Advertisement

Phagocytes

  • Tyler Nygaard
  • Natalia Malachowa
  • Scott D. Kobayashi
  • Frank R. DeLeoEmail author
Chapter
First Online:

Abstract

Phagocytes are a heterogeneous group of white cells or leukocytes—comprised of granulocytes and mononuclear phagocytes—that are important for innate and acquired immunity. Phagocytic leukocytes originate from bone marrow stem cells during hematopoiesis or from fetal precursor cells that seed tissues during embryogenesis. A primary function of mature phagocytes is to ingest and kill microorganisms. These leukocytes use oxygen-dependent and oxygen-independent processes to kill and degrade microbes. Phagocytes also generate extracellular traps, which can ensnare microbes and thereby contribute to host defense. Some phagocytes function as antigen-presenting cells and thus serve as a bridge between innate and acquired immunity. In addition to playing an important role in host defense, phagocytes eliminate dead host cells and debris, a process that maintains steady-state tissue homeostasis.

Keywords

Phagocyte Phagocytosis Macrophage Monocyte Granulocyte Neutrophil Polymorphonuclear leukocyte PMN Innate immunity Inflammation 

Abbreviations

APC

Antigen-presenting cell

BMCP

Basophil-MC progenitor cell

BPI

Bactericidal/permeability-increasing protein

CCL2

CC-chemokine ligand 2

cDC

Classical DC

CDP

Common DC progenitor

CLP

Common lymphoid progenitor

CMP

Common myeloid progenitor

CXCL8

CXC-chemokine ligand 8 (IL-8)

DAMP

Damage-associated molecular pattern

DC

Dendritic cell

EPC

Embryonic progenitor cell

ESL1

E-selectin ligand 1

ET

Extracellular trap

GAG

Glycosaminoglycan

GMP

Granulocyte-macrophage progenitor

H2O2

Hydrogen peroxide

HMGB1

High-mobility group box 1

HNP

Human neutrophil peptide

HOCl

Hypochlorous acid

HSC

Hematopoietic stem cell

ICAM-1

Intercellular adhesion molecule 1

iNOS

Inducible nitric oxide synthase

JAM-A

Junctional adhesion molecule A

JAM-C

Junctional adhesion molecule C

LMPP

Lymphoid-myeloid multipotent progenitor

LPS

Lipopolysaccharide

MDP

Macrophage-DC progenitor

MEP

Megakaryocyte-erythrocyte progenitor

MHC

Major histocompatibility complex

MPO

Myeloperoxidase

MPP

Multipotent progenitor

NET

Neutrophil extracellular trap

PAMP

Pathogen-associated molecular pattern

pDC

Plasmacytoid DC

PECAM-1

Platelet-endothelial cell adhesion molecule-1 (CD31)

PMN

Polymorphonuclear leukocyte (or neutrophil)

PRR

Pattern recognition receptor

PSGL1

P-selectin glycoprotein ligand 1

RNS

Reactive nitrogen species

ROS

Reactive oxygen species

SYK

Spleen tyrosine kinase

TCR

T cell receptor

TEM

Transendothelial cell migration

TNF

Tumor necrosis factor

VCAM-1

Vasculature intercellular adhesion molecule 1

VLA-4

Very late antigen 4

This is a preview of subscription content, log in to check access.

Notes

Acknowledgments

The authors thank Ryan Kissinger (National Institute of Allergy and Infectious Diseases) for preparation of illustrations. The authors are supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health.

References

  1. 1.
    Laiosa CV, Stadtfeld M, Graf T. Determinants of lymphoid-myeloid lineage diversification. Annu Rev Immunol. 2006;24:705–38.PubMedCrossRefGoogle Scholar
  2. 2.
    Sieweke MH, Allen JE. Beyond stem cells: self-renewal of differentiated macrophages. Science. 2013;342:1242974.PubMedCrossRefGoogle Scholar
  3. 3.
    Ginhoux F, Jung S. Monocytes and macrophages: developmental pathways and tissue homeostasis. Nat Rev Immunol. 2014;14:392–404.PubMedCrossRefGoogle Scholar
  4. 4.
    Laslo P, Pongubala JM, Lancki DW, Singh H. Gene regulatory networks directing myeloid and lymphoid cell fates within the immune system. Semin Immunol. 2008;20:228–35.PubMedCrossRefGoogle Scholar
  5. 5.
    Nimmo RA, May GE, Enver T. Primed and ready: understanding lineage commitment through single cell analysis. Trends Cell Biol. 2015;25:459–67.PubMedCrossRefGoogle Scholar
  6. 6.
    Davies LC, Taylor PR. Tissue-resident macrophages: then and now. Immunology. 2015;144:541–8.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    van Furth R, Cohn ZA. The origin and kinetics of mononuclear phagocytes. J Exp Med. 1968;128:415–35.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Guilliams M, Ginhoux F, Jakubzick C, Naik SH, Onai N, Schraml BU, et al. Dendritic cells, monocytes and macrophages: a unified nomenclature based on ontogeny. Nat Rev Immunol. 2014;14:571–8.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Geissmann F, Manz MG, Jung S, Sieweke MH, Merad M, Ley K. Development of monocytes, macrophages, and dendritic cells. Science. 2010;327:656–61.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Jenkins SJ, Hume DA. Homeostasis in the mononuclear phagocyte system. Trends Immunol. 2014;35:358–67.PubMedCrossRefGoogle Scholar
  11. 11.
    Epelman S, Lavine KJ, Randolph GJ. Origin and functions of tissue macrophages. Immunity. 2014;41:21–35.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Ackermann M, Liebhaber S, Klusmann JH, Lachmann N. Lost in translation: pluripotent stem cell-derived hematopoiesis. EMBO Mol Med. 2015;7:1388–1402.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Pittet MJ, Nahrendorf M, Swirski FK. The journey from stem cell to macrophage. Ann N Y Acad Sci. 2014;1319:1–18.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Manz MG, Boettcher S. Emergency granulopoiesis. Nat Rev Immunol. 2014;14:302–14.PubMedCrossRefGoogle Scholar
  15. 15.
    Alvarez-Errico D, Vento-Tormo R, Sieweke M, Ballestar E. Epigenetic control of myeloid cell differentiation, identity and function. Nat Rev Immunol. 2015;15:7–17.PubMedCrossRefGoogle Scholar
  16. 16.
    van Furth R, Cohn ZA, Hirsch JG, Humphrey JH, Spector WG, Langevoort HL. The mononuclear phagocyte system: a new classification of macrophages, monocytes, and their precursor cells. Bull World Health Organ. 1972;46:845–52.PubMedPubMedCentralGoogle Scholar
  17. 17.
    Meuret G, Hoffmann G. Monocyte kinetic studies in normal and disease states. Br J Haematol. 1973;24:275–85.PubMedCrossRefGoogle Scholar
  18. 18.
    Dutta P, Nahrendorf M. Regulation and consequences of monocytosis. Immunol Rev. 2014;262:167–78.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Italiani P, Boraschi D. From Monocytes to M1/M2 Macrophages: phenotypical vs. functional differentiation. Front Immunol. 2014;5:514.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Yona S, Kim KW, Wolf Y, Mildner A, Varol D, Breker M, et al. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity. 2013;38:79–91.PubMedCrossRefGoogle Scholar
  21. 21.
    Fogg DK, Sibon C, Miled C, Jung S, Aucouturier P, Littman DR, et al. A clonogenic bone marrow progenitor specific for macrophages and dendritic cells. Science. 2006;311:83–7.PubMedCrossRefGoogle Scholar
  22. 22.
    Mildner A, Yona S, Jung S. A close encounter of the third kind: monocyte-derived cells. Adv Immunol. 2013;120:69–103.PubMedCrossRefGoogle Scholar
  23. 23.
    Passlick B, Flieger D, Ziegler-Heitbrock HW. Identification and characterization of a novel monocyte subpopulation in human peripheral blood. Blood. 1989;74:2527–34.PubMedGoogle Scholar
  24. 24.
    Geissmann F, Jung S, Littman DR. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity. 2003;19:71–82.PubMedCrossRefGoogle Scholar
  25. 25.
    Wynn TA, Chawla A, Pollard JW. Macrophage biology in development, homeostasis and disease. Nature. 2013;496:445–55.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Martinez FO, Gordon S. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep. 2014;6:13.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Mills CD, Kincaid K, Alt JM, Heilman MJ, Hill AM. M-1/M-2 macrophages and the Th1/Th2 paradigm. J Immunol. 2000;164:6166–73.PubMedCrossRefGoogle Scholar
  28. 28.
    Locati M, Mantovani A, Sica A. Macrophage activation and polarization as an adaptive component of innate immunity. Adv Immunol. 2013;120:163–84.PubMedCrossRefGoogle Scholar
  29. 29.
    Galli SJ, Borregaard N, Wynn TA. Phenotypic and functional plasticity of cells of innate immunity: macrophages, mast cells and neutrophils. Nat Immunol. 2011;12:1035–44.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Murray PJ, Allen JE, Biswas SK, Fisher EA, Gilroy DW, Goerdt S, et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity. 2014;41:14–20.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Price JV, Vance RE. The macrophage paradox. Immunity. 2014;41:685–93.PubMedCrossRefGoogle Scholar
  32. 32.
    Steinman RM, Witmer MD. Lymphoid dendritic cells are potent stimulators of the primary mixed leukocyte reaction in mice. Proc Natl Acad Sci U S A. 1978;75:5132–6.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Miller JC, Brown BD, Shay T, Gautier EL, Jojic V, Cohain A, et al. Deciphering the transcriptional network of the dendritic cell lineage. Nat Immunol. 2012;13:888–99.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Merad M, Manz MG, Karsunky H, Wagers A, Peters W, Charo I, et al. Langerhans cells renew in the skin throughout life under steady-state conditions. Nat Immunol. 2002;3:1135–41.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Merad M, Sathe P, Helft J, Miller J, Mortha A. The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Annu Rev Immunol. 2013;31:563–604.PubMedCrossRefGoogle Scholar
  36. 36.
    Steinman RM, Cohn ZA. Identification of a novel cell type in peripheral lymphoid organs of mice. I. Morphology, quantitation, tissue distribution. J Exp Med. 1973;137:1142–62.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Mildner A, Jung S. Development and function of dendritic cell subsets. Immunity. 2014;40:642–56.PubMedCrossRefGoogle Scholar
  38. 38.
    Serbina NV, Salazar-Mather TP, Biron CA, Kuziel WA, Pamer EG. TNF/iNOS-producing dendritic cells mediate innate immune defense against bacterial infection. Immunity. 2003;19:59–70.PubMedCrossRefGoogle Scholar
  39. 39.
    Schlitzer A, McGovern N, Ginhoux F. Dendritic cells and monocyte-derived cells: two complementary and integrated functional systems. Semin Cell Dev Biol. 2015;41:9–22.PubMedCrossRefGoogle Scholar
  40. 40.
    Bainton DF, Ullyot JL, Farquhar MG. The development of neutrophilic polymorphonuclear leukocytes in human bone marrow. J Exp Med. 1971;134:907–34.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Kennedy AD, DeLeo FR. Neutrophil apoptosis and the resolution of infection. Immunol Res. 2009;43:25–61.PubMedCrossRefGoogle Scholar
  42. 42.
    Athens JW, Haab OP, Raab SO, Mauer AM, Ashenbrucker H, Cartwright GE, et al. Leukokinetic studies. IV. The total blood, circulating and marginal granulocyte pools and the granulocyte turnover rate in normal subjects. J Clin Invest. 1961;40:989–95.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Borregaard N, Sorensen OE, Theilgaard-Monch K. Neutrophil granules: a library of innate immunity proteins. Trends Immunol. 2007;28:340–5.PubMedCrossRefGoogle Scholar
  44. 44.
    Faurschou M, Borregaard N. Neutrophil granules and secretory vesicles in inflammation. Microbes Infect. 2003;5:1317–27.PubMedCrossRefGoogle Scholar
  45. 45.
    DeLeo FR, Nauseef WM. Granulocytic phagocytes. In: Bennett JE, Dolin R, Blaser MJ, editors. Mandell, Douglas, and Bennett’s principles and practice of infectious diseases. 1. 8th ed. Philadelphia: Elsevier Saunders; 2014. p. 78–92.Google Scholar
  46. 46.
    Borregaard N, Heiple JM, Simons ER, Clark RA. Subcellular localization of the b-cytochrome component of the human neutrophil microbicidal oxidase: translocation during activation. J Cell Biol. 1983;97:52–61.PubMedCrossRefGoogle Scholar
  47. 47.
    Nauseef WM, Borregaard N. Neutrophils at work. Nat Immunol. 2014;15:602–11.PubMedCrossRefGoogle Scholar
  48. 48.
    Karasuyama H, Mukai K, Obata K, Tsujimura Y, Wada T. Nonredundant roles of basophils in immunity. Annu Rev Immunol. 2011;29:45–69.PubMedCrossRefGoogle Scholar
  49. 49.
    Rothenberg ME, Hogan SP. The eosinophil. Annu Rev Immunol. 2006;24:147–74.PubMedCrossRefGoogle Scholar
  50. 50.
    Taylor ML, Metcalfe DD. Mast cells in allergy and host defense. Allergy Asthma Proc. 2001;22:115–9.PubMedCrossRefGoogle Scholar
  51. 51.
    Yousefi S, Gold JA, Andina N, Lee JJ, Kelly AM, Kozlowski E, et al. Catapult-like release of mitochondrial DNA by eosinophils contributes to antibacterial defense. Nat Med. 2008;14:949–53.PubMedCrossRefGoogle Scholar
  52. 52.
    Persson T, Andersson P, Bodelsson M, Laurell M, Malm J, Egesten A. Bactericidal activity of human eosinophilic granulocytes against Escherichia coli. Infect Immun. 2001;69:3591–6.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Rosenberg HF, Dyer KD, Foster PS. Eosinophils: changing perspectives in health and disease. Nat Rev Immunol. 2013;13:9–22.PubMedCrossRefGoogle Scholar
  54. 54.
    Ribatti D, Crivellato E. Mast cell ontogeny: an historical overview. Immunol Lett. 2014;159:11–4.PubMedCrossRefGoogle Scholar
  55. 55.
    Feger F, Varadaradjalou S, Gao Z, Abraham SN, Arock M. The role of mast cells in host defense and their subversion by bacterial pathogens. Trends Immunol. 2002;23:151–8.PubMedCrossRefGoogle Scholar
  56. 56.
    Dahlin JS, Hallgren J. Mast cell progenitors: origin, development and migration to tissues. Mol Immunol. 2015;63:9–17.PubMedCrossRefGoogle Scholar
  57. 57.
    Nilsson G, Costa JJ, Metcalfe DD. Mast cells and basophils. In: Gallin JI, Snyderman R, editors. Inflammation: basic principles and clinical correlates. 1. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 1999. p. 97–117.Google Scholar
  58. 58.
    Butcher EC, Picker LJ. Lymphocyte homing and homeostasis. Science. 1996;272:60–6.PubMedCrossRefGoogle Scholar
  59. 59.
    Ley K, Laudanna C, Cybulsky MI, Nourshargh S. Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nat Rev Immunol. 2007;7:678–89.PubMedCrossRefGoogle Scholar
  60. 60.
    Kolaczkowska E, Kubes P. Neutrophil recruitment and function in health and inflammation. Nat Rev Immunol. 2013;13:159–75.PubMedCrossRefGoogle Scholar
  61. 61.
    Nourshargh S, Alon R. Leukocyte migration into inflamed tissues. Immunity. 2014;41:694–707.PubMedCrossRefGoogle Scholar
  62. 62.
    Soehnlein O, Lindbom L. Phagocyte partnership during the onset and resolution of inflammation. Nat Rev Immunol. 2010;10:427–39.PubMedCrossRefGoogle Scholar
  63. 63.
    Petri B, Phillipson M, Kubes P. The physiology of leukocyte recruitment: an in vivo perspective. J Immunol. 2008;180:6439–46.PubMedCrossRefGoogle Scholar
  64. 64.
    Kobayashi SD, Voyich JM, Burlak C, DeLeo FR. Neutrophils in the innate immune response. Arch Immunol Ther Exp. 2005;53:505–17.Google Scholar
  65. 65.
    McPhail LC, Clayton CC, Snyderman R. The NADPH oxidase of human polymorphonuclear leukocytes. Evidence for regulation by multiple signals. J Biol Chem. 1984;259:5768–75.PubMedGoogle Scholar
  66. 66.
    Guthrie LA, McPhail LC, Henson PM, Johnston RB Jr. Priming of neutrophils for enhanced release of oxygen metabolites by bacterial lipopolysaccharide. Evidence for increased activity of the superoxide-producing enzyme. J Exp Med. 1984;160:1656–71.PubMedCrossRefGoogle Scholar
  67. 67.
    Rigby KM, DeLeo FR. Neutrophils in innate host defense against Staphylococcus aureus infections. Semin Immunopathol. 2012;34:237–59.PubMedCrossRefGoogle Scholar
  68. 68.
    Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell. 2010;140:805–20.PubMedCrossRefPubMedCentralGoogle Scholar
  69. 69.
    Chen GY, Nunez G. Sterile inflammation: sensing and reacting to damage. Nat Rev Immunol. 2010;10:826–37.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Canton J, Neculai D, Grinstein S. Scavenger receptors in homeostasis and immunity. Nat Rev Immunol. 2013;13:621–34.PubMedCrossRefGoogle Scholar
  71. 71.
    Nestle FO, Di Meglio P, Qin JZ, Nickoloff BJ. Skin immune sentinels in health and disease. Nat Rev Immunol. 2009;9:679–91.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Shi C, Pamer EG. Monocyte recruitment during infection and inflammation. Nat Rev Immunol. 2011;11:762–74.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Kinashi T. Intracellular signalling controlling integrin activation in lymphocytes. Nat Rev Immunol. 2005;5:546–59.PubMedCrossRefGoogle Scholar
  74. 74.
    Arnaout MA. Biology and structure of leukocyte beta 2 integrins and their role in inflammation. F1000Res. 2016;5:2433.CrossRefGoogle Scholar
  75. 75.
    Laudanna C, Kim JY, Constantin G, Butcher E. Rapid leukocyte integrin activation by chemokines. Immunol Rev. 2002;186:37–46.PubMedCrossRefGoogle Scholar
  76. 76.
    Shattil SJ, Kim C, Ginsberg MH. The final steps of integrin activation: the end game. Nat Rev Mol Cell Biol. 2010;11:288–300.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Abram CL, Lowell CA. The ins and outs of leukocyte integrin signaling. Annu Rev Immunol. 2009;27:339–62.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Weninger W, Biro M, Jain R. Leukocyte migration in the interstitial space of non-lymphoid organs. Nat Rev Immunol. 2014;14:232–46.PubMedCrossRefGoogle Scholar
  79. 79.
    Muller WA. Leukocyte-endothelial-cell interactions in leukocyte transmigration and the inflammatory response. Trends Immunol. 2003;24:327–34.PubMedGoogle Scholar
  80. 80.
    Nourshargh S, Hordijk PL, Sixt M. Breaching multiple barriers: leukocyte motility through venular walls and the interstitium. Nat Rev Mol Cell Biol. 2010;11:366–78.PubMedCrossRefGoogle Scholar
  81. 81.
    Heinrich V. Controlled one-on-one encounters between immune cells and microbes reveal mechanisms of phagocytosis. Biophys J. 2015;109:469–76.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Brown GD, Gordon S. Immune recognition. A new receptor for beta-glucans. Nature. 2001;413:36–7.PubMedCrossRefGoogle Scholar
  83. 83.
    Herre J, Marshall AS, Caron E, Edwards AD, Williams DL, Schweighoffer E, et al. Dectin-1 uses novel mechanisms for yeast phagocytosis in macrophages. Blood. 2004;104:4038–45.PubMedCrossRefGoogle Scholar
  84. 84.
    Li X, Utomo A, Cullere X, Choi MM, Milner DA Jr, Venkatesh D, et al. The beta-glucan receptor Dectin-1 activates the integrin Mac-1 in neutrophils via Vav protein signaling to promote Candida albicans clearance. Cell Host Microbe. 2011;10:603–15.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Anderson CL, Shen L, Eicher DM, Wewers MD, Gill JK. Phagocytosis mediated by three distinct Fc gamma receptor classes on human leukocytes. J Exp Med. 1990;171:1333–45.PubMedCrossRefGoogle Scholar
  86. 86.
    Springer TA, Dustin ML. Integrin inside-out signaling and the immunological synapse. Curr Opin Cell Biol. 2012;24:107–15.PubMedCrossRefGoogle Scholar
  87. 87.
    Caron E, Self AJ, Hall A. The GTPase Rap1 controls functional activation of macrophage integrin alphaMbeta2 by LPS and other inflammatory mediators. Curr Biol. 2000;10:974–8.PubMedCrossRefGoogle Scholar
  88. 88.
    Patel PC, Harrison RE. Membrane ruffles capture C3bi-opsonized particles in activated macrophages. Mol Biol Cell. 2008;19:4628–39.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Kress H, Stelzer EH, Holzer D, Buss F, Griffiths G, Rohrbach A. Filopodia act as phagocytic tentacles and pull with discrete steps and a load-dependent velocity. Proc Natl Acad Sci U S A. 2007;104:11633–8.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Flannagan RS, Harrison RE, Yip CM, Jaqaman K, Grinstein S. Dynamic macrophage “probing” is required for the efficient capture of phagocytic targets. J Cell Biol. 2010;191:1205–18.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Kheir WA, Gevrey JC, Yamaguchi H, Isaac B, Cox D. A WAVE2-Abi1 complex mediates CSF-1-induced F-actin-rich membrane protrusions and migration in macrophages. J Cell Sci. 2005;118:5369–79.PubMedCrossRefGoogle Scholar
  92. 92.
    Freeman SA, Grinstein S. Phagocytosis: receptors, signal integration, and the cytoskeleton. Immunol Rev. 2014;262:193–215.PubMedCrossRefGoogle Scholar
  93. 93.
    Levin R, Grinstein S, Schlam D. Phosphoinositides in phagocytosis and macropinocytosis. Biochim Biophys Acta. 1851;2015:805–23.Google Scholar
  94. 94.
    Wang AV, Scholl PR, Geha RS. Physical and functional association of the high affinity immunoglobulin G receptor (Fc gamma RI) with the kinases Hck and Lyn. J Exp Med. 1994;180:1165–70.PubMedCrossRefGoogle Scholar
  95. 95.
    Jaumouille V, Farkash Y, Jaqaman K, Das R, Lowell CA, Grinstein S. Actin cytoskeleton reorganization by Syk regulates Fcgamma receptor responsiveness by increasing its lateral mobility and clustering. Dev Cell. 2014;29:534–46.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Swanson JA. Phosphoinositides and engulfment. Cell Microbiol. 2014;16:1473–83.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Cox D, Berg JS, Cammer M, Chinegwundoh JO, Dale BM, Cheney RE, et al. Myosin X is a downstream effector of PI(3)K during phagocytosis. Nat Cell Biol. 2002;4:469–77.PubMedCrossRefGoogle Scholar
  98. 98.
    Lukacs GL, Rotstein OD, Grinstein S. Phagosomal acidification is mediated by a vacuolar-type H(+)-ATPase in murine macrophages. J Biol Chem. 1990;265:21099–107.PubMedGoogle Scholar
  99. 99.
    El Chemaly A, Nunes P, Jimaja W, Castelbou C, Demaurex N. Hv1 proton channels differentially regulate the pH of neutrophil and macrophage phagosomes by sustaining the production of phagosomal ROS that inhibit the delivery of vacuolar ATPases. J Leukoc Biol. 2014;95:827–839.Google Scholar
  100. 100.
    Savina A, Jancic C, Hugues S, Guermonprez P, Vargas P, Moura IC, et al. NOX2 controls phagosomal pH to regulate antigen processing during crosspresentation by dendritic cells. Cell. 2006;126:205–18.PubMedCrossRefGoogle Scholar
  101. 101.
    Yates RM, Hermetter A, Russell DG. The kinetics of phagosome maturation as a function of phagosome/lysosome fusion and acquisition of hydrolytic activity. Traffic. 2005;6:413–20.PubMedCrossRefGoogle Scholar
  102. 102.
    Claus V, Jahraus A, Tjelle T, Berg T, Kirschke H, Faulstich H, et al. Lysosomal enzyme trafficking between phagosomes, endosomes, and lysosomes in J774 macrophages. Enrichment of cathepsin H in early endosomes. J Biol Chem. 1998;273:9842–51.PubMedCrossRefGoogle Scholar
  103. 103.
    Rybicka JM, Balce DR, Chaudhuri S, Allan ER, Yates RM. Phagosomal proteolysis in dendritic cells is modulated by NADPH oxidase in a pH-independent manner. EMBO J. 2012;31:932–44.PubMedCrossRefGoogle Scholar
  104. 104.
    Delamarre L, Pack M, Chang H, Mellman I, Trombetta ES. Differential lysosomal proteolysis in antigen-presenting cells determines antigen fate. Science. 2005;307:1630–4.PubMedCrossRefGoogle Scholar
  105. 105.
    Delamarre L, Couture R, Mellman I, Trombetta ES. Enhancing immunogenicity by limiting susceptibility to lysosomal proteolysis. J Exp Med. 2006;203:2049–55.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Mantegazza AR, Zajac AL, Twelvetrees A, Holzbaur EL, Amigorena S, Marks MS. TLR-dependent phagosome tubulation in dendritic cells promotes phagosome cross-talk to optimize MHC-II antigen presentation. Proc Natl Acad Sci U S A. 2014;111:15508–13.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Lominadze G, Powell DW, Luerman GC, Link AJ, Ward RA, McLeish KR. Proteomic analysis of human neutrophil granules. Mol Cell Proteomics. 2005;4:1503–21.PubMedCrossRefGoogle Scholar
  108. 108.
    Jankowski A, Scott CC, Grinstein S. Determinants of the phagosomal pH in neutrophils. J Biol Chem. 2002;277:6059–66.PubMedCrossRefGoogle Scholar
  109. 109.
    Morgan D, Capasso M, Musset B, Cherny VV, Rios E, Dyer MJ, et al. Voltage-gated proton channels maintain pH in human neutrophils during phagocytosis. Proc Natl Acad Sci U S A. 2009;106:18022–7.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Capasso M, DeCoursey TE, Dyer MJ. pH regulation and beyond: unanticipated functions for the voltage-gated proton channel, HVCN1. Trends Cell Biol. 2011;21:20–8.PubMedCrossRefPubMedCentralGoogle Scholar
  111. 111.
    Ramsey IS, Ruchti E, Kaczmarek JS, Clapham DE. Hv1 proton channels are required for high-level NADPH oxidase-dependent superoxide production during the phagocyte respiratory burst. Proc Natl Acad Sci U S A. 2009;106:7642–7.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Segal AW, Geisow M, Garcia R, Harper A, Miller R. The respiratory burst of phagocytic cells is associated with a rise in vacuolar pH. Nature. 1981;290:406–9.PubMedCrossRefPubMedCentralGoogle Scholar
  113. 113.
    Nunes P, Demaurex N, Dinauer MC. Regulation of the NADPH oxidase and associated ion fluxes during phagocytosis. Traffic. 2013;14:1118–31.PubMedPubMedCentralGoogle Scholar
  114. 114.
    Babior BM. NADPH oxidase: an update. Blood. 1999;93:1464–76.PubMedPubMedCentralGoogle Scholar
  115. 115.
    Wang G, Nauseef WM. Salt, chloride, bleach, and innate host defense. J Leukoc Biol. 2015;98:163–72.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Klebanoff SJ, Kettle AJ, Rosen H, Winterbourn CC, Nauseef WM. Myeloperoxidase: a front-line defender against phagocytosed microorganisms. J Leukoc Biol. 2013;93:185–98.PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Eiserich JP, Hristova M, Cross CE, Jones AD, Freeman BA, Halliwell B, et al. Formation of nitric oxide-derived inflammatory oxidants by myeloperoxidase in neutrophils. Nature. 1998;391:393–7.PubMedCrossRefPubMedCentralGoogle Scholar
  118. 118.
    Sbarra AJ, Karnovsky ML. The biochemical basis of phagocytosis. I. Metabolic changes during the ingestion of particles by polymorphonuclear leukocytes. J Biol Chem. 1959;234:1355–62.PubMedPubMedCentralGoogle Scholar
  119. 119.
    Baehner RL, Karnovsky ML. Deficiency of reduced nicotinamide-adenine dinucleotide oxidase in chronic granulomatous disease. Science. 1968;162:1277–9.PubMedCrossRefPubMedCentralGoogle Scholar
  120. 120.
    MacMicking J, Xie QW, Nathan C. Nitric oxide and macrophage function. Annu Rev Immunol. 1997;15:323–50.PubMedCrossRefPubMedCentralGoogle Scholar
  121. 121.
    Stuehr DJ. Mammalian nitric oxide synthases. Biochim Biophys Acta. 1999;1411:217–30.PubMedCrossRefGoogle Scholar
  122. 122.
    Schapiro JM, Libby SJ, Fang FC. Inhibition of bacterial DNA replication by zinc mobilization during nitrosative stress. Proc Natl Acad Sci U S A. 2003;100:8496–501.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Bogdan C. Nitric oxide synthase in innate and adaptive immunity: an update. Trends Immunol. 2015;36:161–78.PubMedCrossRefPubMedCentralGoogle Scholar
  124. 124.
    Henard CA, Vazquez-Torres A. Nitric oxide and salmonella pathogenesis. Front Microbiol. 2011;2:84.PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Ganz T, Selsted ME, Szklarek D, Harwig SS, Daher K, Bainton DF, et al. Defensins. Natural peptide antibiotics of human neutrophils. J Clin Invest. 1985;76:1427–35.PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Selsted ME, Harwig SS, Ganz T, Schilling JW, Lehrer RI. Primary structures of three human neutrophil defensins. J Clin Invest. 1985;76:1436–9.PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Ganz T. Extracellular release of antimicrobial defensins by human polymorphonuclear leukocytes. Infect Immun. 1987;55:568–71.PubMedPubMedCentralGoogle Scholar
  128. 128.
    Elsbach P, Weiss J, Franson RC, Beckerdite-Quagliata S, Schneider A, Harris L. Separation and purification of a potent bactericidal/permeability-increasing protein and a closely associated phospholipase A2 from rabbit polymorphonuclear leukocytes. Observations on their relationship. J Biol Chem. 1979;254:11000–9.PubMedGoogle Scholar
  129. 129.
    Egesten A, Breton-Gorius J, Guichard J, Gullberg U, Olsson I. The heterogeneity of azurophil granules in neutrophil promyelocytes: immunogold localization of myeloperoxidase, cathepsin G, elastase, proteinase 3, and bactericidal/permeability increasing protein. Blood. 1994;83:2985–94.PubMedGoogle Scholar
  130. 130.
    Lehrer RI, Ganz T. Cathelicidins: a family of endogenous antimicrobial peptides. Curr Opin Hematol. 2002;9:18–22.PubMedCrossRefPubMedCentralGoogle Scholar
  131. 131.
    Lehrer RI, Lu W. Alpha-Defensins in human innate immunity. Immunol Rev. 2012;245:84–112.PubMedCrossRefPubMedCentralGoogle Scholar
  132. 132.
    Lehrer RI, Barton A, Daher KA, Harwig SS, Ganz T, Selsted ME. Interaction of human defensins with Escherichia coli. Mechanism of bactericidal activity. J Clin Invest. 1989;84:553–61.PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Levy O. A neutrophil-derived anti-infective molecule: bactericidal/permeability-increasing protein. Antimicrob Agents Chemother. 2000;44:2925–31.PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Krasity BC, Troll JV, Weiss JP, McFall-Ngai MJ. LBP/BPI proteins and their relatives: conservation over evolution and roles in mutualism. Biochem Soc Trans. 2011;39:1039–44.PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Balakrishnan A, Marathe SA, Joglekar M, Chakravortty D. Bactericidal/permeability increasing protein: a multifaceted protein with functions beyond LPS neutralization. Innate Immun. 2013;19:339–47.PubMedCrossRefGoogle Scholar
  136. 136.
    Belaaouaj A, Kim KS, Shapiro SD. Degradation of outer membrane protein A in Escherichia coli killing by neutrophil elastase. Science. 2000;289:1185–8.PubMedCrossRefPubMedCentralGoogle Scholar
  137. 137.
    Reeves EP, Lu H, Jacobs HL, Messina CG, Bolsover S, Gabella G, et al. Killing activity of neutrophils is mediated through activation of proteases by K+ flux. Nature. 2002;416:291–7.PubMedCrossRefGoogle Scholar
  138. 138.
    Campanelli D, Melchior M, Fu Y, Nakata M, Shuman H, Nathan C, et al. Cloning of cDNA for proteinase 3: a serine protease, antibiotic, and autoantigen from human neutrophils. J Exp Med. 1990;172:1709–15.PubMedCrossRefGoogle Scholar
  139. 139.
    Campanelli D, Detmers PA, Nathan CF, Gabay JE. Azurocidin and a homologous serine protease from neutrophils. Differential antimicrobial and proteolytic properties. J Clin Invest. 1990;85:904–15.PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Morgan JG, Sukiennicki T, Pereira HA, Spitznagel JK, Guerra ME, Larrick JW. Cloning of the cDNA for the serine protease homolog CAP37/azurocidin, a microbicidal and chemotactic protein from human granulocytes. J Immunol. 1991;147:3210–4.PubMedGoogle Scholar
  141. 141.
    Hahn I, Klaus A, Janze AK, Steinwede K, Ding N, Bohling J, et al. Cathepsin G and neutrophil elastase play critical and nonredundant roles in lung-protective immunity against Streptococcus pneumoniae in mice. Infect Immun. 2011;79:4893–901.PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Tkalcevic J, Novelli M, Phylactides M, Iredale JP, Segal AW, Roes J. Impaired immunity and enhanced resistance to endotoxin in the absence of neutrophil elastase and cathepsin G. Immunity. 2000;12:201–10.PubMedCrossRefPubMedCentralGoogle Scholar
  143. 143.
    Kolset SO, Tveit H. Serglycin––structure and biology. Cell Mol Life Sci. 2008;65:1073–85.PubMedCrossRefPubMedCentralGoogle Scholar
  144. 144.
    Niemann CU, Cowland JB, Klausen P, Askaa J, Calafat J, Borregaard N. Localization of serglycin in human neutrophil granulocytes and their precursors. J Leukoc Biol. 2004;76:406–15.PubMedCrossRefPubMedCentralGoogle Scholar
  145. 145.
    Pham CT. Neutrophil serine proteases: specific regulators of inflammation. Nat Rev Immunol. 2006;6:541–50.PubMedCrossRefPubMedCentralGoogle Scholar
  146. 146.
    Belaaouaj A, McCarthy R, Baumann M, Gao Z, Ley TJ, Abraham SN, et al. Mice lacking neutrophil elastase reveal impaired host defense against gram negative bacterial sepsis. Nat Med. 1998;4:615–8.PubMedCrossRefPubMedCentralGoogle Scholar
  147. 147.
    Scocchi M, Skerlavaj B, Romeo D, Gennaro R. Proteolytic cleavage by neutrophil elastase converts inactive storage proforms to antibacterial bactenecins. Eur J Biochem. 1992;209:589–95.PubMedCrossRefPubMedCentralGoogle Scholar
  148. 148.
    Meyer-Hoffert U. Neutrophil-derived serine proteases modulate innate immune responses. Front Biosci (Landmark Ed). 2009;14:3409–18.CrossRefGoogle Scholar
  149. 149.
    Tongaonkar P, Golji AE, Tran P, Ouellette AJ, Selsted ME. High fidelity processing and activation of the human alpha-defensin HNP1 precursor by neutrophil elastase and proteinase 3. PLoS One. 2012;7:e32469.PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    Sorensen OE, Follin P, Johnsen AH, Calafat J, Tjabringa GS, Hiemstra PS, et al. Human cathelicidin, hCAP-18, is processed to the antimicrobial peptide LL-37 by extracellular cleavage with proteinase 3. Blood. 2001;97:3951–9.PubMedCrossRefPubMedCentralGoogle Scholar
  151. 151.
    Meyer-Hoffert U, Wiedow O. Neutrophil serine proteases: mediators of innate immune responses. Curr Opin Hematol. 2011;18:19–24.PubMedCrossRefPubMedCentralGoogle Scholar
  152. 152.
    Bangalore N, Travis J, Onunka VC, Pohl J, Shafer WM. Identification of the primary antimicrobial domains in human neutrophil cathepsin G. J Biol Chem. 1990;265:13584–8.PubMedPubMedCentralGoogle Scholar
  153. 153.
    Shafer WM, Martin LE, Spitznagel JK. Cationic antimicrobial proteins isolated from human neutrophil granulocytes in the presence of diisopropyl fluorophosphate. Infect Immun. 1984;45:29–35.PubMedPubMedCentralGoogle Scholar
  154. 154.
    Shafer WM, Onunka VC, Martin LE. Antigonococcal activity of human neutrophil cathepsin G. Infect Immun. 1986;54:184–8.PubMedPubMedCentralGoogle Scholar
  155. 155.
    Zeya HI, Spitznagel JK. Cationic proteins of polymorphonuclear leukocyte lysosomes. II. Composition, properties, and mechanism of antibacterial action. J Bacteriol. 1966;91:755–62.PubMedPubMedCentralGoogle Scholar
  156. 156.
    Kao RC, Wehner NG, Skubitz KM, Gray BH, Hoidal JR. Proteinase 3. A distinct human polymorphonuclear leukocyte proteinase that produces emphysema in hamsters. J Clin Invest. 1988;82:1963–73.PubMedPubMedCentralCrossRefGoogle Scholar
  157. 157.
    Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, et al. Neutrophil extracellular traps kill bacteria. Science. 2004;303:1532–5.PubMedCrossRefPubMedCentralGoogle Scholar
  158. 158.
    von Kockritz-Blickwede M, Goldmann O, Thulin P, Heinemann K, Norrby-Teglund A, Rohde M, et al. Phagocytosis-independent antimicrobial activity of mast cells by means of extracellular trap formation. Blood. 2008;111:3070–80.CrossRefGoogle Scholar
  159. 159.
    Chow OA, von Kockritz-Blickwede M, Bright AT, Hensler ME, Zinkernagel AS, Cogen AL, et al. Statins enhance formation of phagocyte extracellular traps. Cell Host Microbe. 2010;8:445–54.PubMedPubMedCentralCrossRefGoogle Scholar
  160. 160.
    Boe DM, Curtis BJ, Chen MM, Ippolito JA, Kovacs EJ. Extracellular traps and macrophages: new roles for the versatile phagocyte. J Leukoc Biol. 2015;97:1023–35.PubMedPubMedCentralCrossRefGoogle Scholar
  161. 161.
    Loures FV, Rohm M, Lee CK, Santos E, Wang JP, Specht CA, et al. Recognition of Aspergillus fumigatus hyphae by human plasmacytoid dendritic cells is mediated by dectin-2 and results in formation of extracellular traps. PLoS Pathog. 2015;11:e1004643.PubMedPubMedCentralCrossRefGoogle Scholar
  162. 162.
    Yousefi S, Morshed M, Amini P, Stojkov D, Simon D, von Gunten S, et al. Basophils exhibit antibacterial activity through extracellular trap formation. Allergy. 2015;70:1184–8.PubMedCrossRefPubMedCentralGoogle Scholar
  163. 163.
    Morshed M, Hlushchuk R, Simon D, Walls AF, Obata-Ninomiya K, Karasuyama H, et al. NADPH oxidase-independent formation of extracellular DNA traps by basophils. J Immunol. 2014;192:5314–23.PubMedCrossRefPubMedCentralGoogle Scholar
  164. 164.
    Clark SR, Ma AC, Tavener SA, McDonald B, Goodarzi Z, Kelly MM, et al. Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat Med. 2007;13:463–9.PubMedCrossRefGoogle Scholar
  165. 165.
    Kaplan MJ, Radic M. Neutrophil extracellular traps: double-edged swords of innate immunity. J Immunol. 2012;189:2689–95.PubMedPubMedCentralCrossRefGoogle Scholar
  166. 166.
    Menegazzi R, Decleva E, Dri P. Killing by neutrophil extracellular traps: fact or folklore? Blood. 2012;119:1214–6.PubMedCrossRefGoogle Scholar
  167. 167.
    Parker H, Albrett AM, Kettle AJ, Winterbourn CC. Myeloperoxidase associated with neutrophil extracellular traps is active and mediates bacterial killing in the presence of hydrogen peroxide. J Leukoc Biol. 2012;91:369–76.PubMedCrossRefGoogle Scholar
  168. 168.
    Scharrig E, Carestia A, Ferrer MF, Cedola M, Pretre G, Drut R, et al. Neutrophil extracellular traps are involved in the innate immune response to infection with Leptospira. PLoS Negl Trop Dis. 2015;9:e0003927.PubMedPubMedCentralCrossRefGoogle Scholar
  169. 169.
    de Jong HK, Koh GC, Achouiti A, van der Meer AJ, Bulder I, Stephan F, et al. Neutrophil extracellular traps in the host defense against sepsis induced by Burkholderia pseudomallei (melioidosis). Intensive Care Med Exp. 2014;2:21.PubMedPubMedCentralCrossRefGoogle Scholar
  170. 170.
    Mejia SP, Cano LE, Lopez JA, Hernandez O, Gonzalez A. Human neutrophils produce extracellular traps against Paracoccidioides brasiliensis. Microbiology. 2015;161:1008–17.PubMedCrossRefGoogle Scholar
  171. 171.
    Gunderson CW, Seifert HS. Neisseria gonorrhoeae elicits extracellular traps in primary neutrophil culture while suppressing the oxidative burst. MBio. 2015;6:e02452–14.PubMedPubMedCentralCrossRefGoogle Scholar
  172. 172.
    Juneau RA, Pang B, Armbruster CE, Murrah KA, Perez AC, Swords WE. Peroxiredoxin-glutaredoxin and catalase promote resistance of nontypeable Haemophilus influenzae 86-028NP to oxidants and survival within neutrophil extracellular traps. Infect Immun. 2015;83:239–46.PubMedCrossRefGoogle Scholar
  173. 173.
    Shan Q, Dwyer M, Rahman S, Gadjeva M. Distinct susceptibilities of corneal Pseudomonas aeruginosa clinical isolates to neutrophil extracellular trap-mediated immunity. Infect Immun. 2014;82:4135–43.PubMedPubMedCentralCrossRefGoogle Scholar
  174. 174.
    Dohrmann S, Anik S, Olson J, Anderson EL, Etesami N, No H, et al. Role for streptococcal collagen-like protein 1 in M1T1 group A Streptococcus resistance to neutrophil extracellular traps. Infect Immun. 2014;82:4011–20.PubMedPubMedCentralCrossRefGoogle Scholar
  175. 175.
    Bonne-Annee S, Kerepesi LA, Hess JA, Wesolowski J, Paumet F, Lok JB, et al. Extracellular traps are associated with human and mouse neutrophil and macrophage mediated killing of larval Strongyloides stercoralis. Microbes Infect. 2014;16:502–11.PubMedPubMedCentralCrossRefGoogle Scholar
  176. 176.
    Liu P, Wu X, Liao C, Liu X, Du J, Shi H, et al. Escherichia coli and Candida albicans induced macrophage extracellular trap-like structures with limited microbicidal activity. PLoS One. 2014;9:e90042.PubMedPubMedCentralCrossRefGoogle Scholar
  177. 177.
    Thammavongsa V, Missiakas DM, Schneewind O. Staphylococcus aureus degrades neutrophil extracellular traps to promote immune cell death. Science. 2013;342:863–6.PubMedPubMedCentralCrossRefGoogle Scholar
  178. 178.
    Short KR, von Kockritz-Blickwede M, Langereis JD, Chew KY, Job ER, Armitage CW, et al. Antibodies mediate formation of neutrophil extracellular traps in the middle ear and facilitate secondary pneumococcal otitis media. Infect Immun. 2014;82:364–70.PubMedPubMedCentralCrossRefGoogle Scholar
  179. 179.
    Seper A, Hosseinzadeh A, Gorkiewicz G, Lichtenegger S, Roier S, Leitner DR, et al. Vibrio cholerae evades neutrophil extracellular traps by the activity of two extracellular nucleases. PLoS Pathog. 2013;9:e1003614.PubMedPubMedCentralCrossRefGoogle Scholar
  180. 180.
    Derre-Bobillot A, Cortes-Perez NG, Yamamoto Y, Kharrat P, Couve E, Da Cunha V, et al. Nuclease A (Gbs0661), an extracellular nuclease of Streptococcus agalactiae, attacks the neutrophil extracellular traps and is needed for full virulence. Mol Microbiol. 2013;89:518–31.PubMedCrossRefGoogle Scholar
  181. 181.
    Lappann M, Danhof S, Guenther F, Olivares-Florez S, Mordhorst IL, Vogel U. In vitro resistance mechanisms of Neisseria meningitidis against neutrophil extracellular traps. Mol Microbiol. 2013;89:433–49.PubMedCrossRefGoogle Scholar
  182. 182.
    Menten-Dedoyart C, Faccinetto C, Golovchenko M, Dupiereux I, Van Lerberghe PB, Dubois S, et al. Neutrophil extracellular traps entrap and kill Borrelia burgdorferi sensu stricto spirochetes and are not affected by Ixodes ricinus tick saliva. J Immunol. 2012;189:5393–401.PubMedCrossRefGoogle Scholar
  183. 183.
    McDonald B, Urrutia R, Yipp BG, Jenne CN, Kubes P. Intravascular neutrophil extracellular traps capture bacteria from the bloodstream during sepsis. Cell Host Microbe. 2012;12:324–33.PubMedCrossRefGoogle Scholar
  184. 184.
    Riyapa D, Buddhisa S, Korbsrisate S, Cuccui J, Wren BW, Stevens MP, et al. Neutrophil extracellular traps exhibit antibacterial activity against burkholderia pseudomallei and are influenced by bacterial and host factors. Infect Immun. 2012;80:3921–9.PubMedPubMedCentralCrossRefGoogle Scholar
  185. 185.
    Young RL, Malcolm KC, Kret JE, Caceres SM, Poch KR, Nichols DP, et al. Neutrophil extracellular trap (NET)-mediated killing of Pseudomonas aeruginosa: evidence of acquired resistance within the CF airway, independent of CFTR. PLoS One. 2011;6:e23637.PubMedPubMedCentralCrossRefGoogle Scholar
  186. 186.
    Abel J, Goldmann O, Ziegler C, Holtje C, Smeltzer MS, Cheung AL, et al. Staphylococcus aureus evades the extracellular antimicrobial activity of mast cells by promoting its own uptake. J Innate Immun. 2011;3:495–507.PubMedCrossRefGoogle Scholar
  187. 187.
    Berends ET, Horswill AR, Haste NM, Monestier M, Nizet V, von Kockritz-Blickwede M. Nuclease expression by Staphylococcus aureus facilitates escape from neutrophil extracellular traps. J Innate Immun. 2010;2:576–86.PubMedPubMedCentralCrossRefGoogle Scholar
  188. 188.
    Urban CF, Reichard U, Brinkmann V, Zychlinsky A. Neutrophil extracellular traps capture and kill Candida albicans yeast and hyphal forms. Cell Microbiol. 2006;8:668–76.PubMedCrossRefGoogle Scholar
  189. 189.
    Buchanan JT, Simpson AJ, Aziz RK, Liu GY, Kristian SA, Kotb M, et al. DNase expression allows the pathogen group A Streptococcus to escape killing in neutrophil extracellular traps. Curr Biol. 2006;16:396–400.PubMedCrossRefGoogle Scholar
  190. 190.
    Sumby P, Barbian KD, Gardner DJ, Whitney AR, Welty DM, Long RD, et al. Extracellular deoxyribonuclease made by group A Streptococcus assists pathogenesis by enhancing evasion of the innate immune response. Proc Natl Acad Sci U S A. 2005;102:1679–84.PubMedPubMedCentralCrossRefGoogle Scholar
  191. 191.
    Lee MJ, Liu H, Barker BM, Snarr BD, Gravelat FN, Al Abdallah Q, et al. The fungal exopolysaccharide galactosaminogalactan mediates virulence by enhancing resistance to neutrophil extracellular traps. PLoS Pathog. 2015;11:e1005187.PubMedPubMedCentralCrossRefGoogle Scholar
  192. 192.
    Branzk N, Lubojemska A, Hardison SE, Wang Q, Gutierrez MG, Brown GD, et al. Neutrophils sense microbe size and selectively release neutrophil extracellular traps in response to large pathogens. Nat Immunol. 2014;15:1017–25.PubMedPubMedCentralCrossRefGoogle Scholar
  193. 193.
    Fuchs TA, Abed U, Goosmann C, Hurwitz R, Schulze I, Wahn V, et al. Novel cell death program leads to neutrophil extracellular traps. J Cell Biol. 2007;176:231–41.PubMedPubMedCentralCrossRefGoogle Scholar
  194. 194.
    Papayannopoulos V, Metzler KD, Hakkim A, Zychlinsky A. Neutrophil elastase and myeloperoxidase regulate the formation of neutrophil extracellular traps. J Cell Biol. 2010;191:677–91.PubMedPubMedCentralCrossRefGoogle Scholar
  195. 195.
    Neumann A, Berends ET, Nerlich A, Molhoek EM, Gallo RL, Meerloo T, et al. The antimicrobial peptide LL-37 facilitates the formation of neutrophil extracellular traps. Biochem J. 2014;464:3–11.PubMedCrossRefGoogle Scholar
  196. 196.
    Wang Y, Li M, Stadler S, Correll S, Li P, Wang D, et al. Histone hypercitrullination mediates chromatin decondensation and neutrophil extracellular trap formation. J Cell Biol. 2009;184:205–13.PubMedPubMedCentralCrossRefGoogle Scholar
  197. 197.
    Li P, Li M, Lindberg MR, Kennett MJ, Xiong N, Wang Y. PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps. J Exp Med. 2010;207:1853–62.PubMedPubMedCentralCrossRefGoogle Scholar
  198. 198.
    Yousefi S, Mihalache C, Kozlowski E, Schmid I, Simon HU. Viable neutrophils release mitochondrial DNA to form neutrophil extracellular traps. Cell Death Differ. 2009;16:1438–44.PubMedCrossRefGoogle Scholar
  199. 199.
    Pilsczek FH, Salina D, Poon KK, Fahey C, Yipp BG, Sibley CD, et al. A novel mechanism of rapid nuclear neutrophil extracellular trap formation in response to Staphylococcus aureus. J Immunol. 2010;185:7413–25.PubMedCrossRefGoogle Scholar
  200. 200.
    Malachowa N, Kobayashi SD, Freedman B, Dorward DW, DeLeo FR. Staphylococcus aureus leukotoxin GH promotes formation of neutrophil extracellular traps. J Immunol. 2013;191:6022–9.PubMedPubMedCentralCrossRefGoogle Scholar
  201. 201.
    Behnen M, Leschczyk C, Moller S, Batel T, Klinger M, Solbach W, et al. Immobilized immune complexes induce neutrophil extracellular trap release by human neutrophil granulocytes via FcgammaRIIIB and Mac-1. J Immunol. 2014;193:1954–65.PubMedCrossRefGoogle Scholar
  202. 202.
    Lu T, Kobayashi SD, Quinn MT, Deleo FR. A NET Outcome. Front Immunol. 2012;3:365.PubMedPubMedCentralCrossRefGoogle Scholar
  203. 203.
    Simon D, Simon HU, Yousefi S. Extracellular DNA traps in allergic, infectious, and autoimmune diseases. Allergy. 2013;68:409–16.PubMedCrossRefGoogle Scholar
  204. 204.
    Darrah E, Andrade F. NETs: the missing link between cell death and systemic autoimmune diseases? Front Immunol. 2012;3:428.PubMedGoogle Scholar
  205. 205.
    Cortjens B, de Boer OJ, de Jong R, Antonis AF, Sabogal Pineros YS, Lutter R, et al. Neutrophil extracellular traps cause airway obstruction during respiratory syncytial virus disease. J Pathol. 2016;238:401–411.PubMedCrossRefGoogle Scholar
  206. 206.
    Grabcanovic-Musija F, Obermayer A, Stoiber W, Krautgar`tner WD, Steinbacher P, Winterberg N, et al. Neutrophil extracellular trap (NET) formation characterises stable and exacerbated COPD and correlates with airflow limitation. Respir Res. 2015;16:59.PubMedPubMedCentralCrossRefGoogle Scholar
  207. 207.
    Obermayer A, Stoiber W, Krautgartner WD, Klappacher M, Kofler B, Steinbacher P, et al. New aspects on the structure of neutrophil extracellular traps from chronic obstructive pulmonary disease and in vitro generation. PLoS One. 2014;9:e97784.PubMedPubMedCentralCrossRefGoogle Scholar
  208. 208.
    Marcos V, Zhou Z, Yildirim AO, Bohla A, Hector A, Vitkov L, et al. CXCR2 mediates NADPH oxidase-independent neutrophil extracellular trap formation in cystic fibrosis airway inflammation. Nat Med. 2010;16:1018–23.PubMedCrossRefGoogle Scholar
  209. 209.
    Zenaro E, Pietronigro E, Della Bianca V, Piacentino G, Marongiu L, Budui S, et al. Neutrophils promote Alzheimer's disease-like pathology and cognitive decline via LFA-1 integrin. Nat Med. 2015;21:880–6.PubMedCrossRefGoogle Scholar
  210. 210.
    Warnatsch A, Ioannou M, Wang Q, Papayannopoulos V. Inflammation. Neutrophil extracellular traps license macrophages for cytokine production in atherosclerosis. Science. 2015;349:316–20.PubMedPubMedCentralCrossRefGoogle Scholar
  211. 211.
    Spengler J, Lugonja B, Jimmy Ytterberg A, Zubarev RA, Creese AJ, Pearson MJ, et al. Release of active peptidyl arginine deiminases by neutrophils can explain production of extracellular citrullinated autoantigens in rheumatoid arthritis synovial fluid. Arthritis Rheumatol. 2015;67:3135–45.PubMedPubMedCentralCrossRefGoogle Scholar
  212. 212.
    Wright HL, Moots RJ, Edwards SW. The multifactorial role of neutrophils in rheumatoid arthritis. Nat Rev Rheumatol. 2014;10:593–601.PubMedCrossRefGoogle Scholar
  213. 213.
    Cools-Lartigue J, Spicer J, Najmeh S, Ferri L. Neutrophil extracellular traps in cancer progression. Cell Mol Life Sci. 2014;71:4179–94.PubMedCrossRefGoogle Scholar
  214. 214.
    Cools-Lartigue J, Spicer J, McDonald B, Gowing S, Chow S, Giannias B, et al. Neutrophil extracellular traps sequester circulating tumor cells and promote metastasis. J Clin Invest. 2013;123:3446–3458PubMedCentralCrossRefPubMedGoogle Scholar
  215. 215.
    Chen G, Zhang D, Fuchs TA, Manwani D, Wagner DD, Frenette PS. Heme-induced neutrophil extracellular traps contribute to the pathogenesis of sickle cell disease. Blood. 2014;123:3818–27.PubMedPubMedCentralCrossRefGoogle Scholar
  216. 216.
    Martinod K, Wagner DD. Thrombosis: tangled up in NETs. Blood. 2014;123:2768–76.PubMedPubMedCentralCrossRefGoogle Scholar
  217. 217.
    Demers M, Krause DS, Schatzberg D, Martinod K, Voorhees JR, Fuchs TA, et al. Cancers predispose neutrophils to release extracellular DNA traps that contribute to cancer-associated thrombosis. Proc Natl Acad Sci U S A. 2012;109:13076–81.PubMedPubMedCentralCrossRefGoogle Scholar
  218. 218.
    Fuchs TA, Brill A, Duerschmied D, Schatzberg D, Monestier M, Myers DD Jr, et al. Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci U S A. 2010;107:15880–5.PubMedPubMedCentralCrossRefGoogle Scholar
  219. 219.
    Dorner T. SLE in 2011: deciphering the role of NETs and networks in SLE. Nat Rev Rheumatol. 2012;8:68–70.PubMedCrossRefGoogle Scholar
  220. 220.
    Lande R, Ganguly D, Facchinetti V, Frasca L, Conrad C, Gregorio J, et al. Neutrophils activate plasmacytoid dendritic cells by releasing self-DNA-peptide complexes in systemic lupus erythematosus. Sci Transl Med. 2011;3:73ra19.PubMedPubMedCentralCrossRefGoogle Scholar
  221. 221.
    Garcia-Romo GS, Caielli S, Vega B, Connolly J, Allantaz F, Xu Z, et al. Netting neutrophils are major inducers of type I IFN production in pediatric systemic lupus erythematosus. Sci Transl Med. 2011;3:73ra20.PubMedPubMedCentralCrossRefGoogle Scholar
  222. 222.
    Hakkim A, Furnrohr BG, Amann K, Laube B, Abed UA, Brinkmann V, et al. Impairment of neutrophil extracellular trap degradation is associated with lupus nephritis. Proc Natl Acad Sci U S A. 2010;107:9813–8.PubMedPubMedCentralCrossRefGoogle Scholar
  223. 223.
    Kambayashi T, Laufer TM. Atypical MHC class II-expressing antigen-presenting cells: can anything replace a dendritic cell? Nat Rev Immunol. 2014;14:719–30.PubMedCrossRefGoogle Scholar
  224. 224.
    Guermonprez P, Valladeau J, Zitvogel L, Thery C, Amigorena S. Antigen presentation and T cell stimulation by dendritic cells. Annu Rev Immunol. 2002;20:621–67.PubMedCrossRefGoogle Scholar
  225. 225.
    Iwasaki A, Medzhitov R. Control of adaptive immunity by the innate immune system. Nat Immunol. 2015;16:343–53.PubMedPubMedCentralCrossRefGoogle Scholar
  226. 226.
    Kapsenberg ML. Dendritic-cell control of pathogen-driven T-cell polarization. Nat Rev Immunol. 2003;3:984–93.PubMedCrossRefGoogle Scholar
  227. 227.
    Blum JS, Wearsch PA, Cresswell P. Pathways of antigen processing. Annu Rev Immunol. 2013;31:443–73.PubMedPubMedCentralCrossRefGoogle Scholar
  228. 228.
    Roche PA, Furuta K. The ins and outs of MHC class II-mediated antigen processing and presentation. Nat Rev Immunol. 2015;15:203–16.PubMedCrossRefGoogle Scholar
  229. 229.
    Savina A, Amigorena S. Phagocytosis and antigen presentation in dendritic cells. Immunol Rev. 2007;219:143–56.PubMedCrossRefGoogle Scholar
  230. 230.
    Neefjes J, Jongsma ML, Paul P, Bakke O. Towards a systems understanding of MHC class I and MHC class II antigen presentation. Nat Rev Immunol. 2011;11:823–36.PubMedCrossRefPubMedCentralGoogle Scholar
  231. 231.
    Jensen PE. Recent advances in antigen processing and presentation. Nat Immunol. 2007;8:1041–8.PubMedCrossRefPubMedCentralGoogle Scholar
  232. 232.
    Joffre OP, Segura E, Savina A, Amigorena S. Cross-presentation by dendritic cells. Nat Rev Immunol. 2012;12:557–69.PubMedCrossRefPubMedCentralGoogle Scholar
  233. 233.
    Jutras I, Desjardins M. Phagocytosis: at the crossroads of innate and adaptive immunity. Annu Rev Cell Dev Biol. 2005;21:511–27.PubMedCrossRefPubMedCentralGoogle Scholar
  234. 234.
    Vyas JM, Van der Veen AG, Ploegh HL. The known unknowns of antigen processing and presentation. Nat Rev Immunol. 2008;8:607–18.PubMedPubMedCentralCrossRefGoogle Scholar
  235. 235.
    Lopez-Bravo M, Ardavin C. In vivo induction of immune responses to pathogens by conventional dendritic cells. Immunity. 2008;29:343–51.PubMedCrossRefPubMedCentralGoogle Scholar
  236. 236.
    Alvarez D, Vollmann EH, von Andrian UH. Mechanisms and consequences of dendritic cell migration. Immunity. 2008;29:325–42.PubMedPubMedCentralCrossRefGoogle Scholar
  237. 237.
    Randolph GJ, Angeli V, Swartz MA. Dendritic-cell trafficking to lymph nodes through lymphatic vessels. Nat Rev Immunol. 2005;5:617–28.PubMedCrossRefPubMedCentralGoogle Scholar
  238. 238.
    Chen L, Flies DB. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol. 2013;13:227–42.PubMedPubMedCentralCrossRefGoogle Scholar
  239. 239.
    Sims R, van der Lee SJ, Naj AC, Bellenguez C, Badarinarayan N, Jakobsdottir J, et al. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer’s disease. Nat Genet. 2017;49:1373–84.PubMedPubMedCentralCrossRefGoogle Scholar
  240. 240.
    Neu KE, Tang Q, Wilson PC, Khan AA. Single-cell genomics: approaches and utility in immunology. Trends Immunol. 2017;38:140–9.PubMedPubMedCentralCrossRefGoogle Scholar
  241. 241.
    Zhou F, Li X, Wang W, Zhu P, Zhou J, He W, et al. Tracing haematopoietic stem cell formation at single-cell resolution. Nature. 2016;533:487–92.PubMedCrossRefPubMedCentralGoogle Scholar
  242. 242.
    Gierahn TM, Wadsworth MH 2nd, Hughes TK, Bryson BD, Butler A, Satija R, et al. Seq-well: portable, low-cost RNA sequencing of single cells at high throughput. Nat Methods. 2017;14:395–8.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Tyler Nygaard
    • 1
  • Natalia Malachowa
    • 1
  • Scott D. Kobayashi
    • 1
  • Frank R. DeLeo
    • 1
    Email author
  1. 1.Laboratory of Bacteriology, Rocky Mountain LaboratoriesNational Institute of Allergy and Infectious Diseases, National Institutes of HealthHamiltonUSA

Personalised recommendations

Cite chapter

Buy options