Philip M Murphy

National Institutes of Health, Maryland, United States

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Publications (111)865.24 Total impact

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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; · 2.61 Impact Factor
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  • Nature Immunology 02/2014; 15(3):207-8. · 26.20 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 identifier for this study is NCT00967785.
    Blood 02/2014; · 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. · 17.00 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; · 15.39 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. · 13.02 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).
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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. · 1.04 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; · 15.39 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; · 2.38 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; · 5.81 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. · 5.08 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; · 4.65 Impact Factor
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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; · 5.04 Impact Factor
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    ABSTRACT: Invasive candidiasis is the 4(th) leading cause of nosocomial bloodstream infection in the US with mortality that exceeds 40% despite administration of antifungal therapy; neutropenia is a major risk factor for poor outcome after invasive candidiasis. In a fatal mouse model of invasive candidiasis that mimics human bloodstream-derived invasive candidiasis, the most highly infected organ is the kidney and neutrophils are the major cellular mediators of host defense; however, factors regulating neutrophil recruitment have not been previously defined. Here we show that mice lacking chemokine receptor Ccr1, which is widely expressed on leukocytes, had selectively impaired accumulation of neutrophils in the kidney limited to the late phase of the time course of the model; surprisingly, this was associated with improved renal function and survival without affecting tissue fungal burden. Consistent with this, neutrophils from wild-type mice in blood and kidney switched from Ccr1(lo) to Ccr1(high) at late time-points post-infection, when Ccr1 ligands were produced at high levels in the kidney and were chemotactic for kidney neutrophils ex vivo. Further, when a 1∶1 mixture of Ccr1(+/+) and Ccr1(-/-) donor neutrophils was adoptively transferred intravenously into Candida-infected Ccr1(+/+) recipient mice, neutrophil trafficking into the kidney was significantly skewed toward Ccr1(+/+) cells. Thus, neutrophil Ccr1 amplifies late renal immunopathology and increases mortality in invasive candidiasis by mediating excessive recruitment of neutrophils from the blood to the target organ.
    PLoS Pathogens 08/2012; 8(8):e1002865. · 8.14 Impact Factor
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    ABSTRACT: Cultured bacteria release N-formylpeptides, which are potent chemoattractants for phagocytic leukocytes acting at G-protein-coupled receptors FPR1 and FPR2. However, the distribution and immunologic activity of these molecules at mucosal surfaces, where large numbers of bacteria are separated from the immune system by epithelium, remain undefined. To investigate this for the gut, we tested leukocyte responses to cell-free gut luminal contents from C57Bl/6 mice fed a chow diet. Small and large intestine contents were able to compete with labeled N-formylpeptide for binding to FPR1, indicating the presence of FPR1 ligands in the gut lumen. Material from both small and large intestine induced robust calcium flux responses by primary FPR1(+) leukocytes (mouse bone marrow cells and splenocytes and human peripheral blood neutrophils and mononuclear cells), as well as chemotactic responses by both mouse bone marrow cells and human peripheral blood neutrophils. However, unlike defined N-formylpeptides, calcium flux responses induced by gut luminal contents were insensitive both to pertussis toxin treatment of leukocytes and to proteinase K digestion of the samples. Moreover, the gut samples were fully active on neutrophils from mice lacking Fpr1, and the kinetics of the calcium flux response differed markedly for neutrophils and peripheral blood mononuclear cells. The active factor(s) could be dialyzed using a 3.5-kDa pore size membrane. Thus, mouse intestinal lumen contains small, potent and highly efficacious leukocyte chemotactic and activating factors that may be distinct from neutrophils and peripheral blood mononuclear cells and distinct from Fpr1 agonists.
    Journal of Innate Immunity 06/2012; · 4.46 Impact Factor
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    Philip M Murphy, David H McDermott
    Blood 06/2012; 119(24):5610-2. · 9.78 Impact Factor
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    ABSTRACT: WHIM syndrome is a rare, autosomal dominant, immunodeficiency disorder so-named because it is characterized by warts, hypogammaglobulinemia, infections, and myelokathexis (defective neutrophil egress from the BM). Gain-of-function mutations that truncate the C-terminus of the chemokine receptor CXCR4 by 10-19 amino acids cause WHIM syndrome. We have identified a family with autosomal dominant inheritance of WHIM syndrome that is caused by a missense mutation in CXCR4, E343K (1027G → A). This mutation is also located in the C-terminal domain, a region responsible for negative regulation of the receptor. Accordingly, like CXCR4(R334X), the most common truncation mutation in WHIM syndrome, CXCR4(E343K) mediated approximately 2-fold increased signaling in calcium flux and chemotaxis assays relative to wild-type CXCR4; however, CXCR4(E343K) had a reduced effect on blocking normal receptor down-regulation from the cell surface. Therefore, in addition to truncating mutations in the C-terminal domain of CXCR4, WHIM syndrome may be caused by a single charge-changing amino acid substitution in this domain, E343K, that results in increased receptor signaling.
    Blood 05/2012; 120(1):181-9. · 9.78 Impact Factor
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    ABSTRACT: Despite the clear major contribution of hyperlipidemia to the prevalence of cardiovascular disease in the developed world, the direct effects of lipoproteins on endothelial cells have remained obscure and are under debate. Here we report a previously uncharacterized mechanism of vessel growth modulation by lipoprotein availability. Using a genetic screen for vascular defects in zebrafish, we initially identified a mutation, stalactite (stl), in the gene encoding microsomal triglyceride transfer protein (mtp), which is involved in the biosynthesis of apolipoprotein B (ApoB)-containing lipoproteins. By manipulating lipoprotein concentrations in zebrafish, we found that ApoB negatively regulates angiogenesis and that it is the ApoB protein particle, rather than lipid moieties within ApoB-containing lipoproteins, that is primarily responsible for this effect. Mechanistically, we identified downregulation of vascular endothelial growth factor receptor 1 (VEGFR1), which acts as a decoy receptor for VEGF, as a key mediator of the endothelial response to lipoproteins, and we observed VEGFR1 downregulation in hyperlipidemic mice. These findings may open new avenues for the treatment of lipoprotein-related vascular disorders.
    Nature medicine 05/2012; 18(6):967-73. · 27.14 Impact Factor

Publication Stats

5k Citations
865.24 Total Impact Points


  • 2004–2013
    • National Institutes of Health
      • • Section on Cellular Signaling
      • • Laboratory of Cellular and Molecular Immunology
      Maryland, United States
  • 2012
    • Third Military Medical University
      • Institute of Pathology and Southwest Cancer Center
      Ch’ung-ch’ing-shih, Chongqing Shi, China
    • University of Michigan
      • Department of Pharmacology
      Ann Arbor, Michigan, United States
  • 1997–2012
    • National Institute of Allergy and Infectious Diseases
      • • Laboratory of Immunoregulation
      • • Laboratory of Parasitic Diseases (LPD)
      Maryland, United States
  • 2011
    • Mount Sinai School of Medicine
      • Department of Microbiology
      Manhattan, NY, United States
  • 2009
    • University of Illinois at Chicago
      • Department of Pharmacology (Chicago)
      Chicago, IL, United States
  • 2002
    • Brigham and Women's Hospital
      • Division of Renal Medicine
      Boston, MA, United States
    • Leidos Biomedical Research
      Maryland, United States