The impact of human and mouse differences in NOS2 gene expression on the brain’s redox and immune environment

Molecular Neurodegeneration

Carol A Colton³  David A Wink²  Angela Everhart³  Marilyn Jansen³  Joan Wilson³  Lisa A Ridnour²  Michael P Vitek³  Michael D Hoos¹ 

[1] Department of Neurosurgery, Stonybrook Health Sciences, Stony Brook, NY 11794, USA;Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA;Department of Neurology, Duke University Medical Center, Durham, NC 27710, USA

关键词: Nitric oxide;    Inflammation;    Redox;    Neurodegeneration;    Mouse models;    NOS2;   

Others  :  1138628
DOI  :  10.1186/1750-1326-9-50

 received in 2014-05-15, accepted in 2014-10-10,  发布年份 2014

【 摘 要 】

Background

Mouse models are used in the study of human disease. Despite well-known homologies, the difference in immune response between mice and humans impacts the application of data derived from mice to human disease outcomes. Nitric oxide synthase-2 (NOS2) is a key gene that displays species-specific outcomes via altered regulation of the gene promoter and via post-transcriptional mechanisms in humans that are not found in mice. The resulting levels of NO produced by activation of human NOS2 are different from the levels of NO produced by mouse Nos2. Since both tissue redox environment and immune responsiveness are regulated by the level of NO and its interactions, we investigated the significance of mouse and human differences on brain oxidative stress and on immune activation in HuNOS2^tg/mNos2^-/- mice that express the entire human NOS2 gene and that lack a functional mNos2 compared to wild type (WT) mice that express normal mNos2.

Methods/results

Similarly to human, brain tissue from HuNOS2^tg/mNos2^-/- mice showed the presence of a NOS2 gene 3′UTR binding site. We also identified miRNA-939, the binding partner for this site, in mouse brain lysates and further demonstrated reduced levels of nitric oxide (NO) typical of the human immune response on injection with lipopolysaccharide (LPS). HuNOS2^tg/mNos2^-/- brain samples were probed for characteristic differences in redox and immune gene profiles compared to WT mice using gene arrays. Selected genes were also compared against mNos2^-/- brain lysates. Reconstitution of the human NOS2 gene significantly altered genes that encode multiple anti-oxidant proteins, oxidases, DNA repair, mitochondrial proteins and redox regulated immune proteins. Expression levels of typical pro-inflammatory, anti-inflammatory and chemokine genes were not significantly different with the exception of increased TNFα and Ccr1 mRNA expression in the HuNOS2^tg/mNos2^-/- mice compared to WT or mNos2^-/- mice.

Conclusions

NO is a principle factor in establishing the tissue redox environment and changes in NO levels impact oxidative stress and immunity, both of which are primary characteristics of neurodegenerative diseases. The HuNOS2^tg/mNos2^-/- mice provide a potentially useful mechanism to address critical species- specific immune differences that can impact the study of human diseases.

【 授权许可】

   
2014 Hoos et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Galasko D, Bell J, Mancuso JY, Kupiec JW, Sabbagh MN, van Dyck C, Thomas RG, Aisen PS: Clinical trial of an inhibitor of RAGE-abeta interactions in alzheimer disease. Neurology 2014, 82:1536-1542.
• [2]Salloway S, Sperling R, Fox NC, Blennow K, Klunk W, Raskind M, Sabbagh M, Honig LS, Porsteinsson AP, Ferris S, Reichert M, Ketter N, Nejadnik B, Guenzler V, Miloslavsky M, Wang D, Lu Y, Lull J, Tudor IC, Liu E, Grundman M, Yuen E, Black R, Brashear HR, Bapineuzumab 301 and 303 clinical trial investigators: Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N Engl J Med 2014, 370:322-333.
• [3]Becker RE, Greig NH, Giacobini E: Why do so many drugs for alzheimer’s disease fail in development? Time for new methods and new practices? J Alzheimers Dis 2008, 15:303-325.
• [4]Schor NF: What the halted phase III gamma-secretase inhibitor trial may (or may not) be telling us. Ann Neurol 2011, 69:237-239.
• [5]Finch CE, Marchalonis JJ: Evolutionary perspectives on amyloid and inflammatory features of Alzheimer disease. Neurobiol Aging 1996, 17:809-815.
• [6]Griffin WS, Sheng JG, Royston MC, Gentleman SM, McKenzie JE, Graham DI, Roberts GW, Mrak RE: Glial-neuronal interactions in alzheimer’s disease: the potential role of a ‘cytokine cycle’ in disease progression. Brain Pathol 1998, 8:65-72.
• [7]Mrak RE, Griffin WS: Glia and their cytokines in progression of neurodegeneration. Neurobiol Aging 2005, 26:349-354.
• [8]Eikelenboom P, van Exel E, Hoozemans JJ, Veerhuis R, Rozemuller AJ, van Gool WA: Neuroinflammation - an early event in both the history and pathogenesis of alzheimer’s disease. Neurodegener Dis 2010, 7:38-41.
• [9]Akiyama H, McGeer PL: Brain microglia constitutively express beta-2 integrins. J Neuroimmunol 1990, 30:81-93.
• [10]McGeer PL, Itagaki S, Tago H, McGeer EG: Reactive microglia in patients with senile dementia of the alzheimer type are positive for the histocompatibility glycoprotein HLA-DR. Neurosci Lett 1987, 79:195-200.
• [11]Jones L, Holmans PA, Hamshere ML, Harold D, Moskvina V, Ivanov D, Pocklington A, Abraham R, Hollingworth P, Sims R, Gerrish A, Pahwa JS, Jones N, Stretton A, Morgan AR, Lovestone S, Powell J, Proitsi P, Lupton MK, Brayne C, Rubinsztein DC, Gill M, Lawlor N, Lynch A, Morgan K, Brown KS, Passmore PA, Craig D, McGuinness B, Todd S, et al.: Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of alzheimer’s disease. PLoS One 2010, 5:e13950.
• [12]Kamboh MI, Demirci FY, Wang X, Minster RL, Carrasquillo MM, Pankratz VS, Younkin SG, Saykin AJ, Jun G, Baldwin C, Logue MW, Buros J, Farrer L, Pericak-Vance MA, Haines JL, Sweet RA, Ganguli M, Feingold E, DeKosky ST, Lopez OL, Barmada MM, for the Alzheimer’s Disease Neuroimaging Initiative: Genome-wide association study of alzheimer’s disease. Transl Psychiatry 2012, 2:e117.
• [13]Morgan K: The three new pathways leading to alzheimer’s disease. Neuropathol Appl Neurobiol 2011, 37:353-357.
• [14]Colton CA, Brown CM, Vitek MP: Sex steroids, APOE genotype and the innate immune system. Neurobiol Aging 2005, 26:363-372.
• [15]Crehan H, Holton P, Wray S, Pocock J, Guerreiro R, Hardy J: Complement receptor 1 (CR1) and alzheimer’s disease. Immunobiology 2012, 217:244-250.
• [16]Bertram L, Lange C, Mullin K, Parkinson M, Hsiao M, Hogan MF, Schjeide BM, Hooli B, Divito J, Ionita I, Jiang H, Laird N, Moscarillo T, Ohlsen KL, Elliott K, Wang X, Hu-Lince D, Ryder M, Murphy A, Wagner SL, Blacker D, Becker KD, Tanzi RE: Genome-wide association analysis reveals putative alzheimer’s disease susceptibility loci in addition to APOE. Am J Hum Genet 2008, 83:623-632.
• [17]Zhang B, Gaiteri C, Bodea LG, Wang Z, McElwee J, Podtelezhnikov AA, Zhang C, Xie T, Tran L, Dobrin R, Fluder E, Clurman B, Melquest S, Narayanan M, Suver C, Shah H, Mahajan M, Gillis T, Mysore J, MacDonald M, Lamb JR, Bennett DA, Molony C, Stone DJ, Gudnason V, Myers AJ, Schadt EE, Neumann H, Zhu J, Emilsson V: Integrated systems approach identifies genetic nodes and networks in late-onset alzheimer’s disease. Cell 2013, 153:707-720.
• [18]Guerreiro R, Hardy J: TREM2 and neurodegenerative disease. N Engl J Med 2013, 369:1569-1570.
• [19]Seok J, Warren HS, Cuenca AG, Mindrinos MN, Baker HV, Xu W, Richards DR, McDonald-Smith GP, Gao H, Hennessy L, Finnerty CC, Lopez CM, Honari S, Moore EE, Minei JP, Cushieri J, Bankey PE, Johnson JL, Sperry J, Nathens AB, Billiar TR, West MA, Jeschke MG, Klein PH, Gamelli RL, Gibran NS, Brownstein BH, Miller-Graziano C, Calvano ES, Mason PH, Cobb JP, et al.: Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc Natl Acad Sci U S A 2013, 110:3507-3512.
• [20]Takao K, Miyakawa T: Genomic responses in mouse models greatly mimic human inflammatory diseases. Proc Natl Acad Sci U S A 2014. Aug 4, E pub ahead of print
• [21]Mestas J, Hughes CC: Of mice and not men: differences between mouse and human immunology. J Immunol 2004, 172:2731-2738.
• [22]Colton CA: Induction of nitric oxide in cultured microglia: evidence for a cytoprotective role. Adv Neuroimmunol 1995, 5:491-503.
• [23]Colton C, Wilt S, Gilbert D, Chernyshev O, Snell J, Dubois-Dalcq M: Species differences in the generation of reactive oxygen species by microglia. Mol Chem Neuropathol 1996, 28:15-20.
• [24]Weinberg JB, Misukonis MA, Shami PJ, Mason SN, Sauls DL, Dittman WA, Wood ER, Smith GK, McDonald B, Bachus KE, Haney AF, Granger DL: Human mononuclear phagocyte inducible nitric oxide synthase (iNOS): analysis of iNOS mRNA, iNOS protein, biopterin, and nitric oxide production by blood monocytes and peritoneal macrophages. Blood 1995, 86:1184-1195.
• [25]Taylor BS, de Vera ME, Ganster RW, Wang Q, Shapiro RA, Morris SM Jr, Billiar TR, Geller DA: Multiple NF-kappaB enhancer elements regulate cytokine induction of the human inducible nitric oxide synthase gene. J Biol Chem 1998, 273:15148-15156.
• [26]Schneemann M, Schoeden G: Macrophage biology and immunology: man is not a mouse. J Leukoc Biol 2007, 81:579. discussion 580
• [27]Haley PJ: Species differences in the structure and function of the immune system. Toxicology 2003, 188:49-71.
• [28]Ganster RW, Taylor BS, Shao L, Geller DA: Complex regulation of human inducible nitric oxide synthase gene transcription by Stat 1 and NF-kappa B. Proc Natl Acad Sci U S A 2001, 98:8638-8643.
• [29]Guo Z, Shao L, Zheng L, Du Q, Li P, John B, Geller DA: miRNA-939 regulates human inducible nitric oxide synthase posttranscriptional gene expression in human hepatocytes. Proc Natl Acad Sci U S A 2012, 109:5826-5831.
• [30]Du Q, Park KS, Guo Z, He P, Nagashima M, Shao L, Sahai R, Geller DA, Hussain SP: Regulation of human nitric oxide synthase 2 expression by Wnt beta-catenin signaling. Cancer Res 2006, 66:7024-7031.
• [31]Guo Z, Shao L, Du Q, Park KS, Geller DA: Identification of a classic cytokine-induced enhancer upstream in the human iNOS promoter. FASEB J 2007, 21:535-542.
• [32]Kleinert H, Wallerath T, Fritz G, Ihrig-Biedert I, Rodriguez-Pascual F, Geller DA, Forstermann U: Cytokine induction of NO synthase II in human DLD-1 cells: roles of the JAK-STAT, AP-1 and NF-kappaB-signaling pathways. Br J Pharmacol 1998, 125:193-201.
• [33]Kobzik L: Translating NO biology into clinical advances: still searching for the right dictionary? Am J Respir Cell Mol Biol 2009, 41:9-13.
• [34]Wink DA, Hines HB, Cheng RY, Switzer CH, Flores-Santana W, Vitek MP, Ridnour LA, Colton CA: Nitric oxide and redox mechanisms in the immune response. J Leukoc Biol 2011, 89:873-891.
• [35]Colton CA, Wilcock DM, Wink DA, Davis J, Van Nostrand WE, Vitek MP: The effects of NOS2 gene deletion on mice expressing mutated human AbetaPP. J Alzheimers Dis 2008, 15:571-587.
• [36]Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, Yang F, Cole G: Correlative memory deficits, abeta elevation, and amyloid plaques in transgenic mice. Science 1996, 274:99-102.
• [37]Sullivan PM, Mezdour H, Quarfordt SH, Maeda N: Type III hyperlipoproteinemia and spontaneous atherosclerosis in mice resulting from gene replacement of mouse apoe with human apoe*2. J Clin Invest 1998, 102:130-135.
• [38]Geller DA, Billiar TR: Molecular biology of nitric oxide synthases. Cancer Metastasis Rev 1998, 17:7-23.
• [39]Fukuto JM, Cisneros CJ, Kinkade RL: A comparison of the chemistry associated with the biological signaling and actions of nitroxyl (HNO) and nitric oxide (NO). J Inorg Biochem 2013, 118:201-208.
• [40]Ridnour LA, Thomas DD, Mancardi D, Espey MG, Miranda KM, Paolocci N, Feelisch M, Fukuto J, Wink DA: The chemistry of nitrosative stress induced by nitric oxide and reactive nitrogen oxide species. Putting perspective on stressful biological situations. Biol Chem 2004, 385:1-10.
• [41]Toledo JC Jr, Augusto O: Connecting the chemical and biological properties of nitric oxide. Chem Res Toxicol 2012, 25:975-989.
• [42]Thomas DD, Ridnour LA, Isenberg JS, Flores-Santana W, Switzer CH, Donzelli S, Hussain P, Vecoli C, Paolocci N, Ambs S, Colton CA, Harris CC, Roberts DD, Wink DA: The chemical biology of nitric oxide: implications in cellular signaling. Free Radic Biol Med 2008, 45:18-31.
• [43]Wink DA, Miranda KM, Espey MG, Pluta RM, Hewett SJ, Colton C, Vitek M, Feelisch M, Grisham MB: Mechanisms of the antioxidant effects of nitric oxide. Antioxid Redox Signal 2001, 3:203-213.
• [44]Thomas DD, Ridnour LA, Espey MG, Donzelli S, Ambs S, Hussain SP, Harris CC, DeGraff W, Roberts DD, Mitchell JB, Wink DA: Superoxide fluxes limit nitric oxide-induced signaling. J Biol Chem 2006, 281:25984-25993.
• [45]Vitek MP, Brown C, Xu Q, Dawson H, Mitsuda N, Colton CA: Characterization of NO and cytokine production in immune-activated microglia and peritoneal macrophages derived from a mouse model expressing the human NOS2 gene on a mouse NOS2 knockout background. Antioxid Redox Signal 2006, 8:893-901.
• [46]Combet S, Balligand JL, Lameire N, Goffin E, Devuyst O: A specific method for measurement of nitric oxide synthase enzymatic activity in peritoneal biopsies. Kidney Int 2000, 57:332-338.
• [47]Livak KJ, Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-delta delta C(T)) method. Methods 2001, 25:402-408.
• [48]Ambs S, Glynn SA: Candidate pathways linking inducible nitric oxide synthase to a basal-like transcription pattern and tumor progression in human breast cancer. Cell Cycle 2011, 10:619-624.
• [49]Ambs S, Merriam WG, Ogunfusika MO, Bennett WP, Ishibe N, Hussain SP, Tzeng EE, Geller DA, Billiar TR, Harris CC: p53 and vascular endothelial growth factor regulate tumor growth of NOS2-expressing human carcinoma cells. Nat Med 1998, 4:1371-1376.
• [50]Liu S, Grigoryan MM, Vasilevko V, Sumbria RK, Paganini-Hill A, Cribbs DH, Fisher MJ: Comparative analysis of H&E and prussian blue staining in a mouse model of cerebral microbleeds. J Histochem Cytochem 2014. July 25. E published ahead of print
• [51]Wilcock DM, Morgan D, Gordon MN, Taylor TL, Ridnour LA, Wink DA, Colton CA: Activation of matrix metalloproteinases following anti-abeta immunotherapy; implications for microhemorrhage occurrence. J Neuroinflammation 2011, 8:115. BioMed Central Full Text
• [52]Wilcock DM, Rojiani A, Rosenthal A, Subbarao S, Freeman MJ, Gordon MN, Morgan D: Passive immunotherapy against abeta in aged APP-transgenic mice reverses cognitive deficits and depletes parenchymal amyloid deposits in spite of increased vascular amyloid and microhemorrhage. J Neuroinflammation 2004, 1:24. BioMed Central Full Text
• [53]Yang Y, Estrada EY, Thompson JF, Liu W, Rosenberg GA: Matrix metalloproteinase-mediated disruption of tight junction proteins in cerebral vessels is reversed by synthetic matrix metalloproteinase inhibitor in focal ischemia in rat. J Cereb Blood Flow Metab 2007, 27:697-709.
• [54]Ridnour LA, Thomas DD, Switzer C, Flores-Santana W, Isenberg JS, Ambs S, Roberts DD, Wink DA: Molecular mechanisms for discrete nitric oxide levels in cancer. Nitric Oxide 2008, 19:73-76.
• [55]Bogdan C: Nitric oxide and the immune response. Nat Immunol 2001, 2:907-916.
• [56]Markesbery WR: Oxidative stress hypothesis in alzheimer’s disease. Free Radic Biol Med 1997, 23:134-147.
• [57]Floyd RA: Antioxidants, oxidative stress, and degenerative neurological disorders. Proc Soc Exp Biol Med 1999, 222:236-245.
• [58]Smith MA, Nunomura A, Zhu X, Takeda A, Perry G: Metabolic, metallic, and mitotic sources of oxidative stress in alzheimer disease. Antioxid Redox Signal 2000, 2:413-420.
• [59]Fischer MT, Sharma R, Lim JL, Haider L, Frischer JM, Drexhage J, Mahad D, Bradl M, van Horssen J, Lassmann H: NADPH oxidase expression in active multiple sclerosis lesions in relation to oxidative tissue damage and mitochondrial injury. Brain 2012, 135:886-899.
• [60]Gherasim C, Yadav PK, Kabil O, Niu WN, Banerjee R: Nitrite reductase activity and inhibition of H(2)S biogenesis by human cystathionine ss-synthase. PLoS One 2014, 9:e85544.
• [61]Haas J, Storch-Hagenlocher B, Biessmann A, Wildemann B: Inducible nitric oxide synthase and argininosuccinate synthetase: co-induction in brain tissue of patients with alzheimer’s dementia and following stimulation with beta-amyloid 1–42 in vitro. Neurosci Lett 2002, 322:121-125.
• [62]Malinski T: Nitric oxide and nitroxidative stress in alzheimer’s disease. J Alzheimers Dis 2007, 11:207-218.
• [63]Rodrigo J, Fernandez-Vizarra P, Castro-Blanco S, Bentura ML, Nieto M, Gomez-Isla T, Martinez-Murillo R, MartInez A, Serrano J, Fernandez AP: Nitric oxide in the cerebral cortex of amyloid-precursor protein (SW) Tg2576 transgenic mice. Neuroscience 2004, 128:73-89.
• [64]Ridnour L, Dhanapal S, Hoos M, Wilson J, Lee J, Cheng R, Brueggemann E, Hines H, Wilcock D, Vitek M, Wink DA, Colton CA: Nitric oxide-mediated regulation of beta-amyloid clearance via alterations of MMP-9/TIMP-1. J Neurochem 2012, 234:736-749.
• [65]Thomas DD, Espey MG, Pociask DA, Ridnour LA, Donzelli S, Wink DA: Asbestos redirects nitric oxide signaling through rapid catalytic conversion to nitrite. Cancer Res 2006, 66:11600-11604.
• [66]Radde R, Duma C, Goedert M, Jucker M: The value of incomplete mouse models of alzheimer’s disease. Eur J Nucl Med Mol Imaging 2008, 35(Suppl 1):S70-S74.
• [67]Colton CA, Wilson JG, Everhart A, Wilcock DM, Puolivali J, Heikkinen T, Oksman J, Jaaskelainen O, Lehtimaki K, Laitinen T, Vartiainen N, Vitek MP: mNos2 deletion and human NOS2 replacement in alzheimer disease models. J Neuropathol Exp Neurol 2014, 73:752-769.
• [68]Fernandez-Vizarra P, Fernandez AP, Castro-Blanco S, Encinas JM, Serrano J, Bentura ML, Munoz P, Martinez-Murillo R, Rodrigo J: Expression of nitric oxide system in clinically evaluated cases of alzheimer’s disease. Neurobiol Dis 2004, 15:287-305.
• [69]Braman RS, Hendrix SA: Nanogram nitrite and nitrate determination in environmental and biological materials by vanadium (III) reduction with chemiluminescence detection. Anal Chem 1989, 61:2715-2718.
• [70]Wilcock DM, Lewis MR, Van Nostrand WE, Davis J, Previti ML, Gharkholonarehe N, Vitek MP, Colton CA: Progression of amyloid pathology to alzheimer’s disease pathology in an amyloid precursor protein transgenic mouse model by removal of nitric oxide synthase 2. J Neurosci 2008, 28:1537-1545.