Disease
      United States
    • University of Michigan
      • Department of Pharmacology
      Ann Arbor, Michigan, United States
  • 2007
    • National Eye Institute
      베서스다, Maryland, United States
  • 2005
    • National Human Genome Research Institute
      베서스다, Maryland, United States
  • 2002
    • Leidos Biomedical Research
      Maryland, United States
  • 2001
    • William Harvey Research Institute
      Londinium, England, United Kingdom
  • 1987
    • Universität Heidelberg
      Heidelburg, Baden-Württemberg, Germany