Physiological and Pathological Role of Reactive Oxygen Species in the Immune Cells

  • Aleksandra M. Urbanska
  • Valerio Zolla
  • Paolo Verzani
  • Laura SantambrogioEmail author


Production of reactive oxygen, chlorine, and nitrogen species is a pivotal and effective mechanism utilized by different immune cells to respond to invading pathogens. During the last decades the molecular pathways involved in the production of reactive species and their intersection with the cellular molecular sensors (nicotinamide adenine dinucleotide phosphate-oxidase, inflammasomes, Toll-like receptor) have been elucidated. At the same time, it has also been recognized that excessive or chronic production of reactive species, as occurred in chronic inflammatory, degenerative, and autoimmune diseases, is detrimental to the immune system. This integrated view of both the physiological and pathological role of reactive species in maintaining the cellular redox balance is coming to light.


Reactive Oxygen Species Reactive Oxygen Species Production NADPH Oxidase Reactive Species Chronic Granulomatous Disease 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Anders MW, Robotham JL, Sheu SS (2006) Mitochondria: new drug targets for oxidative stress-induced diseases. Expert Opin Drug Metab Toxicol 2(1):71–79PubMedCrossRefGoogle Scholar
  2. Bai J, Cederbaum AI (2001) Mitochondrial catalase and oxidative injury. Biol Signals Recept 10(3–4):189–199PubMedCrossRefGoogle Scholar
  3. Balce DR, Li B, Allan ER et al (2011) Alternative activation of macrophages by IL-4 enhances the proteolytic capacity of their phagosomes through synergistic mechanisms. Blood 118(15):4199–4208PubMedCrossRefGoogle Scholar
  4. Banchereau J, Steinman RM (1998) Dendritic cells and the control of immunity. Nature 392(6673):245–252PubMedCrossRefGoogle Scholar
  5. Bargagli R (2000) Trace metals in Antarctica related to climate change and increasing human impact. Rev Environ Contam Toxicol 166:129–173PubMedGoogle Scholar
  6. Bedard K, Krause KH (2007) The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev 87(1):245–313PubMedCrossRefGoogle Scholar
  7. Bianco AC, Salvatore D, Gereben B et al (2002) Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases. Endocr Rev 23(1):38–89PubMedCrossRefGoogle Scholar
  8. Blanchard C, Rothenberg ME (2009) Biology of the eosinophil. Adv Immunol 101:81–121PubMedGoogle Scholar
  9. Bouayed J, Bohn T (2010) Exogenous antioxidants – double-edged swords in cellular redox state: health beneficial effects at physiologic doses versus deleterious effects at high doses. Oxid Med Cell Longev 3(4):228–237PubMedCrossRefGoogle Scholar
  10. Brown MS, Goldstein JL (1983) Lipoprotein metabolism in the macrophage: implications for cholesterol deposition in atherosclerosis. Annu Rev Biochem 52:223–261PubMedCrossRefGoogle Scholar
  11. Cathcart MK (2004) Regulation of superoxide anion production by NADPH oxidase in monocytes/macrophages: contributions to atherosclerosis. Arterioscler Thromb Vasc Biol 24(1):23–28PubMedCrossRefGoogle Scholar
  12. Chan RC, Wang M, Li N et al (2006) Pro-oxidative diesel exhaust particle chemicals inhibit LPS-induced dendritic cell responses involved in T-helper differentiation. J Allergy Clin Immunol 118(2):455–465PubMedCrossRefGoogle Scholar
  13. Chance B (1961) The interaction of energy and electron transfer reactions in mitochondria. V. The energy transfer pathway. J Biol Chem 236:1569–1576PubMedGoogle Scholar
  14. Chance B, Sies H, Boveris A (1979) Hydroperoxide metabolism in mammalian organs. Physiol Rev 59(3):527–605PubMedGoogle Scholar
  15. Chen GY, Nunez G (2010) Sterile inflammation: sensing and reacting to damage. Nat Rev Immunol 10(12):826–837PubMedCrossRefGoogle Scholar
  16. Ciz M, Denev P, Kratchanova M et al (2012) Flavonoids inhibit the respiratory burst of neutrophils in mammals. Oxid Med Cell Longev 2012:181295PubMedCrossRefGoogle Scholar
  17. Czech MP, Lawrence JC Jr, Lynn WS (1974) Evidence for the involvement of sulfhydryl oxidation in the regulation of fat cell hexose transport by insulin. Proc Natl Acad Sci U S A 71(10):4173–4177PubMedCrossRefGoogle Scholar
  18. Dang PM, Dewas C, Gaudry M et al (1999) Priming of human neutrophil respiratory burst by granulocyte/macrophage colony-stimulating factor (GM-CSF) involves partial phosphorylation of p47(phox). J Biol Chem 274(29):20704–20708PubMedCrossRefGoogle Scholar
  19. Droge W (2002) Free radicals in the physiological control of cell function. Physiol Rev 82(1):47–95PubMedGoogle Scholar
  20. Dunne DW, Resnick D, Greenberg J et al (1994) The type I macrophage scavenger receptor binds to gram-positive bacteria and recognizes lipoteichoic acid. Proc Natl Acad Sci U S A 91(5):1863–1867PubMedCrossRefGoogle Scholar
  21. El Benna J, Hayem G, Dang PM et al (2002) NADPH oxidase priming and p47phox phosphorylation in neutrophils from synovial fluid of patients with rheumatoid arthritis and spondylarthropathy. Inflammation 26(6):273–278PubMedCrossRefGoogle Scholar
  22. Elbim C, Bailly S, Chollet-Martin S et al (1994) Differential priming effects of proinflammatory cytokines on human neutrophil oxidative burst in response to bacterial N-formyl peptides. Infect Immun 62(6):2195–2201PubMedGoogle Scholar
  23. El-Sonbaty SM, El-Hadedy DE (2012) Combined effect of cadmium, lead, and UV rays on Bacillus cereus using comet assay and oxidative stress parameters. Environ Sci Pollut Res Int. EpubGoogle Scholar
  24. Erlemann KR, Rokach J, Powell WS (2004) Oxidative stress stimulates the synthesis of the eosinophil chemoattractant 5-oxo-6,8,11,14-eicosatetraenoic acid by inflammatory cells. J Biol Chem 279(39):40376–40384PubMedCrossRefGoogle Scholar
  25. Fabriek BO, van Bruggen R, Deng DM et al (2009) The macrophage scavenger receptor CD163 functions as an innate immune sensor for bacteria. Blood 113(4):887–892PubMedCrossRefGoogle Scholar
  26. Fariss MW, Chan CB, Patel M et al (2005) Role of mitochondria in toxic oxidative stress. Mol Interv 5(2):94–111PubMedCrossRefGoogle Scholar
  27. Fisher AB (2009) Redox signaling across cell membranes. Antioxid Redox Signal 11(6):1349–1356PubMedCrossRefGoogle Scholar
  28. Gougerot-Pocidalo MA, el Benna J, Elbim C et al (2002) Regulation of human neutrophil oxidative burst by pro- and anti-inflammatory cytokines. J Soc Biol 196(1):37–46PubMedGoogle Scholar
  29. Grant GE, Rokach J, Powell WS (2009) 5-Oxo-ETE and the OXE receptor. Prostaglandins Other Lipid Mediat 89(3–4):98–104PubMedCrossRefGoogle Scholar
  30. Grant GE, Rubino S, Gravel S et al (2011) Enhanced formation of 5-oxo-6,8,11,14-eicosatetraenoic acid by cancer cells in response to oxidative stress, docosahexaenoic acid and neutrophil-derived 5-hydroxy-6,8,11,14-eicosatetraenoic acid. Carcinogenesis 32(6):822–828PubMedCrossRefGoogle Scholar
  31. Guzik TJ, Griendling KK (2009) NADPH oxidases: molecular understanding finally reaching the clinical level? Antioxid Redox Signal 11(10):2365–2370PubMedCrossRefGoogle Scholar
  32. Hazen SL, Hsu FF, Duffin K et al (1996) Molecular chlorine generated by the myeloperoxidase-hydrogen peroxide-chloride system of phagocytes converts low density lipoprotein cholesterol into a family of chlorinated sterols. J Biol Chem 271(38):23080–23088PubMedCrossRefGoogle Scholar
  33. Holmes B, Page AR, Good RA (1967) Studies of the metabolic activity of leukocytes from patients with a genetic abnormality of phagocytic function. J Clin Invest 46(9):1422–1432PubMedCrossRefGoogle Scholar
  34. Honda K, Chihara J (1999) Eosinophil activation by eotaxin–eotaxin primes the production of reactive oxygen species from eosinophils. Allergy 54(12):1262–1269PubMedCrossRefGoogle Scholar
  35. Janero DR, Hreniuk D, Sharif HM (1991) Hydrogen peroxide-induced oxidative stress to the mammalian heart-muscle cell (cardiomyocyte): lethal peroxidative membrane injury. J Cell Physiol 149(3):347–364PubMedCrossRefGoogle Scholar
  36. Jendrysik MA, Vasilevsky S, Yi L et al (2011) NADPH oxidase-2 derived ROS dictates murine DC cytokine-mediated cell fate decisions during CD4 T helper-cell commitment. PLoS One 6(12):e28198PubMedCrossRefGoogle Scholar
  37. Kadota S, Fantus IG, Deragon G et al (1987) Stimulation of insulin-like growth factor II receptor binding and insulin receptor kinase activity in rat adipocytes. Effects of vanadate and H2O2. J Biol Chem 262(17):8252–8256PubMedGoogle Scholar
  38. Katsuyama M, Matsuno K, Yabe-Nishimura C (2012) Physiological roles of NOX/NADPH oxidase, the superoxide-generating enzyme. J Clin Biochem Nutr 50(1):9–22PubMedCrossRefGoogle Scholar
  39. Kidd P (2003) Th1/Th2 balance: the hypothesis, its limitations, and implications for health and disease. Altern Med Rev 8(3):223–246PubMedGoogle Scholar
  40. Kirkham P (2007) Oxidative stress and macrophage function: a failure to resolve the inflammatory response. Biochem Soc Trans 35(Pt 2):284–287PubMedGoogle Scholar
  41. Korantzopoulos P, Kolettis TM, Galaris D et al (2007) The role of oxidative stress in the pathogenesis and perpetuation of atrial fibrillation. Int J Cardiol 115(2):135–143PubMedCrossRefGoogle Scholar
  42. Kotsias F, Hoffmann E, Amigorena S et al (2013) Reactive oxygen species production in the phagosome: impact on antigen presentation in dendritic cells. Antioxid Redox Signal 18(6):714–729PubMedCrossRefGoogle Scholar
  43. Krieger M, Herz J (1994) Structures and functions of multiligand lipoprotein receptors: macrophage scavenger receptors and LDL receptor-related protein (LRP). Annu Rev Biochem 63:601–637PubMedCrossRefGoogle Scholar
  44. Krishnaswamy JK, Chu T, Eisenbarth SC (2013) Beyond pattern recognition: NOD-like receptors in dendritic cells. Trends Immunol 34:224–233PubMedCrossRefGoogle Scholar
  45. Laihia JK, Jansen CT (1997) Up-regulation of human epidermal Langerhans’ cell B7-1 and B7-2 co-stimulatory molecules in vivo by solar-simulating irradiation. Eur J Immunol 27(4):984–989PubMedCrossRefGoogle Scholar
  46. Le SB, Hailer MK, Buhrow S et al (2007) Inhibition of mitochondrial respiration as a source of adaphostin-induced reactive oxygen species and cytotoxicity. J Biol Chem 282(12):8860–8872PubMedCrossRefGoogle Scholar
  47. Lenaz G (1998) Role of mitochondria in oxidative stress and ageing. Biochim Biophys Acta 1366(1–2):53–67PubMedGoogle Scholar
  48. Leto TL, Morand S, Hurt D et al (2009) Targeting and regulation of reactive oxygen species generation by Nox family NADPH oxidases. Antioxid Redox Signal 11(10):2607–2619PubMedCrossRefGoogle Scholar
  49. Liu WF, Ma M, Bratlie KM et al (2011) Real-time in vivo detection of biomaterial-induced reactive oxygen species. Biomaterials 32(7):1796–1801PubMedCrossRefGoogle Scholar
  50. Matsumoto A, Naito M, Itakura H et al (1990) Human macrophage scavenger receptors: primary structure, expression, and localization in atherosclerotic lesions. Proc Natl Acad Sci U S A 87(23):9133–9137PubMedCrossRefGoogle Scholar
  51. Mishra D, Mehta A, Flora SJ (2008) Reversal of arsenic-induced hepatic apoptosis with combined administration of DMSA and its analogues in guinea pigs: role of glutathione and linked enzymes. Chem Res Toxicol 21(2):400–407PubMedCrossRefGoogle Scholar
  52. Mitchell P (1961) Coupling of phosphorylation to electron and hydrogen transfer by a chemi-osmotic type of mechanism. Nature 191:144–148PubMedCrossRefGoogle Scholar
  53. Mogensen TH (2009) Pathogen recognition and inflammatory signaling in innate immune defenses. Clin Microbiol Rev 22(2):240–273PubMedCrossRefGoogle Scholar
  54. Muster B, Kohl W, Wittig I et al (2010) Respiratory chain complexes in dynamic mitochondria display a patchy distribution in life cells. PLoS One 5(7):e11910PubMedCrossRefGoogle Scholar
  55. Netzer N, Goodenbour JM, David A et al (2009) Innate immune and chemically triggered oxidative stress modifies translational fidelity. Nature 462(7272):522–526PubMedCrossRefGoogle Scholar
  56. Newkirk MM, Goldbach-Mansky R, Lee J et al (2003) Advanced glycation end-product (AGE)-damaged IgG and IgM autoantibodies to IgG-AGE in patients with early synovitis. Arthritis Res Ther 5(2):R82–R90PubMedCrossRefGoogle Scholar
  57. Omori K, Ohira T, Uchida Y et al (2008) Priming of neutrophil oxidative burst in diabetes requires preassembly of the NADPH oxidase. J Leukoc Biol 84(1):292–301PubMedCrossRefGoogle Scholar
  58. Pawelec G, Derhovanessian E, Larbi A (2010) Immunosenescence and cancer. Crit Rev Oncol Hematol 75(2):165–172PubMedCrossRefGoogle Scholar
  59. Peled A, Gonzalo JA, Lloyd C et al (1998) The chemotactic cytokine eotaxin acts as a granulocyte-macrophage colony-stimulating factor during lung inflammation. Blood 91(6):1909–1916PubMedGoogle Scholar
  60. Petreccia DC, Nauseef WM, Clark RA (1987) Respiratory burst of normal human eosinophils. J Leukoc Biol 41(4):283–288PubMedGoogle Scholar
  61. Pickrell AM, Fukui H, Moraes CT (2009) The role of cytochrome c oxidase deficiency in ROS and amyloid plaque formation. J Bioenerg Biomembr 41(5):453–456PubMedCrossRefGoogle Scholar
  62. Poli G, Leonarduzzi G, Biasi F et al (2004) Oxidative stress and cell signalling. Curr Med Chem 11(9):1163–1182PubMedCrossRefGoogle Scholar
  63. Rada B, Leto TL (2008) Oxidative innate immune defenses by Nox/Duox family NADPH oxidases. Contrib Microbiol 15:164–187PubMedGoogle Scholar
  64. Rutault K, Alderman C, Chain BM et al (1999) Reactive oxygen species activate human peripheral blood dendritic cells. Free Radic Biol Med 26(1–2):232–238PubMedCrossRefGoogle Scholar
  65. Rybicka JM, Balce DR, Khan MF et al (2010) NADPH oxidase activity controls phagosomal proteolysis in macrophages through modulation of the lumenal redox environment of phagosomes. Proc Natl Acad Sci U S A 107(23):10496–10501PubMedCrossRefGoogle Scholar
  66. Sheng KC, Pietersz GA, Tang CK et al (2010) Reactive oxygen species level defines two functionally distinctive stages of inflammatory dendritic cell development from mouse bone marrow. J Immunol 184(6):2863–2872PubMedCrossRefGoogle Scholar
  67. Shult PA, Graziano FM, Wallow IH et al (1985) Comparison of superoxide generation and luminol-dependent chemiluminescence with eosinophils and neutrophils from normal individuals. J Lab Clin Med 106(6):638–645PubMedGoogle Scholar
  68. Sies H, Cadenas E (1985) Oxidative stress: damage to intact cells and organs. Philos Trans R Soc Lond B Biol Sci 311(1152):617–631PubMedCrossRefGoogle Scholar
  69. Song L, Lee C, Schindler C (2011) Deletion of the murine scavenger receptor CD68. J Lipid Res 52(8):1542–1550PubMedCrossRefGoogle Scholar
  70. Starkov AA, Fiskum G, Chinopoulos C et al (2004) Mitochondrial alpha-ketoglutarate dehydrogenase complex generates reactive oxygen species. J Neurosci 24(36):7779–7788PubMedCrossRefGoogle Scholar
  71. Steinman RM (1991) The dendritic cell system and its role in immunogenicity. Annu Rev Immunol 9:271–296PubMedCrossRefGoogle Scholar
  72. Straumann A, Safroneeva E (2012) Eosinophils in the gastrointestinal tract: friends or foes? Acta Gastroenterol Belg 75(3):310–315PubMedGoogle Scholar
  73. Sundaram S, Ghosh J (2006) Expression of 5-oxoETE receptor in prostate cancer cells: critical role in survival. Biochem Biophys Res Commun 339(1):93–98PubMedCrossRefGoogle Scholar
  74. Tang L, Lucas AH, Eaton JW (1993) Inflammatory responses to implanted polymeric biomaterials: role of surface-adsorbed immunoglobulin G. J Lab Clin Med 122(3):292–300PubMedGoogle Scholar
  75. Turrens JF (2003) Mitochondrial formation of reactive oxygen species. J Physiol 552(Pt 2):335–344PubMedCrossRefGoogle Scholar
  76. Underhill DM, Goodridge HS (2012) Information processing during phagocytosis. Nat Rev Immunol 12(7):492–502PubMedCrossRefGoogle Scholar
  77. VanderVen BC, Hermetter A, Huang A et al (2010) Development of a novel, cell-based chemical screen to identify inhibitors of intraphagosomal lipolysis in macrophages. Cytometry A 77(8):751–760PubMedGoogle Scholar
  78. Winterbourn CC, Vissers MC, Kettle AJ (2000) Myeloperoxidase. Curr Opin Hematol 7(1):53–58PubMedCrossRefGoogle Scholar
  79. Xie L, Tsaprailis G, Chen QM (2005) Proteomic identification of insulin-like growth factor-binding protein-6 induced by sublethal H2O2 stress from human diploid fibroblasts. Mol Cell Proteomics 4(9):1273–1283PubMedCrossRefGoogle Scholar
  80. Zhong J, Rao X, Deiuliis J et al (2013) A potential role for dendritic cell/macrophage-expressing DPP4 in obesity-induced visceral inflammation. Diabetes 62(1):149–157PubMedCrossRefGoogle Scholar
  81. Zhou R, Tardivel A, Thorens B et al (2010) Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat Immunol 11(2):136–140PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Aleksandra M. Urbanska
    • 1
  • Valerio Zolla
    • 1
  • Paolo Verzani
    • 1
  • Laura Santambrogio
    • 1
    Email author
  1. 1.Department of PathologyAlbert Einstein College of MedicineNew YorkUSA

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