Neutrophils: The Role of Oxidative and Nitrosative Stress in Health and Disease

  • Aneta Manda-Handzlik
  • Urszula Demkow
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 857)


Neutrophils constitute the first line of the innate immunity in humans. They employ several strategies to trap and kill microorganisms, such as phagocytosis, degranulation, and the formation of extracellular traps (NETs). It has been well documented, that generation of reactive oxygen and nitrogen species (ROS and RNS) is crucial in the life cycle of a polymorphonuclear phagocyte. These compounds due to high reactivity act as powerful antimicrobial factors in the process of pathogens clearance and can also modulate immunological response. On the other hand, excessive amount of free radicals may have detrimental effect on host tissues and markers of oxidative and nitrosative stress are detectable in many diseases. It is necessary to maintain the balance between ROS/RNS formation and removal. The review highlights our current understanding of the role of ROS and RNS produced by neutrophils in health and disease.


Cell signaling Nitrosative stress Neutrophils Oxidative stress Pathology 


Conflicts of Interest

The authors declare no conflicts of interest in relation to this article.


  1. Brill A, Fuchs TA, Savchenko AS, Thomas GM, Martinod K, De Meyer SF, Bhandari AA, Wagner DD (2012) Neutrophil extracellular traps promote deep vein thrombosis in mice. J Thromb Haemost 10:136–144PubMedCentralPubMedCrossRefGoogle Scholar
  2. Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, Weinrauch Y, Zychlinsky A (2004) Neutrophil extracellular traps kill bacteria. Science 303:1532–1535PubMedCrossRefGoogle Scholar
  3. Britigan BE, Coffman TJ, Buettner GR (1990) Spin trapping evidence for the lack of significant hydroxyl radical production during the respiration burst of human phagocytes using a spin adduct resistant to superoxide-mediated destruction. J Biol Chem 265:2650–2656PubMedGoogle Scholar
  4. Byun MS, Jeon KI, Choi JW, Shim JY, Jue DM (2002) Dual effect of oxidative stress on NF-kappakB activation in HeLa cells. Exp Mol Med 34:332–339PubMedCrossRefGoogle Scholar
  5. Cadden KA, Walsh SW (2008) Neutrophils, but not lymphocytes or monocytes, infiltrate maternal systemic vasculature in women with preeclampsia. Hypertens Pregnancy 27:396–405PubMedCentralPubMedCrossRefGoogle Scholar
  6. Celec P (2004) Nuclear factor kappa B-molecular biomedicine: the next generation. Biomed Pharmacother 58:365–371PubMedCrossRefGoogle Scholar
  7. Chappell LC, Seed PT, Briley AL, Kelly FJ, Lee R, Hunt BJ, Parmar K, Bewley SJ, Shennan AH, Steer PJ, Poston L (1999) Effect of antioxidants on the occurrence of pre-eclampsia in women at increased risk: a randomised trial. Lancet 354:810–816PubMedCrossRefGoogle Scholar
  8. Colucci-Guyon E, Tinevez JY, Renshaw SA, Herbomel P (2011) Strategies of professional phagocytes in vivo: unlike macrophages, neutrophils engulf only surface-associated microbes. J Cell Sci 124:3053–3059PubMedCrossRefGoogle Scholar
  9. Cools-Lartigue J, Spicer J, McDonald B, Gowing S, Chow S, Giannias B, Bourdeau F, Kubes P, Ferri L (2013) Neutrophil extracellular traps sequester circulating tumor cells and promote metastasis. J Clin Invest 123:3446–3458PubMedCentralCrossRefGoogle Scholar
  10. Cosentino-Gomes D, Rocco-Machado N, Meyer-Fernandes JR (2012) Cell signaling through protein kinase C oxidation and activation. Int J Mol Sci 13:10697–10721PubMedCentralPubMedCrossRefGoogle Scholar
  11. Craig R, Larkin A, Mingo AM, Thuerauf DJ, Andrews C, McDonough PM, Glembotski CC (2000) p38 MAPK and NF-kappa B collaborate to induce interleukin-6 gene expression and release. Evidence for a cytoprotective autocrine signaling pathway in a cardiac myocyte model system. J Biol Chem 275:23814–23824PubMedCrossRefGoogle Scholar
  12. Cuzzocrea S, Mazzon E, Dugo L, Caputi AP, Aston K, Riley DP, Salvemini D (2001) Protective effects of a new stable, highly active SOD mimetic, M40401 in splanchnic artery occlusion and reperfusion. Br J Pharmacol 132:19–29PubMedCentralPubMedCrossRefGoogle Scholar
  13. Dal Secco D, Paron JA, de Oliveira SH, Ferreira SH, Silva JS, Cunha Fde Q (2003) Neutrophil migration in inflammation: nitric oxide inhibits rolling, adhesion and induces apoptosis. Nitric Oxide 9:153–164PubMedCrossRefGoogle Scholar
  14. Dalle-Donne I, Scaloni A, Giustarini D, Cavarra E, Tell G, Lungarella G, Colombo R, Rossi R, Milzani A (2005) Proteins as biomarkers of oxidative/nitrosative stress in diseases: the contribution of redox proteomics. Mass Spectrom Rev 24:55–99PubMedCrossRefGoogle Scholar
  15. Eiserich JP, Patel RP, O’Donnell VB (1998) Pathophysiology of nitric oxide and related species: free radical reactions and modification of biomolecules. Mol Aspects Med 19:221–357PubMedCrossRefGoogle Scholar
  16. Elbim C, Pillet S, Prevost MH, Preira A, Girard PM, Rogine N, Hakim J, Israel N, Gougerot-Pocidalo MA (2001) The role of phagocytes in HIV-related oxidative stress. J Clin Virol 20:99–109PubMedCrossRefGoogle Scholar
  17. Ermert D, Urban CF, Laube B, Goosmann C, Zychlinsky A, Brinkmann V (2009) Mouse neutrophil extracellular traps in microbial infections. J Innate Immun 1:181–193PubMedCrossRefGoogle Scholar
  18. Fialkow L, Chan CK, Rotin D, Grinstein S, Downey GP (1994) Activation of the mitogen-activated protein kinase signaling pathway in neutrophils. Role of oxidants. J Biol Chem 269:31234–31242PubMedGoogle Scholar
  19. Fialkow L, Chan CK, Downey GP (1997) Inhibition of CD45 during neutrophil activation. J Immunol 158:5409–5417PubMedGoogle Scholar
  20. Fialkow L, Wang Y, Downey GP (2007) Reactive oxygen and nitrogen species as signaling molecules regulating neutrophil function. Free Radic Biol Med 42:153–164PubMedCrossRefGoogle Scholar
  21. Fuchs TA, Abed U, Goosmann C, Hurwitz R, Schulze I, Wahn V, Weinrauch Y, Brinkmann V, Zychlinsky A (2007) Novel cell death program leads to neutrophil extracellular traps. J Cell Biol 176:231–241PubMedCentralPubMedCrossRefGoogle Scholar
  22. Gresham HD, McGarr JA, Shackelford PG, Brown EJ (1988) Studies on the molecular mechanisms of human Fc receptor-mediated phagocytosis. Amplification of ingestion is dependent on the generation of reactive oxygen metabolites and is deficient in polymorphonuclear leukocytes from patients with chronic granulomatous disease. J Clin Investig 82:1192–1201PubMedCentralPubMedCrossRefGoogle Scholar
  23. Gupta AK, Hasler P, Holzgreve W, Hahn S (2007) Neutrophil NETs: a novel contributor to preeclampsia-associated placental hypoxia? Semin Immunopathol 29:163–167PubMedCrossRefGoogle Scholar
  24. Hanai H, Takeuchi K, Iida T, Kashiwagi N, Saniabadi AR, Matsushita I, Sato Y, Kasuga N, Nakamura T (2004) Relationship between fecal calprotectin, intestinal inflammation, and peripheral blood neutrophils in patients with active ulcerative colitis. Dig Dis Sci 49:1438–1443PubMedCrossRefGoogle Scholar
  25. Hattori H, Subramanian KK, Sakai J, Luo HR (2010) Reactive oxygen species as signaling molecules in neutrophil chemotaxis. Commun Integr Biol 3:278–281PubMedCentralPubMedCrossRefGoogle Scholar
  26. Herscovitch M, Comb W, Ennis T, Coleman K, Yong S, Armstead B, Kalaitzidis D, Chandani S, Gilmore TD (2008) Intermolecular disulfide bond formation in the NEMO dimer requires Cys54 and Cys347. Biochem Biophys Res Commun 367:103–108PubMedCentralPubMedCrossRefGoogle Scholar
  27. Hilliquin P, Borderie D, Hernvann A, Menkes CJ, Ekindjian OG (1997) Nitric oxide as S-nitrosoproteins in rheumatoid arthritis. Arthritis Rheum 40:1512–1517PubMedCrossRefGoogle Scholar
  28. Jamaluddin M, Wang S, Boldogh I, Tian B, Brasier AR (2007) TNF-alpha-induced NF-kappaB/RelA Ser(276) phosphorylation and enhanceosome formation is mediated by an ROS-dependent PKAc pathway. Cell Signal 19:1419–1433PubMedCrossRefGoogle Scholar
  29. Jyoti A, Singh AK, Dubey M, Kumar S, Saluja R, Keshari RS, Verma A, Chandra T, Kumar A, Bajpai VK, Barthwal MK, Dikshit M (2014) Interaction of inducible nitric oxide synthase with rac2 regulates reactive oxygen and nitrogen species generation in the human neutrophil phagosomes: implication in microbial killing. Antioxid Redox Signal 20:417–431PubMedCrossRefGoogle Scholar
  30. Kaur H, Halliwell B (1994) Evidence for nitric oxide-mediated oxidative damage in chronic inflammation. Nitrotyrosine in serum and synovial fluid from rheumatoid patients. FEBS Lett 350:9–12PubMedCrossRefGoogle Scholar
  31. Keshari RS, Verma A, Barthwal MK, Dikshit M (2013) Reactive oxygen species-induced activation of ERK and p38 MAPK mediates PMA-induced NETs release from human neutrophils. J Cell Biochem 114:532–540PubMedCrossRefGoogle Scholar
  32. Khan F, Siddiqui AA (2006) Prevalence of anti-3-nitrotyrosine antibodies in the joint synovial fluid of patients with rheumatoid arthritis, osteoarthritis and systemic lupus erythematosus. Clin Chim Acta 370:100–107PubMedCrossRefGoogle Scholar
  33. Kirchner T, Moller S, Klinger M, Solbach W, Laskay T, Behnen M (2012) The impact of various reactive oxygen species on the formation of neutrophil extracellular traps. Mediators Inflamm 2012:849136PubMedCentralPubMedCrossRefGoogle Scholar
  34. Klatt P, Lamas S (2000) Regulation of protein function by S-glutathiolation in response to oxidative and nitrosative stress. Eur J Biochem 267:4928–4944PubMedCrossRefGoogle Scholar
  35. Knaus UG, Heyworth PG, Evans T, Curnutte JT, Bokoch GM (1991) Regulation of phagocyte oxygen radical production by the GTP-binding protein Rac 2. Science 254:1512–1515PubMedCrossRefGoogle Scholar
  36. Kobayashi K, Takahashi K, Nagasawa S (1995) The role of tyrosine phosphorylation and Ca2+ accumulation in Fc gamma-receptor-mediated phagocytosis of human neutrophils. J Biochem 117:1156–1161PubMedGoogle Scholar
  37. Kundu S, Ghosh P, Datta S, Ghosh A, Chattopadhyay S, Chatterjee M (2012) Oxidative stress as a potential biomarker for determining disease activity in patients with rheumatoid arthritis. Free Radic Res 46:1482–1489PubMedCrossRefGoogle Scholar
  38. Lang JD, McArdle PJ, O’Reilly PJ, Matalon S (2002) Oxidant-antioxidant balance in acute lung injury. Chest 122:314S–320SPubMedCrossRefGoogle Scholar
  39. Lang R, Hammer M, Mages J (2006) DUSP meet immunology: dual specificity MAPK phosphatases in control of the inflammatory response. J Immunol 177:7497–7504PubMedCrossRefGoogle Scholar
  40. MacManus-Spencer LA, McNeill K (2005) Quantification of singlet oxygen production in the reaction of superoxide with hydrogen peroxide using a selective chemiluminescent probe. J Am Chem Soc 127:8954–8955PubMedCrossRefGoogle Scholar
  41. Maor I, Rainis T, Lanir A, Lavy A (2008) Oxidative stress, inflammation and neutrophil superoxide release in patients with Crohn’s disease: distinction between active and non-active disease. Dig Dis Sci 53:2208–2214PubMedCrossRefGoogle Scholar
  42. Marcos V, Zhou Z, Yildirim AO, Bohla A, Hector A, Vitkov L, Wiedenbauer EM, Krautgartner WD, Stoiber W, Belohradsky BH, Rieber N, Kormann M, Koller B, Roscher A, Roos D, Griese M, Eickelberg O, Doring G, Mall MA, Hartl D (2010) CXCR2 mediates NADPH oxidase-independent neutrophil extracellular trap formation in cystic fibrosis airway inflammation. Nat Med 16:1018–1023PubMedCrossRefGoogle Scholar
  43. Matthews JR, Kaszubska W, Turcatti G, Wells TN, Hay RT (1993) Role of cysteine62 in DNA recognition by the P50 subunit of NF-kappa B. Nucleic Acids Res 21:1727–1734PubMedCentralPubMedCrossRefGoogle Scholar
  44. Morrison D, Rahman I, Lannan S, MacNee W (1999) Epithelial permeability, inflammation, and oxidant stress in the air spaces of smokers. Am J Respir Crit Care Med 159:473–479PubMedCrossRefGoogle Scholar
  45. Nakamura H, Masutani H, Yodoi J (2002) Redox imbalance and its control in HIV infection. Antioxid Redox Signal 4:455–464PubMedCrossRefGoogle Scholar
  46. Niu XF, Ibbotson G, Kubes P (1996) A balance between nitric oxide and oxidants regulates mast cell-dependent neutrophil-endothelial cell interactions. Circ Res 79:992–999PubMedCrossRefGoogle Scholar
  47. Nolan S, Dixon R, Norman K, Hellewell P, Ridger V (2008) Nitric oxide regulates neutrophil migration through microparticle formation. Am J Pathol 172:265–273PubMedCentralPubMedCrossRefGoogle Scholar
  48. Papayannopoulos V, Metzler KD, Hakkim A, Zychlinsky A (2010) Neutrophil elastase and myeloperoxidase regulate the formation of neutrophil extracellular traps. J Cell Biol 191:677–691PubMedCentralPubMedCrossRefGoogle Scholar
  49. Papayannopoulos V, Staab D, Zychlinsky A (2011) Neutrophil elastase enhances sputum solubilization in cystic fibrosis patients receiving DNase therapy. PLoS One 6:e28526PubMedCentralPubMedCrossRefGoogle Scholar
  50. Parker H, Winterbourn CC (2012) Reactive oxidants and myeloperoxidase and their involvement in neutrophil extracellular traps. Front Immunol 3:424PubMedCentralPubMedGoogle Scholar
  51. Patel KD, Zimmerman GA, Prescott SM, McEver RP, McIntyre TM (1991) Oxygen radicals induce human endothelial cells to express GMP-140 and bind neutrophils. J Cell Biol 112:749–759PubMedCrossRefGoogle Scholar
  52. Patel S, Kumar S, Jyoti A, Srinag BS, Keshari RS, Saluja R, Verma A, Mitra K, Barthwal MK, Krishnamurthy H, Bajpai VK, Dikshit M (2010) Nitric oxide donors release extracellular traps from human neutrophils by augmenting free radical generation. Nitric Oxide 22:226–234PubMedCrossRefGoogle Scholar
  53. Patino PJ, Perez JE, Lopez JA, Condino-Neto A, Grumach AS, Botero JH, Curnutte JT, Garcia de Olarte D (1999) Molecular analysis of chronic granulomatous disease caused by defects in gp91-phox. Hum Mutat 13:29–37PubMedCrossRefGoogle Scholar
  54. Pignatelli B, Li CQ, Boffetta P, Chen Q, Ahrens W, Nyberg F, Mukeria A, Bruske-Hohlfeld I, Fortes C, Constantinescu V, Ischiropoulos H, Ohshima H (2001) Nitrated and oxidized plasma proteins in smokers and lung cancer patients. Cancer Res 61:778–784PubMedGoogle Scholar
  55. Pilsczek FH, Salina D, Poon KK, Fahey C, Yipp BG, Sibley CD, Robbins SM, Green FH, Surette MG, Sugai M, Bowden MG, Hussain M, Zhang K, Kubes P (2010) A novel mechanism of rapid nuclear neutrophil extracellular trap formation in response to Staphylococcus aureus. J Immunol 185:7413–7425PubMedCrossRefGoogle Scholar
  56. Rahman I, Skwarska E, MacNee W (1997) Attenuation of oxidant/antioxidant imbalance during treatment of exacerbations of chronic obstructive pulmonary disease. Thorax 52:565–568PubMedCentralPubMedCrossRefGoogle Scholar
  57. Ramonaite R, Skieceviciene J, Kiudelis G, Jonaitis L, Tamelis A, Cizas P, Borutaite V, Kupcinskas L (2013) Influence of NADPH oxidase on inflammatory response in primary intestinal epithelial cells in patients with ulcerative colitis. BMC Gastroenterol 13:159PubMedCentralPubMedCrossRefGoogle Scholar
  58. Ramos CL, Pou S, Britigan BE, Cohen MS, Rosen GM (1992) Spin trapping evidence for myeloperoxidase-dependent hydroxyl radical formation by human neutrophils and monocytes. J Biol Chem 267:8307–8312PubMedGoogle Scholar
  59. Reynaert NL, Ckless K, Korn SH, Vos N, Guala AS, Wouters EF, van der Vliet A, Janssen-Heininger YM (2004) Nitric oxide represses inhibitory kappaB kinase through S-nitrosylation. Proc Natl Acad Sci U S A 101:8945–8950PubMedCentralPubMedCrossRefGoogle Scholar
  60. Rhee SG, Chang TS, Bae YS, Lee SR, Kang SW (2003) Cellular regulation by hydrogen peroxide. J Am Soc Nephrol 14:S211–S215PubMedCrossRefGoogle Scholar
  61. Salmon JE, Millard SS, Brogle NL, Kimberly RP (1995) Fc gamma receptor IIIb enhances Fc gamma receptor IIa function in an oxidant-dependent and allele-sensitive manner. J Clin Investig 95:2877–2885PubMedCentralPubMedCrossRefGoogle Scholar
  62. Schoonbroodt S, Ferreira V, Best-Belpomme M, Boelaert JR, Legrand-Poels S, Korner M, Piette J (2000) Crucial role of the amino-terminal tyrosine residue 42 and the carboxyl-terminal PEST domain of I kappa B alpha in NF-kappa B activation by an oxidative stress. J Immunol 164:4292–4300PubMedCrossRefGoogle Scholar
  63. Seril DN, Liao J, Yang GY, Yang CS (2003) Oxidative stress and ulcerative colitis-associated carcinogenesis: studies in humans and animal models. Carcinogenesis 24:353–362PubMedCrossRefGoogle Scholar
  64. Simard JC, Girard D, Tessier PA (2010) Induction of neutrophil degranulation by S100A9 via a MAPK-dependent mechanism. J Leukoc Biol 87:905–914PubMedCrossRefGoogle Scholar
  65. Sumii H, Inoue H, Onoue J, Mori A, Oda T, Tsubokura T (1996) Superoxide dismutase activity in arthropathy: its role and measurement in the joints. Hiroshima J Med Sci 45:51–55PubMedGoogle Scholar
  66. Summers C, Rankin SM, Condliffe AM, Singh N, Peters AM, Chilvers ER (2010) Neutrophil kinetics in health and disease. Trends Immunol 31:318–324PubMedCentralPubMedCrossRefGoogle Scholar
  67. Takada Y, Mukhopadhyay A, Kundu GC, Mahabeleshwar GH, Singh S, Aggarwal BB (2003) Hydrogen peroxide activates NF-kappa B through tyrosine phosphorylation of I kappa B alpha and serine phosphorylation of p65: evidence for the involvement of I kappa B alpha kinase and Syk protein-tyrosine kinase. J Biol Chem 278:24233–24241PubMedCrossRefGoogle Scholar
  68. Tonks NK (2005) Redox redux: revisiting PTPs and the control of cell signaling. Cell 121:667–670PubMedCrossRefGoogle Scholar
  69. Urban CF, Ermert D, Schmid M, Abu-Abed U, Goosmann C, Nacken W, Brinkmann V, Jungblut PR, Zychlinsky A (2009) Neutrophil extracellular traps contain calprotectin, a cytosolic protein complex involved in host defense against Candida albicans. PLoS Pathog 5:e1000639PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Department of Laboratory Diagnostics and Clinical Immunology of Developmental AgeWarsaw Medical UniversityWarsawPoland
  2. 2.Postgraduate School of Molecular MedicineWarsaw Medical UniversityWarsawPoland

Personalised recommendations