The online version of this article (doi:10.1186/1750-1326-9-50) contains supplementary material, which is available to authorized users.
Other- Michael P. Vitek is an employee of Duke University and is the CEO of Cognosci, Inc., Research Triangle Park, North Carolina. Carol A. Colton has spousal-based, non-financial competing interest with Cognosci, Inc. and with Oncotide, Inc. Vitek and Colton conflict of interest is managed by the Duke Committee on Conflict of Interest. Remaining authors (Wink, Ridnour, Hoos, Wilson, Jansen, Everhart) have no competing interests.
MH carried out the molecular genetic studies and the measurement of NOx activity; DW provided guidance on the chemical biology of NO and provided interpretation of results; LR provided interpretation of results and assisted with production of the manuscript; JW carried out the animal experimentation procedures; MJ carried out molecular gene analysis experiments; AE performed all histochemical studies; MV provided guidance on the molecular biological and mouse genetics; CC initiated and supervised the experimental aspects of the project including data analysis and production of the manuscript. All authors read and approved the final manuscript.
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.
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.
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.
Authors’ original file for figure 113024_2014_559_MOESM1_ESM.tif
Authors’ original file for figure 213024_2014_559_MOESM2_ESM.tif
Authors’ original file for figure 313024_2014_559_MOESM3_ESM.pdf
Authors’ original file for figure 413024_2014_559_MOESM4_ESM.tif
Authors’ original file for figure 513024_2014_559_MOESM5_ESM.tif
Authors’ original file for figure 613024_2014_559_MOESM6_ESM.tif
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. 10.1056/NEJMoa1304839. PubMedCentralCrossRefPubMed
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: e13950-10.1371/journal.pone.0013950. PubMedCentralCrossRefPubMed
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: e117-10.1038/tp.2012.45. PubMedCentralCrossRefPubMed
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. 10.1016/j.ajhg.2008.10.008. PubMedCentralCrossRefPubMed
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. 10.1016/j.cell.2013.03.030. PubMedCentralCrossRefPubMed
Guerreiro R, Hardy J: TREM2 and neurodegenerative disease. N Engl J Med. 2013, 369: 1569-1570. PubMed
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. 10.1073/pnas.1222878110. PubMedCentralCrossRefPubMed
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
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. PubMed
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. 10.1038/sj.bjp.0702039. PubMedCentralCrossRefPubMed
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. 10.1016/j.freeradbiomed.2008.03.020. PubMedCentralCrossRefPubMed
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. 10.1089/ars.2006.8.893. CrossRefPubMed
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
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: 24-10.1186/1742-2094-1-24. PubMedCentralCrossRefPubMed
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. 10.1093/brain/aws012. PubMedCentralCrossRefPubMed
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. 10.1016/S0304-3940(02)00095-2. CrossRefPubMed
Malinski T: Nitric oxide and nitroxidative stress in alzheimer’s disease. J Alzheimers Dis. 2007, 11: 207-218. PubMed
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. 10.1016/j.neuroscience.2004.06.030. CrossRefPubMed
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. CrossRef
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. 10.1097/NEN.0000000000000094. PubMedCentralCrossRefPubMed
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. 10.1523/JNEUROSCI.5066-07.2008. PubMedCentralCrossRefPubMed
- The impact of human and mouse differences in NOS2 gene expression on the brain’s redox and immune environment
Michael D Hoos
Michael P Vitek
Lisa A Ridnour
David A Wink
Carol A Colton
- BioMed Central
Neu in den Fachgebieten Neurologie und Psychiatrie
Meistgelesene Bücher in der Neurologie & Psychiatrie