Abstract
Oxidative stress plays an important role in periodontal health and disease. The phagocyte nicotinamide adenine dinucleotide phosphate oxidase NOX2 is most likely one of the key sources of reactive oxygen species (ROS) in periodontal tissues. This review will discuss three clinical aspects of NOX2 function. We will first focus on oral pathology in NOX2 deficiency such as chronic granulomatous disease (CGD). CGD patients are thought to suffer from infections and sterile hyperinflammation in the oral cavity. Indeed, the periodontium appears to be the most common site of infection in CGD patients; however, as periodontitis is also common in the general population, it is not clear to which extent these infections can be attributed to the disease. Secondly, the role of oxidative stress in periodontal disease of diabetic patients will be reviewed. Diabetes is indeed a major risk factor to develop periodontal disease, and increased activity of leukocytes is commonly observed. Enhanced NOX2 activity is likely to be involved in the pathomechanism, but data remains somewhat preliminary. The strongest case for involvement of NOX2 in periodontal diseases is aggressive periodontitis. Increased ROS generation by leukocytes from patients with aggressive periodontitis has clearly been documented. This increased ROS generation is to be caused by two factors: (1) genetically enhanced ROS generation and (2) oral pathogens that enhance NOX function. NOX enzymes in the oral cavity have so far received little attention but are likely to be important players in this setting. New therapies could be derived from these new concepts.
Similar content being viewed by others
References
Bedard K, Krause KH (2007) The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev 87:245–313
Martire B, Rondelli R, Soresina A et al (2008) Clinical features, long-term follow-up and outcome of a large cohort of patients with chronic granulomatous disease: an Italian multicenter study. Clin Immunol (Orlando, FL) 126:155–164
Wolf JE, Ebel LK (1978) Chronic granulomatous disease: report of case and review of the literature. J Am Dent Assoc (1939) 96:292–295
Buduneli N, Baylas H, Aksu G et al (2001) Prepubertal periodontitis associated with chronic granulomatous disease. J Clin Periodontol 28:589–593
Charon JA, Mergenhagen SE, Gallin JI (1985) Gingivitis and oral ulceration in patients with neutrophil dysfunction. J Oral Pathol 14:150–155
Cohen MS, Leong PA, Simpson DM (1985) Phagocytic cells in periodontal defense. Periodontal status of patients with chronic granulomatous disease of childhood. J Periodontol 56:611–617
Winkelstein JA, Marino MC, Johnston RB Jr et al (2000) Chronic granulomatous disease. Report on a national registry of 368 patients. Medicine 79:155–169
Hasui M, Japan TSGOPDO (1999) Chronic granulomatous disease in Japan: incidence and natural history. Pediatr Int 41:589–593
Soler-Palacin P, Margareto C, Llobet P et al (2007) Chronic granulomatous disease in pediatric patients: 25 years of experience. Allergol Immunopathol (Madr) 35:83–89
Carnide EG, Jacob CA, Castro AM et al (2005) Clinical and laboratory aspects of chronic granulomatous disease in description of eighteen patients. Pediatr Allergy Immunol 16:5–9
Lekstrom-Himes JA, Gallin JI (2000) Immunodeficiency diseases caused by defects in phagocytes. N Engl J Med 343:1703–1714
Jenkins WM, Papapanou PN (2001) Epidemiology of periodontal disease in children and adolescents. Periodontol 2000 26:16–32
Hoffmann T (2006) Parodontalerkrankungen. In: Micheelis W, Schiffner U (eds) Vierte Deutsche Mundgesundheitsstudie. Deutscher Zahnärzteverlag, Cologne
Grossi SG, Genco RJ (1998) Periodontal disease and diabetes mellitus: a two-way relationship. Annals of Periodontology/The American Academy of Periodontology 3:51–61
Khader YS, Dauod AS, El-Qaderi SS et al (2006) Periodontal status of diabetics compared with nondiabetics: a meta-analysis. J Diabetes Its Complicat 20:59–68
Taylor GW, Burt BA, Becker MP et al (1996) Severe periodontitis and risk for poor glycemic control in patients with non-insulin-dependent diabetes mellitus. J Periodontol 67:1085–1093
Taylor GW, Burt BA, Becker MP et al (1998) Non-insulin dependent diabetes mellitus and alveolar bone loss progression over 2 years. J Periodontol 69:76–83
Sastrowijoto SH, Hillemans P, van Steenbergen TJ et al (1989) Periodontal condition and microbiology of healthy and diseased periodontal pockets in type 1 diabetes mellitus patients. J Clin Periodontol 16:316–322
Zambon JJ, Reynolds H, Fisher JG et al (1988) Microbiological and immunological studies of adult periodontitis in patients with noninsulin-dependent diabetes mellitus. J Periodontol 59:23–31
Manouchehr-Pour M, Spagnuolo PJ, Rodman HM et al (1981) Comparison of neutrophil chemotactic response in diabetic patients with mild and severe periodontal disease. J Periodontol 52:410–415
McMullen JA, Van Dyke TE, Horoszewicz HU et al (1981) Neutrophil chemotaxis in individuals with advanced periodontal disease and a genetic predisposition to diabetes mellitus. J Periodontol 52:167–173
Salvi GE, Collins JG, Yalda B et al (1997) Monocytic TNF alpha secretion patterns in IDDM patients with periodontal diseases. J Clin Periodontol 24:8–16
Salvi GE, Yalda B, Collins JG et al (1997) Inflammatory mediator response as a potential risk marker for periodontal diseases in insulin-dependent diabetes mellitus patients. J Periodontol 68:127–135
Rodriguez-Manas L, Angulo J, Vallejo S et al (2003) Early and intermediate Amadori glycosylation adducts, oxidative stress, and endothelial dysfunction in the streptozotocin-induced diabetic rats vasculature. Diabetologia 46:556–566
Schmidt AM, Weidman E, Lalla E et al (1996) Advanced glycation endproducts (AGEs) induce oxidant stress in the gingiva: a potential mechanism underlying accelerated periodontal disease associated with diabetes. J Periodontal Res 31:508–515
Brownlee M (2001) Biochemistry and molecular cell biology of diabetic complications. Nature 414:813–820
Ceriello A (2000) Oxidative stress and glycemic regulation. Metabolism 49:27–29
Nauseef WM (2004) Assembly of the phagocyte NADPH oxidase. Histochem Cell Biol 122:277–291
Karima M, Kantarci A, Ohira T et al (2005) Enhanced superoxide release and elevated protein kinase C activity in neutrophils from diabetic patients: association with periodontitis. J Leukoc Biol 78:862–870
Gyurko R, Siqueira CC, Caldon N et al (2006) Chronic hyperglycemia predisposes to exaggerated inflammatory response and leukocyte dysfunction in Akita mice. J Immunol 177:7250–7256
Asman B (1988) Peripheral PMN cells in juvenile periodontitis. Increased release of elastase and of oxygen radicals after stimulation with opsonized bacteria. J Clin Periodontol 15:360–364
Asman B, Bergstrom K (1992) Expression of Fc-γ-RIII and fibronectin in peripheral neutrophils with increased response to Fc stimulation in patients with juvenile periodontitis. Arch Oral Biol 37:991–995
Asman B, Gustafsson A, Bergstrom K (1996) Priming of neutrophils with TNFα measured as Fcγ receptor-mediated respiratory burst correlates with increased complement receptor 3 membrane density. Int J Clin Lab Res 26:236–239
Yoneda M, Maeda K, Aono M (1990) Suppression of bactericidal activity of human polymorphonuclear leukocytes by Bacteroides gingivalis. Infect Immun 58:406–411
Fredriksson M, Figueredo CMS, Gustafsson A et al (1999) Effect of periodontitis and smoking on blood leukocytes and acute-phase proteins. J Periodontol 70:1355–1360
Fredriksson M, Gustafsson A, Asman B et al (1999) Periodontitis increases chemiluminescence of the peripheral neutrophils independently of priming by the preparation method. Oral Dis 5:229–233
Fredriksson M, Gustafsson A, Bergstrom K et al (1998) Hyper-reactive peripheral neutrophils in adult periodontitis: generation of chemiluminescence and intracellular hydrogen peroxide after in vitro priming and FcγR-stimulation. J Clin Periodontol 25:395–398
Wright HJ, Chapple ILC, Cooper PR et al (2004) Extracellular oxygen radical release from peripheral neutrophils in chronic periodontitis. J Dent Res 83:208
Asman B, Bergstrom K, Wijkander P et al (1988) Peripheral PMN cell activity in relation to treatment of juvenile periodontitis. Scand J Dent Res 96:418–420
Fredriksson M, Gustafsson A, Bergstrom K et al (2003) Constitutionally hyperreactive neutrophils in periodontitis. J Periodontol 74:219–224
Biasi D, Bambara LM, Carletto A et al (1999) Neutrophil migration, oxidative metabolism and adhesion in early onset periodontitis. J Clin Periodontol 26:563–568
Gainet J, Dang PMC, Chollet-Martin S et al (1999) Neutrophil dysfunctions, IL-8, and soluble L-selectin plasma levels in rapidly progressive vs. adult and localized juvenile periodontitis: variations according to disease severity and microbial flora. J Immunol 163:5013–5019
Guarnieri C, Zucchelli G, Bernardi F et al (1991) Enhanced superoxide production with no change of the antioxidant activity in gingival fluid of patients with chronic adult periodontitis. Free Radic Res Commun 15:11–16
Loesche WJ, Robinson JP, Flynn M et al (1988) Reduced oxidative function in gingival crevicular neutrophils in periodontal disease. Infect Immun 56:156–160
Matthews JB, Wright HJ, Roberts A et al (2007) Neutrophil hyper-responsiveness in periodontitis. J Dent Res 86:718–722
Johnstone AM, Koh A, Goldberg MB et al (2007) A hyperactive neutrophil phenotype in patients with refractory periodontitis. J Periodontol 78:1788–1794
Gustafsson A, Asman B, Bergstrom K (1997) Priming response to inflammatory mediators in hyperreactive peripheral neutrophils from adult periodontitis. Oral Dis 3:167–171
Loos BG, John RP, Laine ML (2005) Identification of genetic risk factors for periodontitis and possible mechanisms of action. J Clin Periodontol 32(Suppl 6):159–179
Shapira L, Wilensky A, Kinane DF (2005) Effect of genetic variability on the inflammatory response to periodontal infection. J Clin Periodontol 32(Suppl 6):72–86
Nibali L, Parkar M, Brett P et al (2006) NADPH oxidase (CYBA) and FcgammaR polymorphisms as risk factors for aggressive periodontitis: a case-control association study. J Clin Periodontol 33:529–539
Yang S, Zhang Y, Ries W et al (2004) Expression of Nox4 in osteoclasts. J Cell Biochem 92:238–248
Sheikhi M, Gustafsson A, Jarstrand C (2000) Cytokine, elastase and oxygen radical release by Fusobacterium nucleatum-activated leukocytes: a possible pathogenic factor in periodontitis. J Clin Periodontol 27:758–762
Mydel P, Takahashi Y, Yumoto H et al (2006) Roles of the host oxidative immune response and bacterial antioxidant rubrerythrin during Porphyromonas gingivalis infection. PLoS Pathog 2:e76
Donko A, Peterfi Z, Sum A et al (2005) Dual oxidases. Philos Trans R Soc Lond 360:2301–2308
Tateishi Y, Sasabe E, Ueta E et al (2008) Ionizing irradiation induces apoptotic damage of salivary gland acinar cells via NADPH oxidase 1-dependent superoxide generation. Biochem Biophys Res Commun 366:301–307
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Giannopoulou, C., Krause, KH. & Müller, F. The NADPH oxidase NOX2 plays a role in periodontal pathologies. Semin Immunopathol 30, 273–278 (2008). https://doi.org/10.1007/s00281-008-0128-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00281-008-0128-1