How neutrophils kill microbes.

Neutrophils provide the first line of defense of the innate immune system by phagocytosing, killing, and digesting bacteria and fungi. Killing was previously believed to be accomplished by oxygen free radicals and other reactive oxygen species generated by the NADPH oxidase, and by oxidized halides produced by myeloperoxidase. We now know this is incorrect. The oxidase pumps electrons into the phagocytic vacuole, thereby inducing a charge across the membrane that must be compensated. The movement of compensating ions produces conditions in the vacuole conducive to microbial killing and digestion by enzymes released into the vacuole from the cytoplasmic granules.

[1]  A. Segal,et al.  The NADPH oxidase of professional phagocytes--prototype of the NOX electron transport chain systems. , 2004, Biochimica et biophysica acta.

[2]  T. DeCoursey During the Respiratory Burst, Do Phagocytes Need Proton Channels or Potassium Channels, or Both? , 2004, Science's STKE.

[3]  A. Kettle,et al.  Superoxide Converts Indigo Carmine to Isatin Sulfonic Acid , 2004, Journal of Biological Chemistry.

[4]  M. Duchen,et al.  The large-conductance Ca2+-activated K+ channel is essential for innate immunity , 2004, Nature.

[5]  Ruma Banerjee,et al.  The many faces of vitamin B12: catalysis by cobalamin-dependent enzymes. , 2003, Annual review of biochemistry.

[6]  F. Cainelli,et al.  Infections in patients with cancer undergoing chemotherapy: aetiology, prevention, and treatment. , 2003, The Lancet. Oncology.

[7]  T. Ganz Defensins: antimicrobial peptides of innate immunity , 2003, Nature Reviews Immunology.

[8]  A. Segal,et al.  Reassessment of the microbicidal activity of reactive oxygen species and hypochlorous acid with reference to the phagocytic vacuole of the neutrophil granulocyte. , 2003, Journal of medical microbiology.

[9]  M. Hensel,et al.  Inducible nitric oxide synthase and control of intracellular bacterial pathogens. , 2003, Microbes and infection.

[10]  Deri Morgan,et al.  The voltage dependence of NADPH oxidase reveals why phagocytes need proton channels , 2003, Nature.

[11]  P. Wentworth,et al.  Investigating antibody-catalyzed ozone generation by human neutrophils , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[12]  A. Segal,et al.  PX domain takes shape , 2003, Current opinion in hematology.

[13]  T. DeCoursey,et al.  The gp91phox Component of NADPH Oxidase Is Not a Voltage-gated Proton Channel , 2002, The Journal of general physiology.

[14]  R. Lerner,et al.  Evidence for Antibody-Catalyzed Ozone Formation in Bacterial Killing and Inflammation , 2002, Science.

[15]  P. Vignais The superoxide-generating NADPH oxidase: structural aspects and activation mechanism , 2002, Cellular and Molecular Life Sciences CMLS.

[16]  Haruo Watanabe,et al.  Critical role of myeloperoxidase and nicotinamide adenine dinucleotide phosphate-oxidase in high-burden systemic infection of mice with Candida albicans. , 2002, The Journal of infectious diseases.

[17]  J. Roes,et al.  Catalase negative Staphylococcus aureus retain virulence in mouse model of chronic granulomatous disease , 2002, FEBS letters.

[18]  A. Kettle,et al.  Chlorination of Bacterial and Neutrophil Proteins during Phagocytosis and Killing of Staphylococcus aureus * , 2002, The Journal of Biological Chemistry.

[19]  Giorgio Gabella,et al.  Killing activity of neutrophils is mediated through activation of proteases by K+ flux , 2002, Nature.

[20]  T. Bächi,et al.  Reconstitution of bactericidal activity in chronic granulomatous disease cells by glucose-oxidase-containing liposomes. , 2001, Blood.

[21]  R. Hotchkiss,et al.  Neutrophils employ the myeloperoxidase system to generate antimicrobial brominating and chlorinating oxidants during sepsis , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[22]  S. Ryser,et al.  Heme Histidine Ligands within gp91 phox Modulate Proton Conduction by the Phagocyte NADPH Oxidase* , 2001, The Journal of Biological Chemistry.

[23]  A. Kettle,et al.  A kinetic analysis of the catalase activity of myeloperoxidase. , 2001, Biochemistry.

[24]  H. Koyama,et al.  Differential host susceptibility to pulmonary infections with bacteria and fungi in mice deficient in myeloperoxidase. , 2000, The Journal of infectious diseases.

[25]  Richard B. Johnston,et al.  Chronic Granulomatous Disease: Report on a National Registry of 368 Patients , 2000, Medicine.

[26]  R. Fenna,et al.  X-ray Crystal Structure and Characterization of Halide-binding Sites of Human Myeloperoxidase at 1.8 Å Resolution* , 2000, The Journal of Biological Chemistry.

[27]  K. Lawson,et al.  Potassium channel openers as potential therapeutic weapons in ion channel disease. , 2000, Kidney international.

[28]  J. Roes,et al.  Impaired immunity and enhanced resistance to endotoxin in the absence of neutrophil elastase and cathepsin G. , 2000, Immunity.

[29]  U. Gullberg,et al.  Processing and targeting of granule proteins in human neutrophils. , 1999, Journal of immunological methods.

[30]  T. Ley,et al.  Normal neutrophil function in cathepsin G-deficient mice. , 1999, Blood.

[31]  R. Meech,et al.  Evidence That the Product of the Human X-Linked Cgd Gene, Gp91-phox, Is a Voltage-Gated H+ Pathway , 1999, The Journal of general physiology.

[32]  S. Grinstein,et al.  A Noninvasive Fluorimetric Procedure for Measurement of Membrane Potential , 1999, The Journal of Biological Chemistry.

[33]  N. Maeda,et al.  Severe Impairment in Early Host Defense againstCandida albicans in Mice Deficient in Myeloperoxidase , 1999, Infection and Immunity.

[34]  A. Kettle,et al.  Inside the neutrophil phagosome: oxidants, myeloperoxidase, and bacterial killing. , 1998, Blood.

[35]  S. Holland,et al.  Virulence of catalase-deficient aspergillus nidulans in p47(phox)-/- mice. Implications for fungal pathogenicity and host defense in chronic granulomatous disease. , 1998, The Journal of clinical investigation.

[36]  Ronald McCarthy,et al.  Mice lacking neutrophil elastase reveal impaired host defense against gram negative bacterial sepsis , 1998, Nature Medicine.

[37]  Karl-Heinz Krause,et al.  Electron currents generated by the human phagocyte NADPH oxidase , 1998, Nature.

[38]  O. McManus,et al.  Paxilline Inhibition of the Alpha-subunit of the High-conductance Calcium-activated Potassium Channel , 1996, Neuropharmacology.

[39]  A. Kettle,et al.  Involvement of superoxide and myeloperoxidase in oxygen-dependent killing of Staphylococcus aureus by neutrophils , 1996, Infection and immunity.

[40]  O. McManus,et al.  High-conductance calcium-activated potassium channels; Structure, pharmacology, and function , 1996, Journal of bioenergetics and biomembranes.

[41]  Myron S. Cohen,et al.  Free radicals and phagocytic cells , 1995, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[42]  S. Grinstein,et al.  Assessment of the contribution of the cytochrome b moiety of the NADPH oxidase to the transmembrane H+ conductance of leukocytes. , 1994, The Journal of biological chemistry.

[43]  H. Sengeløv,et al.  Molecular cloning and expression of a cDNA encoding NGAL: a lipocalin expressed in human neutrophils. , 1994, Biochemical and biophysical research communications.

[44]  W. Kroeze,et al.  Secretory vesicles are the intracellular reservoir of complement receptor 1 in human neutrophils. , 1994, Journal of immunology.

[45]  W. Taylor,et al.  A structural model for the nucleotide binding domains of the flavocytochrome b–245 β‐chain , 1993, Protein science : a publication of the Protein Society.

[46]  T. DeCoursey,et al.  Potential, pH, and arachidonate gate hydrogen ion currents in human neutrophils. , 1993, Biophysical journal.

[47]  S. Grinstein,et al.  Activation of vacuolar-type proton pumps by protein kinase C. Role in neutrophil pH regulation. , 1992, The Journal of biological chemistry.

[48]  H. Sengeløv,et al.  Stimulus-dependent secretion of plasma proteins from human neutrophils. , 1992, The Journal of clinical investigation.

[49]  C. Hedrick,et al.  Superoxide generation by the human polymorphonuclear leukocyte in response to latex beads , 1992, Journal of leukocyte biology.

[50]  E. Ligeti,et al.  Phorbol 12-myristate 13-acetate activates an electrogenic H(+)-conducting pathway in the membrane of neutrophils. , 1992, The Biochemical journal.

[51]  S. Grinstein,et al.  Protein kinase C activates an H+ (equivalent) conductance in the plasma membrane of human neutrophils. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[52]  M. Doerfler,et al.  Endotoxin-neutralizing properties of the 25 kD N-terminal fragment and a newly isolated 30 kD C-terminal fragment of the 55-60 kD bactericidal/permeability-increasing protein of human neutrophils , 1991, The Journal of experimental medicine.

[53]  S. O. Kolset,et al.  Proteoglycans in haemopoietic cells. , 1990, Biochimica et biophysica acta.

[54]  J. Curnutte Recent advances in chronic granulomatous disease , 1990 .

[55]  G. Giménez-Gallego,et al.  Purification and characterization of a unique, potent, peptidyl probe for the high conductance calcium-activated potassium channel from venom of the scorpion Buthus tamulus. , 1990, The Journal of biological chemistry.

[56]  D. Hassett,et al.  Neutrophil degranulation inhibits potential hydroxyl-radical formation. Relative impact of myeloperoxidase and lactoferrin release on hydroxyl-radical production by iron-supplemented neutrophils assessed by spin-trapping techniques. , 1989, The Biochemical journal.

[57]  D. Bainton,et al.  Human neutrophil gelatinase is a component of specific granules. , 1989, The Journal of clinical investigation.

[58]  O. Jones,et al.  Superoxide generation by the electrogenic NADPH oxidase of human neutrophils is limited by the movement of a compensating charge. , 1988, The Biochemical journal.

[59]  O. Jones,et al.  Internal pH changes associated with the activity of NADPH oxidase of human neutrophils. Further evidence for the presence of an H+ conducting channel. , 1988, The Biochemical journal.

[60]  P. O'Brien,et al.  Proton release associated with respiratory burst of polymorphonuclear leukocytes. , 1988, Journal of biochemistry.

[61]  O. Jones,et al.  The superoxide-generating NADPH oxidase of human neutrophils is electrogenic and associated with an H+ channel. , 1987, The Biochemical journal.

[62]  R. Genco,et al.  Antimicrobial Properties of Hydrogen Peroxide and Sodium Bicarbonate Individually and in Combination Against Selected Oral, Gram-negative, Facultative Bacteria , 1986, Journal of dental research.

[63]  S. Grinstein,et al.  Cytoplasmic pH regulation in phorbol ester-activated human neutrophils. , 1986, The American journal of physiology.

[64]  L. Simchowitz Chemotactic factor-induced activation of Na+/H+ exchange in human neutrophils. II. Intracellular pH changes. , 1985, The Journal of biological chemistry.

[65]  C. Winterbourn,et al.  Production of the superoxide adduct of myeloperoxidase (compound III) by stimulated human neutrophils and its reactivity with hydrogen peroxide and chloride. , 1985, The Biochemical journal.

[66]  B. Halliwell,et al.  Free radicals in biology and medicine , 1985 .

[67]  A. Tauber,et al.  Proton secretion by stimulated neutrophils. Significance of hexose monophosphate shunt activity as source of electrons and protons for the respiratory burst. , 1984, The Journal of clinical investigation.

[68]  S. Wright,et al.  Phagocytosing macrophages exclude proteins from the zones of contact with opsonized targets , 1984, Nature.

[69]  J. Banga,et al.  Iodination by stimulated human neutrophils. Studies on its stoichiometry, subcellular localization and relevance to microbial killing. , 1983, The Biochemical journal.

[70]  C. Winterbourn Lactoferrin-catalysed hydroxyl radical production. Additional requirement for a chelating agent. , 1983, The Biochemical journal.

[71]  J. Repine,et al.  Hydrogen peroxide mediated killing of bacteria , 1982, Molecular and Cellular Biochemistry.

[72]  M. Kobayashi,et al.  Inactivation of lysosomal enzymes by the respiratory burst of polymorphonuclear leukocytes. Possible involvement of myeloperoxidase-H2O2-halide system. , 1982, The Journal of laboratory and clinical medicine.

[73]  M. Klempner,et al.  Internal pH of human neutrophil lysosomes , 1982, FEBS letters.

[74]  R. García,et al.  The action of cells from patients with chronic granulomatous disease on Staphylococcus aureus. , 1982, Journal of medical microbiology.

[75]  R. C. Thomas,et al.  Hydrogen ion currents and intracellular pH in depolarized voltage-clamped snail neurones , 1982, Nature.

[76]  T. Stossel,et al.  A variant of chronic granulomatous disease: deficient oxidative metabolism due to a low-affinity NADPH oxidase. , 1981, The New England journal of medicine.

[77]  B. Halliwell,et al.  Inhibition of lipid peroxidation by the iron-binding protein lactoferrin. , 1981, The Biochemical journal.

[78]  D. Roos,et al.  Extracellular proton release by stimulated neutrophils. , 1981, The Journal of clinical investigation.

[79]  M. Geisow,et al.  The respiratory burst of phagocytic cells is associated with a rise in vacuolar pH , 1981, Nature.

[80]  R. Johnston,et al.  Lactoferrin enhances hydroxyl radical production by human neutrophils, neutrophil particulate fractions, and an enzymatic generating system. , 1981, The Journal of clinical investigation.

[81]  A. Segal,et al.  Kinetics of fusion of the cytoplasmic granules with phagocytic vacuoles in human polymorphonuclear leukocytes. Biochemical and morphological studies , 1980, The Journal of cell biology.

[82]  A. Segal,et al.  The subcellular distribution and some properties of the cytochrome b component of the microbicidal oxidase system of human neutrophils. , 1979, The Biochemical journal.

[83]  L. Boxer,et al.  Utilization of Liposomes for Correction of the Metabolic and Bactericidal Deficiencies in Chronic Granulomatous Disease , 1979, Pediatric Research.

[84]  T. Meshulam,et al.  Production of superoxide by neutrophils: a reappraisal , 1979, FEBS letters.

[85]  J. Armstrong,et al.  The role of lactoferrin in the bactericidal function of polymorphonuclear leucocytes. , 1979, Immunology.

[86]  H. Rosen,et al.  Bactericidal activity of a superoxide anion-generating system. A model for the polymorphonuclear leukocyte , 1979, The Journal of experimental medicine.

[87]  H. Odeberg,et al.  Purification and characterization of a potent bactericidal and membrane active protein from the granules of human polymorphonuclear leukocytes. , 1978, The Journal of biological chemistry.

[88]  R. Clark,et al.  Iodination by human polymorphonuclear leukocytes: a re-evaluation. , 1977, The Journal of laboratory and clinical medicine.

[89]  J. Spitznagel,et al.  Chicken neutrophils: oxidative metabolism in phagocytic cells devoid of myeloperoxidase. , 1975, Proceedings of the National Academy of Sciences of the United States of America.

[90]  S. Klebanoff Antimicrobial mechanisms in neutrophilic polymorphonuclear leukocytes. , 1975, Seminars in hematology.

[91]  G. Mandell Catalase, superoxide dismutase, and virulence of Staphylococcus aureus. In vitro and in vivo studies with emphasis on staphylococcal--leukocyte interaction. , 1975, The Journal of clinical investigation.

[92]  B. Babior,et al.  Biological defense mechanisms. Evidence for the participation of superoxide in bacterial killing by xanthine oxidase. , 1975, The Journal of laboratory and clinical medicine.

[93]  G. Mandell Bactericidal Activity of Aerobic and Anaerobic Polymorphonuclear Neutrophils , 1974, Infection and immunity.

[94]  J. Pitt,et al.  Role of Peroxide in Phagocytic Killing of Pneumococci , 1974, Infection and immunity.

[95]  D. Bainton,et al.  SEQUENTIAL DEGRANULATION OF THE TWO TYPES OF POLYMORPHONUCLEAR LEUKOCYTE GRANULES DURING PHAGOCYTOSIS OF MICROORGANISMS , 1973, The Journal of cell biology.

[96]  B. Babior,et al.  Biological defense mechanisms. The production by leukocytes of superoxide, a potential bactericidal agent. , 1973, The Journal of clinical investigation.

[97]  D. Bainton,et al.  TEMPORAL CHANGES IN PH WITHIN THE PHAGOCYTIC VACUOLE OF THE POLYMORPHONUCLEAR NEUTROPHILIC LEUKOCYTE , 1973, The Journal of cell biology.

[98]  R. Good,et al.  Laboratory models of chronic granulomatous disease. , 1972, Journal of the Reticuloendothelial Society.

[99]  M. Baggiolini,et al.  FURTHER BIOCHEMICAL AND MORPHOLOGICAL STUDIES OF GRANULE FRACTIONS FROM RABBIT HETEROPHIL LEUKOCYTES , 1970, The Journal of cell biology.

[100]  I. Fridovich,et al.  Superoxide dismutase. An enzymic function for erythrocuprein (hemocuprein). , 1969, The Journal of biological chemistry.

[101]  R. Lehrer,et al.  Defective Bactericidal Activity in Myeloperoxidase-deficient Human Neutrophils , 1969, Nature.

[102]  S. Klebanoff,et al.  Iodination defect in the leukocytes of a patient with chronic granulomatous disease of childhood. , 1969, The New England journal of medicine.

[103]  M. Baggiolini,et al.  RESOLUTION OF GRANULES FROM RABBIT HETEROPHIL LEUKOCYTES INTO DISTINCT POPULATIONS BY ZONAL SEDIMENTATION , 1969, The Journal of cell biology.

[104]  S. Klebanoff Myeloperoxidase-Halide-Hydrogen Peroxide Antibacterial System , 1968, Journal of bacteriology.

[105]  H. I. Zeya,et al.  ARGININE-RICH PROTEINS OF POLYMORPHONUCLEAR LEUKOCYTE LYSOSOMES : ANTIMICROBIAL SPECIFICITY AND BIOCHEMICAL HETEROGENEITY , 1968 .

[106]  H. I. Zeya,et al.  ARGININE-RICH PROTEINS OF POLYMORPHONUCLEAR LEUKOCYTE LYSOSOMES , 1968, The Journal of experimental medicine.

[107]  S. Klebanoff IODINATION OF BACTERIA: A BACTERICIDAL MECHANISM , 1967, The Journal of experimental medicine.

[108]  R. Good,et al.  Studies of the metabolic activity of leukocytes from patients with a genetic abnormality of phagocytic function. , 1967, The Journal of clinical investigation.

[109]  R. Good,et al.  Fatal granulomatous disease of childhood. An inborn abnormality of phagocytic function. , 1966, Lancet.

[110]  J. H. Quastel,et al.  Biochemical Aspects of Phagocytosis , 1961, Nature.

[111]  Z. Cohn,et al.  THE INFLUENCE OF PHAGOCYTOSIS ON THE INTRACELLULAR DISTRIBUTION OF GRANULE-ASSOCIATED COMPONENTS OF POLYMORPHONUCLEAR LEUCOCYTES , 1960, The Journal of experimental medicine.

[112]  H. P. Schwan,et al.  Electrical Properties of Mitochondrial Membranes , 1960, The Journal of biophysical and biochemical cytology.

[113]  J. G. Hirsch PHAGOCYTIN: A BACTERICIDAL SUBSTANCE FROM POLYMORPHONUCLEAR LEUCOCYTES , 1956, The Journal of experimental medicine.

[114]  A. Fleming On a Remarkable Bacteriolytic Element Found in Tissues and Secretions , 1922 .

[115]  R. T. Briggs,et al.  Superoxide production by polymorphonuclear leukocytes , 2004, Histochemistry.

[116]  G. Garcı́a-Cardeña,et al.  Bacterial infection induces nitric oxide synthase in human neutrophils. , 1997, The Journal of clinical investigation.

[117]  P. Ehrlich Granules of the Human Neutrophilic Polymorphonuclear Leukocyte , 1997 .

[118]  D. Bainton Neutrophilic leukocyte granules: from structure to function. , 1993, Advances in experimental medicine and biology.

[119]  B. Britigan,et al.  Application of spin trapping to human phagocytic cells: insight into conditions for formation and limitation of hydroxyl radical. , 1991, Free radical research communications.

[120]  W. Nauseef Myeloperoxidase deficiency. , 1988, Hematology/oncology clinics of North America.

[121]  A. September Superoxide production by polymorphonuclear leukocytes A cytochemical approach , 1986 .

[122]  R. Lehrer,et al.  Phagolysosomal pH of human neutrophils. , 1984, Blood.

[123]  B. Seligmann,et al.  NIH conference. Recent advances in chronic granulomatous disease. , 1983, Annals of internal medicine.

[124]  R. Locksley,et al.  Increased respiratory burst in myeloperoxidase-deficient monocytes. , 1983, Blood.

[125]  H. Rosen Role of hydroxyl radical in polymorphonuclear leukocyte-mediated bactericidal activity. , 1980, Agents and actions. Supplements.

[126]  P. Elsbach,et al.  Partial characterization and purification of a rabbit granulocyte factor that increases permeability of Escherichia coli. , 1975, The Journal of clinical investigation.