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

Publication ,  Journal Article
Hoos, MD; Vitek, MP; Ridnour, LA; Wilson, J; Jansen, M; Everhart, A; Wink, DA; Colton, CA
Published in: Mol Neurodegener
November 17, 2014

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 HuNOS2tg/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 HuNOS2tg/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). HuNOS2tg/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 HuNOS2tg/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 HuNOS2tg/mNos2-/- mice provide a potentially useful mechanism to address critical species- specific immune differences that can impact the study of human diseases.

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Published In

Mol Neurodegener

DOI

EISSN

1750-1326

Publication Date

November 17, 2014

Volume

9

Start / End Page

50

Location

England

Related Subject Headings

  • Transcriptome
  • Species Specificity
  • Oxidative Stress
  • Oxidation-Reduction
  • Nitric Oxide Synthase Type II
  • Neurology & Neurosurgery
  • Mice
  • Humans
  • Disease Models, Animal
  • Brain
 

Citation

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Hoos, M. D., Vitek, M. P., Ridnour, L. A., Wilson, J., Jansen, M., Everhart, A., … Colton, C. A. (2014). The impact of human and mouse differences in NOS2 gene expression on the brain's redox and immune environment. Mol Neurodegener, 9, 50. https://doi.org/10.1186/1750-1326-9-50
Hoos, Michael D., Michael P. Vitek, Lisa A. Ridnour, Joan Wilson, Marilyn Jansen, Angela Everhart, David A. Wink, and Carol A. Colton. “The impact of human and mouse differences in NOS2 gene expression on the brain's redox and immune environment.Mol Neurodegener 9 (November 17, 2014): 50. https://doi.org/10.1186/1750-1326-9-50.
Hoos MD, Vitek MP, Ridnour LA, Wilson J, Jansen M, Everhart A, et al. The impact of human and mouse differences in NOS2 gene expression on the brain's redox and immune environment. Mol Neurodegener. 2014 Nov 17;9:50.
Hoos, Michael D., et al. “The impact of human and mouse differences in NOS2 gene expression on the brain's redox and immune environment.Mol Neurodegener, vol. 9, Nov. 2014, p. 50. Pubmed, doi:10.1186/1750-1326-9-50.
Hoos MD, Vitek MP, Ridnour LA, Wilson J, Jansen M, Everhart A, Wink DA, Colton CA. The impact of human and mouse differences in NOS2 gene expression on the brain's redox and immune environment. Mol Neurodegener. 2014 Nov 17;9:50.
Journal cover image

Published In

Mol Neurodegener

DOI

EISSN

1750-1326

Publication Date

November 17, 2014

Volume

9

Start / End Page

50

Location

England

Related Subject Headings

  • Transcriptome
  • Species Specificity
  • Oxidative Stress
  • Oxidation-Reduction
  • Nitric Oxide Synthase Type II
  • Neurology & Neurosurgery
  • Mice
  • Humans
  • Disease Models, Animal
  • Brain