Neutrophils and immunity: challenges and opportunities

Scientists who study neutrophils often have backgrounds in cell biology, biochemistry, haematology, rheumatology or infectious disease. Paradoxically, immunologists seem to have a harder time incorporating these host-defence cells into the framework of their discipline. The recent literature discussed here indicates that it is appropriate for immunologists to take as much interest in neutrophils as in their lymphohaematopoietic cousins with smooth nuclei. Neutrophils inform and shape immune responses, contribute to the repair of tissue as well as its breakdown, use killing mechanisms that enrich our concepts of specificity, and offer exciting opportunities for the treatment of neoplastic, autoinflammatory and autoimmune disorders.

[1]  C. Nathan,et al.  Beta 2 integrin-dependent tyrosine phosphorylation of paxillin in human neutrophils treated with tumor necrosis factor , 1994, The Journal of cell biology.

[2]  T. Mayadas,et al.  Vav GEFs are required for β2 integrin-dependent functions of neutrophils , 2004, The Journal of cell biology.

[3]  D. Herndon,et al.  Three different neutrophil subsets exhibited in mice with different susceptibilities to infection by methicillin-resistant Staphylococcus aureus. , 2004, Immunity.

[4]  S. Kunkel.  Faculty Opinions recommendation of Cross-talk in the innate immune system: neutrophils instruct recruitment and activation of dendritic cells during microbial infection. , 2003 .

[5]  A. Cohen,et al.  Treatment of ulcerative colitis with a humanized antibody to the alpha4beta7 integrin. , 2005, The New England journal of medicine.

[6]  S. Hedrick,et al.  The acquired immune system: a vantage from beneath. , 2004, Immunity.

[7]  M. Huang,et al.  Signaling by adhesion in human neutrophils: activation of the p72syk tyrosine kinase and formation of protein complexes containing p72syk and Src family kinases in neutrophils spreading over fibrinogen. , 1997, Journal of immunology.

[8]  N. Borregaard,et al.  Neutrophil granules and secretory vesicles in inflammation. , 2003, Microbes and infection.

[9]  C. E. Ooi,et al.  Purification of a cellular (granulocyte) and an extracellular (serum) phospholipase A2 that participate in the destruction of Escherichia coli in a rabbit inflammatory exudate. , 1990, The Journal of biological chemistry.

[10]  C. H. Ong,et al.  Progranulin is a mediator of the wound response , 2003, Nature Medicine.

[11]  L. DiPietro,et al.  Neutrophil function in the healing wound: adding insult to injury? , 2004, Thrombosis and Haemostasis.

[12]  R. Clark,et al.  The neutrophil: Function and clinical disorders , 1978 .

[13]  J J Padgett,et al.  A renewed sense of self. , 1994, Journal of psychosocial nursing and mental health services.

[14]  J. Lambeth.  NOX enzymes and the biology of reactive oxygen , 2004, Nature Reviews Immunology.

[15]  F. Bäckhed,et al.  Host-Bacterial Mutualism in the Human Intestine , 2005, Science.

[16]  K. Ley,et al.  Phagocytosis of apoptotic neutrophils regulates granulopoiesis via IL-23 and IL-17. , 2005, Immunity.

[17]  S. Weiss.  Tissue destruction by neutrophils. , 1989, The New England journal of medicine.

[18]  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.

[19]  C. Nathan.  Respiratory burst in adherent human neutrophils: triggering by colony-stimulating factors CSF-GM and CSF-G. , 1989, Blood.

[20]  H. Schreiber,et al.  Synergy between tumor necrosis factor and bacterial products causes hemorrhagic necrosis and lethal shock in normal mice. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[21]  I. Olsson,et al.  Tumor necrosis factor-induced degranulation in adherent human neutrophils is dependent on CD11b/CD18-integrin-triggered oscillations of cytosolic free Ca2+. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[22]  A. Mócsai,et al.  Syk is required for integrin signaling in neutrophils. , 2002, Immunity.

[23]  C. Haslett,et al.  Granulocyte clearance by apoptosis in the resolution of inflammation. , 1995, Seminars in cell biology.

[24]  J. Stockman.  Treatment of Ulcerative Colitis With a Humanized Antibody to the α4β7 Integrin , 2007 .

[25]  A. Zychlinsky,et al.  Neutrophil Extracellular Traps Kill Bacteria , 2004, Science.

[26]  C. Nathan,et al.  Critical Role of the Carboxyl Terminus of Proline-rich Tyrosine Kinase (Pyk2) in the Activation of Human Neutrophils by Tumor Necrosis Factor , 2003, The Journal of experimental medicine.

[27]  Charles A. Janeway,et al.  Decoding the Patterns of Self and Nonself by the Innate Immune System , 2002, Science.

[28]  R. Alon,et al.  LAD-III, a novel group of leukocyte integrin activation deficiencies. , 2003, Trends in immunology.

[29]  D. Greenhalgh,et al.  Cutaneous Wound Healing , 2007, Journal of burn care & research : official publication of the American Burn Association.

[30]  C. Nathan,et al.  Calcium-sensing soluble adenylyl cyclase mediates TNF signal transduction in human neutrophils , 2005, The Journal of experimental medicine.

[31]  P. Matzinger.  The Danger Model: A Renewed Sense of Self , 2002, Science.

[32]  D. Neuberg,et al.  Vaccination with irradiated autologous melanoma cells engineered to secrete human granulocyte-macrophage colony-stimulating factor generates potent antitumor immunity in patients with metastatic melanoma. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[33]  C. Nathan,et al.  Albumin inhibits neutrophil spreading and hydrogen peroxide release by blocking the shedding of CD43 (sialophorin, leukosialin) , 1993, The Journal of cell biology.

[34]  P. Rieu,et al.  Redox regulation of β2‐integrin CD11b / CD18 activation , 1999 .

[35]  L. Hydo,et al.  Secretory leukocyte protease inhibitor, an inhibitor of neutrophil activation, is elevated in serum in human sepsis and experimental endotoxemia , 2000, Critical care medicine.

[36]  S. Klebanoff.  Myeloperoxidase: friend and foe , 2005, Journal of leukocyte biology.

[37]  S. Rafii,et al.  Recruitment of Stem and Progenitor Cells from the Bone Marrow Niche Requires MMP-9 Mediated Release of Kit-Ligand , 2002, Cell.

[38]  M. Rosenblum,et al.  Hemorrhagic tumor necrosis during a pilot trial of tumor necrosis factor-alpha and anti-GD3 ganglioside monoclonal antibody in patients with metastatic melanoma , 1994 .

[39]  D. Roos,et al.  Hematologically important mutations: leukocyte adhesion deficiency. , 2001, Blood cells, molecules & diseases.

[40]  L. Kilpatrick,et al.  TNFalpha elicits association of PI 3-kinase with the p60TNFR and activation of PI 3-kinase in adherent neutrophils. , 2001, Biochemical and biophysical research communications.

[41]  Shizuo Akira,et al.  Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron , 2004, Nature.

[42]  J. Berger,et al.  Progressive multifocal leukoencephalopathy and natalizumab--unforeseen consequences. , 2005, The New England journal of medicine.

[43]  H. Erdjument-Bromage,et al.  Conversion of Proepithelin to Epithelins Roles of SLPI and Elastase in Host Defense and Wound Repair , 2002, Cell.

[44]  M. Colombo,et al.  Regression of an established tumor genetically modified to release granulocyte colony-stimulating factor requires granulocyte-T cell cooperation and T cell-produced interferon gamma , 1993, The Journal of experimental medicine.

[45]  K. Magnusson,et al.  Actin dynamics in human neutrophils during adhesion and phagocytosis is controlled by changes in intracellular free calcium. , 1993, European journal of cell biology.

[46]  Narayanasami Sukumar,et al.  A Novel, Potent Dual Inhibitor of the Leukocyte Proteases Cathepsin G and Chymase , 2005, Journal of Biological Chemistry.

[47]  R. Soberman,et al.  Specificity of a third kind : reactive oxygen and nitrogen intermediates in cell signaling , 2022 .

[48]  P. Henson,et al.  Tissue injury in inflammation. Oxidants, proteinases, and cationic proteins. , 1987, The Journal of clinical investigation.

[49]  S. Mckercher,et al.  Wound Healing in the PU.1 Null Mouse—Tissue Repair Is Not Dependent on Inflammatory Cells , 2003, Current Biology.

[50]  A. Mócsai,et al.  Adhesion-dependent degranulation of neutrophils requires the Src family kinases Fgr and Hck. , 1999, Journal of immunology.

[51]  M. Selsted,et al.  Mammalian defensins in the antimicrobial immune response , 2005, Nature Immunology.

[52]  M. Dinauer,et al.  Phenotype of mice and macrophages deficient in both phagocyte oxidase and inducible nitric oxide synthase. , 1999, Immunity.

[53]  L. Moldawer,et al.  Macrophages secrete a novel heparin-binding protein with inflammatory and neutrophil chemokinetic properties , 1988, The Journal of experimental medicine.

[54]  J. Casanova,et al.  Inborn errors of immunity to infection , 2005, The Journal of experimental medicine.

[55]  C. Nathan.  Neutrophil activation on biological surfaces. Massive secretion of hydrogen peroxide in response to products of macrophages and lymphocytes. , 1987, The Journal of clinical investigation.

[56]  P. Allen,et al.  Inflammatory arthritis requires Foxo3a to prevent Fas ligand–induced neutrophil apoptosis , 2005, Nature Medicine.

[57]  G. Lyon,et al.  Role of the tyrosine kinase pyk2 in the integrin-dependent activation of human neutrophils by TNF. , 1999, The Journal of clinical investigation.

[58]  C. Nathan,et al.  Cytokine-induced respiratory burst of human neutrophils: dependence on extracellular matrix proteins and CD11/CD18 integrins , 1989, The Journal of cell biology.

[59]  H. Rosen,et al.  mRNA expression profiles for Escherichia coli ingested by normal and phagocyte oxidase-deficient human neutrophils. , 2002, The Journal of clinical investigation.

[60]  M. Parmentier,et al.  Neutrophil-Mediated Maturation of Chemerin: A Link between Innate and Adaptive Immunity1 , 2005, The Journal of Immunology.

[61]  V. Roschke,et al.  Proinflammatory mediators elicit secretion of the intracellular B-lymphocyte stimulator pool (BLyS) that is stored in activated neutrophils: implications for inflammatory diseases. , 2005, Blood.

[62]  C. Bogdan,et al.  Type 1 Interferon (IFNα/β) and Type 2 Nitric Oxide Synthase Regulate the Innate Immune Response to a Protozoan Parasite , 1998 .

[63]  N. Tonks.  Redox Redux: Revisiting PTPs and the Control of Cell Signaling , 2005, Cell.

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

[65]  B. Gérard,et al.  Human neutrophils produce interferon gamma upon stimulation by interleukin-12 , 2004, Laboratory Investigation.

[66]  John D Loike,et al.  A critical concentration of neutrophils is required for effective bacterial killing in suspension , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[67]  W. Shafer,et al.  CAP37, a human neutrophil-derived chemotactic factor with monocyte specific activity. , 1990, The Journal of clinical investigation.

[68]  D. Link,et al.  G-CSF is an essential regulator of neutrophil trafficking from the bone marrow to the blood. , 2002, Immunity.

[69]  V. Nizet,et al.  HIF-1alpha expression regulates the bactericidal capacity of phagocytes. , 2005, The Journal of clinical investigation.

[70]  C. Nathan,et al.  Adhesion-dependent protein tyrosine phosphorylation in neutrophils treated with tumor necrosis factor , 1993, The Journal of cell biology.

[71]  I. Stříž,et al.  Calprotectin - a pleiotropic molecule in acute and chronic inflammation. , 2004, Physiological research.

[72]  Carl Nathan,et al.  Points of control in inflammation , 2002, Nature.

[73]  J. White,et al.  Fatal (chronic) granulomatous disease of childhood: a hereditary defect of leukocyte function. , 1968, Seminars in hematology.

[74]  P. Leder,et al.  Murine interleukin-4 displays potent anti-tumor activity in vivo , 1989, Cell.

[75]  S. Atlas,et al.  Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. , 2005, The New England journal of medicine.

[76]  D. Radzioch,et al.  Secretory Leukocyte Protease Inhibitor: A Macrophage Product Induced by and Antagonistic to Bacterial Lipopolysaccharide , 1997, Cell.

[77]  J. Lekstrom‐Himes,et al.  Immunodeficiency diseases caused by defects in phagocytes. , 2000, The New England journal of medicine.

[78]  C. Serhan.  Novel omega -- 3-derived local mediators in anti-inflammation and resolution. , 2005, Pharmacology & therapeutics.

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

[80]  U. Kucich,et al.  MR889, a neutrophil elastase inhibitor, in patients with chronic obstructive pulmonary disease: a double-blind, randomized, placebo-controlled clinical trial. , 1996, The European respiratory journal.

[81]  Dirk Roos,et al.  Oxidative killing of microbes by neutrophils. , 2003, Microbes and infection.

[82]  V. Nizet,et al.  Staphylococcus aureus golden pigment impairs neutrophil killing and promotes virulence through its antioxidant activity , 2005, The Journal of experimental medicine.

[83]  Ji Ming Wang,et al.  Identification of Human Neutrophil-derived Cathepsin G and Azurocidin/CAP37 as Chemoattractants for Mononuclear Cells and Neutrophils , 1997, The Journal of experimental medicine.

[84]  O. Finn,et al.  Activated granulocytes and granulocyte-derived hydrogen peroxide are the underlying mechanism of suppression of t-cell function in advanced cancer patients. , 2001, Cancer research.

[85]  T. Geijtenbeek,et al.  Neutrophils mediate immune modulation of dendritic cells through glycosylation-dependent interactions between Mac-1 and DC-SIGN , 2005, The Journal of experimental medicine.

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

[87]  G. Bokoch,et al.  The molecular basis for adhesion-mediated suppression of reactive oxygen species generation by human neutrophils. , 2003, The Journal of clinical investigation.

[88]  S. Shapiro,et al.  Serine protease cathepsin G regulates adhesion-dependent neutrophil effector functions by modulating integrin clustering. , 2005, Immunity.

[89]  P. Rieu,et al.  Neutrophils: Molecules, Functions and Pathophysiological Aspects , 2000, Laboratory Investigation.

[90]  I. M. Neiman,et al.  [Inflammation and cancer]. , 1974, Patologicheskaia fiziologiia i eksperimental'naia terapiia.

[91]  C. Nathan,et al.  Azurocidin and a homologous serine protease from neutrophils. Differential antimicrobial and proteolytic properties. , 1990, The Journal of clinical investigation.

[92]  Seaver,et al.  Nitric oxide as a secretory product of mammalian cells , 2004 .

[93]  K. Tyler,et al.  Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. , 2005, The New England journal of medicine.

[94]  T. Raffin,et al.  Recombinant human tumor necrosis factor alpha induces calcium oscillation and calcium-activated chloride current in human neutrophils. The role of calcium/calmodulin-dependent protein kinase. , 1993, The Journal of biological chemistry.

[95]  C. Nathan.  The Moving Frontier in Nitric Oxide–Dependent Signaling , 2004, Science's STKE.

[96]  C. Print,et al.  Hypoxia-induced neutrophil survival is mediated by HIF-1α–dependent NF-κB activity , 2005, The Journal of experimental medicine.

[97]  C. Nathan.  Specificity of a third kind: reactive oxygen and nitrogen intermediates in cell signaling. , 2003, The Journal of clinical investigation.

[98]  M. Fey,et al.  Inflammation-associated Cell Cycle–independent Block of Apoptosis by Survivin in Terminally Differentiated Neutrophils , 2004, The Journal of experimental medicine.