Volume : 09, Issue : 10, October – 2022

Title:

11.DIFFERENT MUTATIONS IN THE NADPH OXIDASE ENZYME LEAD TO DIFFERENT MACROPHAGE RESPONSES

Authors :

Suhailah Khalil Abdulhalim*

Abstract :

Chronic granulomatous disease (CGD) is a genetic disease characterised by a dysfunctional NADPH oxidase with a reduced capacity to produce the reactive oxygen species (ROS) needed to defend against pathogens. Mutations in the various subunits of the NADPH enzyme may lead to the manifestation of CGD. In this study, we theorise that different mutations in the subunits of NADPH oxidase result in an altered macrophage response to infection.
LPS was found to decrease macrophage viability but also cause increased production of TNFa and IL-1b. The build up of dead macrophages may also contribute to the inflammatory response, characterised by TNFα and IL-1β release from the remaining active cells. PMA; used to differentiate U937 cells into macrophages, becomes cytotoxic to macrophages in a time and dose-dependent fashion. Our hypothesis that mutations in the subunits of NADPH oxidase affect the macrophage response to TLR and inflammasome response was confirmed. However, repeat experimentation and further investigations are necessary to further our understanding of the pathogenesis of CGD.
Keywords: CGD, X-linked disorders, NADPH oxidase enzyme, RNA Interference and Mutations in genes.

Cite This Article:

Please cite this article in Suhailah Khalil Abdulhalim, Different Mutations In The NADPH Oxidase Enzyme Lead To Different Macrophage Responses., Indo Am. J. P. Sci, 2022; 09(10).

Number of Downloads : 10

References:

1. Asehnoune, K.; Strassheim, D.; Mitra, S.; Yeol Kim, J. And Abraham, E. (2004) Involvement of Reactive Oxygen Species in Toll-Like Receptor 4-Dependent Activation of NFκB. J Immunol; 172(4): 2522-29
2. Assari; T. (2006) Chronic Granulomatous Disease; fundamental stages in our understanding of CGD. Med Immunol; 5(4): 1-8.
3. Auron; P. E.; Webb; A. C.; Rosenwasser; L. J.; Mucci; S. F.; Rich; A.; Wolff; S. M. & Dinarello; C. A. (2007) Nucleotide sequence of human monocyte interleukin 1 precursor cDNA. Proc. Natl. Acad. Sci. USA 1984. 81: 7907-7911. J Immunol; 178(9): 5413-7.
4. Bianchi; M.; Hakkim; A.; Brinkmann; V.; Siler; U.; Seger; R. A.; Zychlinsky; A. & Reichenbach; J. (2009) Restoration of NET formation by gene therapy in CGD controls aspergillosis. Blood; 114(13): 2619-22.
5. Bjorgvinsdottir; H.; Zhen; L. & Dinauer; M. C. (1996) Cloning of murine gp91phox cDNA and functional expression in a human X-linked chronic granulomatous disease cell line. Blood; 87(5): 2005-10.
6. Bonizzi; G.; Piette; J.; Schoonbroodt; S.; Greimers; R.; Havard; L.; Merville; M. P. & Bours; V. (1999) Reactive oxygen intermediate-dependent NF-kappaB activation by interleukin-1beta requires 5-lipoxygenase or NADPH oxidase activity. Mol Cell Biol; 19(3): 1950-60.
7. Brinkmann; V.; Reichard; U.; Goosmann; C.; Fauler; B.; Uhlemann; Y.; Weiss; D. S.; Weinrauch; Y. & Zychlinsky; A. (2004) Neutrophil extracellular traps kill bacteria. Science; 303(5663): 1532-5.
8. Bu-Ghanim; H. N.; Segal; A. W.; Keep; N. H. & Casimir; C. M. (1995) Molecular analysis in three cases of X91- variant chronic granulomatous disease. Blood; 86(9): 3575-82.
9. Cartun; R. W. & Pedersen; C. A. (1989) An Immunocytochemical Technique Offering Increased Sensitivity and Lowered Cost with a Streptavidin-Horseradish Peroxidase Conjugate. Journal of Histotechnology; 12: 273-277.
10. Cross; A. R.; Yarchover; J. L. & Curnutte; J. T. (1994) The superoxide-generating system of human neutrophils possesses a novel diaphorase activity. Evidence for distinct regulation of electron flow within NADPH oxidase by p67-phox and p47-phox. J Biol Chem; 269(34): 21448-54.
11. Daigneault; M.; Preston; J. A.; Marriott; H. M.; Whyte; M. K. B. & Dockrell; D. H. (2010) The Identification of Markers of Macrophage Differentiation in PMA-Stimulated THP-1 Cells and Monocyte-Derived Macrophages. PLoS One; 5: e8668
12. De Ravin; S. S.; Naumann; N.; Cowen; E. W.; Friend; J.; Hilligoss; D.; Marquesen; M.; Balow; J. E.; Barron; K. S.; Turner; M. L.; Gallin; J. I. & Malech; H. L. (2008) Chronic granulomatous disease as a risk factor for autoimmune disease. J Allergy Clin Immunol; 122(6): 1097-103.
13. DeLeo; F. R.; Allen; L. A.; Apicella; M. & Nauseef; W. M. (1999) NADPH oxidase activation and assembly during phagocytosis. J Immunol; 163(12): 6732-40.
14. DeLeo; F. R.; Ulman; K. V.; Davis; A. R.; Jutila; K. L. & Quinn; M. T. (1996) Assembly of the human neutrophil NADPH oxidase involves binding of p67phox and flavocytochrome b to a common functional domain in p47phox. J Biol Chem; 271(29): 17013-20.
15. Gallin; J. I. & Buescher; E. S. (1983) Abnormal regulation of inflammatory skin responses in male patients with chronic granulomatous disease. Inflammation; 7(3): 227-32.
16. Galvez; J.; Saiz; E.; Linares; L. F.; Climent; A.; Marras; C.; Pina; M. F. & Castellon; P. (2002) Delayed examination of synovial fluid by ordinary and polarised light microscopy to detect and identify crystals. Ann Rheum Dis; 61: 444-7.
17. Gelman; A. (2005) Analysis of variance? Why it is more important than ever. The Annals of Statistics; 33: 1–53.
18. Grimm; M. J.; Vethanayagam; R. R.; Almyroudis; N. G.; Lewandowski; D.; Rall; N.; Blackwell; T. S. & Segal; B. H. (2011) Role of NADPH oxidase in host defense against aspergillosis. Med Mycol; 49 Suppl 1S144-9.
19. Gutierrez; M. J.; McSherry; G. D.; Ishmael; F. T.; Horwitz; A. A. & Nino; G. (2012) Residual NADPH oxidase activity and isolated lung involvement in x-linked chronic granulomatous disease. Case Rep Pediatr; 2012 974561.
20. Hazen; S. L.; Hsu; F. F.; Mueller; D. M.; Crowley; J. R. & Heinecke; J. W. (1996) Human neutrophils employ chlorine gas as an oxidant during phagocytosis. J Clin Invest; 98(6): 1283-9.
21. Heyworth; P. G.; Cross; A. R. & Curnutte; J. T. (2003) Chronic granulomatous disease. Curr Opin Immunol; 15(5): 578-84.
22. Hill; H. R.; Augustine; N. H.; Pryor; R. J.; Reed; G. H.; Bagnato; J. D.; Tebo; A. E.; Bender; J. M.; Pasi; B. M.; Chinen; J.; Hanson; I. C.; de Boer; M.; Roos; D. & Wittwer; C. T. (2010) Rapid genetic analysis of x-linked chronic granulomatous disease by high-resolution melting. J Mol Diagn; 12(3): 368-76.
23. Josephy; P. D.; Eling; T. & Mason; R. P. (1982) The horseradish peroxidase-catalyzed oxidation of 3;5;3′;5′-tetramethylbenzidine. Free radical and charge-transfer complex intermediates. J Biol Chem; 257: 3669-75.
24. Kang; E. M.; Marciano; B. E.; DeRavin; S.; Zarember; K. A.; Holland; S. M. & Malech; H. L. (2011) Chronic granulomatous disease: overview and hematopoietic stem cell transplantation. J Allergy Clin Immunol; 127(6): 1319-34.
25. Khalilzadeh; S.; Bloorsaz; M. R.; Mansouri; D.; Baghaie; N.; Hakimi; S. & Velayati; A. A. (2006) Clinical and radiological aspects of chronic granulomatous disease in children: a case series from Iran. Iran J Allergy Asthma Immunol; 5(2): 85-8.
26. Kim; I. D. & Ha; B. J. (2009) Paeoniflorin protects RAW 264.7 macrophages from LPS-induced cytotoxicity and genotoxicity. Toxicol In Vitro; 23: 1014-9.
27. Krause; K. H. (2007) Aging: a revisited theory based on free radicals generated by NOX family NADPH oxidases. Exp Gerontol; 42(4): 256-62.
28. Kumar; D. 2008. Genetic and Genomic Approaches to Taxonomy of Human Disease. In: Kumar; D. & Weatherall; D. (eds.) Genomics and Clinical Medicine. Oxford: Oxford University Press.
29. Lehmann; M. H. (1998) Recombinant human granulocyte-macrophage colony-stimulating factor triggers interleukin-10 expression in the monocytic cell line U937. Mol Immunol; 35: 479-85
30. Lequin; R. M. (2005) Enzyme immunoassay (EIA)/enzyme-linked immunosorbent assay (ELISA). Clin Chem; 51: 2415-8.
31. Mamishi; S.; Zomorodian; K.; Saadat; F.; Gerami-Shoar; M.; Tarazooie; B. & Siadati; S. A. (2005) A case of invasive aspergillosis in CGD patient successfully treated with Amphotericin B and INF-gamma. Ann Clin Microbiol Antimicrob; 44.
32. Marciano; B. E.; Wesley; R.; De Carlo; E. S.; Anderson; V. L.; Barnhart; L. A.; Darnell; D.; Malech; H. L.; Gallin; J. I. & Holland; S. M. (2004) Long-term interferon-gamma therapy for patients with chronic granulomatous disease. Clin Infect Dis; 39(5): 692-9.
33. Martinon, G.; Mayor, A. And Tschopp, J. (2009) The Inflammasones: Guardians of the Body. Annu. Rev. Immunol; 27: 229-65
34. Mosser; D. M. & Edwards; J. P. (2008) Exploring the full spectrum of macrophage activation. Nat Rev Immunol; 8(12): 958-69.
35. OMIM Statistics. (2013) Online Mendelian Inheritance in Man Statistics for January 7; 2013 [Online]. John Hopkins University. Available: http://www.ncbi.nlm.nih.gov/Omim/mimstats.html [Accessed 04/07/13
36. Pao; M.; Wiggs; E. A.; Anastacio; M. M.; Hyun; J.; DeCarlo; E. S.; Miller; J. T.; Anderson; V. L.; Malech; H. L.; Gallin; J. I. & Holland; S. M. (2004) Cognitive function in patients with chronic granulomatous disease: a preliminary report. Psychosomatics; 45(3): 230-4.
37. Pizzolla; A.; Hultqvist; M.; Nilson; B.; Grimm; M. J.; Eneljung; T.; Jonsson; I. M.; Verdrengh; M.; Kelkka; T.; Gjertsson; I.; Segal; B. H. & Holmdahl; R. (2012) Reactive oxygen species produced by the NADPH oxidase 2 complex in monocytes protect mice from bacterial infections. J Immunol; 188(10): 5003-11.
38. Rajakariar; R.; Newson; J.; Jackson; E. K.; Sawmynaden; P.; Smith; A.; Rahman; F.; Yaqoob; M. M. & Gilroy; D. W. (2009) Nonresolving inflammation in gp91phox-/- mice; a model of human chronic granulomatous disease; has lower adenosine and cyclic adenosine 5′-monophosphate. J Immunol; 182(5): 3262-9.
39. Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007) Dermatology;2(1)-4160-2999-0.
40. Roos; D.; Kuhns; D. B.; Maddalena; A.; Roesler; J.; Lopez; J. A.; Ariga; T.; Avcin; T.; de Boer; M.; Bustamante; J.; Condino-Neto; A.; Di Matteo; G.; He; J.; Hill; H. R.; Holland; S. M.; Kannengiesser; C.; Koker; M. Y.; Kondratenko; I.; van Leeuwen; K.; Malech; H. L.; Marodi; L.; Nunoi; H.; Stasia; M. J.; Ventura; A. M.; Witwer; C. T.; Wolach; B. & Gallin; J. I. (2010) Hematologically important mutations: X-linked chronic granulomatous disease (third update). Blood Cells Mol Dis; 45(3): 246-65.
41. Sadat; M. A.; Pech; N.; Saulnier; S.; Leroy; B. A.; Hossle; J. P.; Grez; M. & Dinauer; M. C. (2003) Long-term high-level reconstitution of NADPH oxidase activity in murine X-linked chronic granulomatous disease using a bicistronic vector expressing gp91phox and a Delta LNGFR cell surface marker. Hum Gene Ther; 14(7): 651-66.
42. Segal; A. W. & Abo; A. (1993) The biochemical basis of the NADPH oxidase of phagocytes. Trends Biochem Sci; 18(2): 43-7.
43. Segal; B. H.; Grimm; M. J.; Khan; A. N.; Han; W. & Blackwell; T. S. (2012) Regulation of innate immunity by NADPH oxidase. Free Radic Biol Med; 53(1): 72-80.
44. Segal; B. H.; Leto; T. L.; Gallin; J. I.; Malech; H. L. & Holland; S. M. (2000a) Genetic; biochemical; and clinical features of chronic granulomatous disease. Medicine (Baltimore); 79(3): 170-200.
45. Segal; B. H.; Sakamoto; N.; Patel; M.; Maemura; K.; Klein; A. S.; Holland; S. M. & Bulkley; G. B. (2000b) Xanthine oxidase contributes to host defense against Burkholderia cepacia in the p47(phox-/-) mouse model of chronic granulomatous disease. Infect Immun; 68(4): 2374-8.
46. Shi; Y.; Mucsi; A. D. & Ng; G. (2010) Monosodium urate crystals in inflammation and immunity. Immunol Rev; 233: 203-17.
47. Song; E.; Jaishankar; G. B.; Saleh; H.; Jithpratuck; W.; Sahni; R. & Krishnaswamy; G. (2011) Chronic granulomatous disease: a review of the infectious and inflammatory complications. Clin Mol Allergy; 9(1): 1-14.
48. Urban; C. F.; Reichard; U.; Brinkmann; V. & Zychlinsky; A. (2006) Neutrophil extracellular traps capture and kill Candida albicans yeast and hyphal forms. Cell Microbiol; 8(4): 668-76.
49. Uzel; G.; Orange; J. S.; Poliak; N.; Marciano; B. E.; Heller; T. & Holland; S. M. (2010) Complications of Tumor Necrosis Factor-± Blockade in Chronic Granulomatous Disease—Related Colitis. Clinical Infectious Diseases; 51(12): 1429-1434.
50. van de Veerdonk, F.L.; Smeekens, S.P.; Joosten, L.A.B.; Kullberg, B.J.; Dinarello, C.A.; van der Meer, J.W.M. and Netea, M.G. (2010) Reactive oxygen species-independent activation of the IL-1β inflammasome in cells from patients with chronic granulomatous disease. PNAS; 107(7): 3030-33
51. van den Berg; J. M.; van Koppen; E.; Ahlin; A.; Belohradsky; B. H.; Bernatowska; E.; Corbeel; L.; Espanol; T.; Fischer; A.; Kurenko-Deptuch; M.; Mouy; R.; Petropoulou; T.; Roesler; J.; Seger; R.; Stasia; M. J.; Valerius; N. H.; Weening; R. S.; Wolach; B.; Roos; D. & Kuijpers; T. W. (2009) Chronic granulomatous disease: the European experience. PLoS One; 4(4): e5234.
52. van Meerloo; J.; Kaspers; G. J. & Cloos; J. (2011) Cell sensitivity assays: the MTT assay. Methods Mol Biol; 731: 237-45.
53. Vignais; P. V. (2002) The superoxide-generating NADPH oxidase: structural aspects and activation mechanism. Cell Mol Life Sci; 59(9): 1428-59.
54. von Löhneysen; K.; Noack; D.; Wood; M. R.; Friedman; J. S. & Knaus; U. G. (2010) Structural insights into Nox4 and Nox2: motifs involved in function and cellular localization. Mol Cell Biol; 30(4): 961-75.
55. West; A. P.; Brodsky; I. E.; Rahner; C.; Woo; D. K.; Erdjument-Bromage; H.; Tempst; P.; Walsh; M. C.; Choi; Y.; Shadel; G. S. & Ghosh; S. (2011) TLR signalling augments macrophage bactericidal activity through mitochondrial ROS. Nature; 472(7344): 476-80.
56. Winkelstein; J. A.; Marino; M. C.; Johnston; R. B.; Jr.; Boyle; J.; Curnutte; J.; Gallin; J. I.; Malech; H. L.; Holland; S. M.; Ochs; H.; Quie; P.; Buckley; R. H.; Foster; C. B.; Chanock; S. J. & Dickler; H. (2000) Chronic granulomatous disease. Report on a national registry of 368 patients. Medicine (Baltimore); 79(3): 155-69.
57. Yi; L.; Liu; Q.; Orandle; M. S.; Sadiq-Ali; S.; Koontz; S. M.; Choi; U.; Torres-Velez; F. J. & Jackson; S. H. (2012) p47(phox) directs murine macrophage cell fate decisions. Am J Pathol; 180(3): 1049-58.
58. Yuzawa; S.; Ogura; K.; Horiuchi; M.; Suzuki; N.N.; Fujioka; Y.; Kataoka; M.; Sumimoto; H. And Inagaki; F. (2004) Solution Structure of the Tandem Src Homology 3 Domains of p47phox in an Autoinhibited Form. The Journal of Biological Chemistry; 279(28); 29752-29760.
59. Zhan; S.; Vazquez; N.; Wientjes; F. B.; Budarf; M. L.; Schrock; E.; Ried; T.; Green; E. D. & Chanock; S. J. (1996) Genomic structure; chromosomal localization; start of transcription; and tissue expression of the human p40-phox; a new component of the nicotinamide adenine dinucleotide phosphate-oxidase complex. Blood; 88(7): 2714-21.
60. Zhen; L.; King; A. A.; Xiao; Y.; Chanock; S. J.; Orkin; S. H. & Dinauer; M. C. (1993) Gene targeting of X chromosome-linked chronic granulomatous disease locus in a human myeloid leukemia cell line and rescue by expression of recombinant gp91phox. Proc Natl Acad Sci U S A; 90(21): 9832-6.