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CCR5 knockout prevents neuronal injury and behavioral impairment induced in a transgenic mouse model by a CXCR4-using HIV-1 glycoprotein 120.
- Source :
-
Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2014 Aug 15; Vol. 193 (4), pp. 1895-910. Date of Electronic Publication: 2014 Jul 16. - Publication Year :
- 2014
-
Abstract
- The innate immune system has been implicated in several neurodegenerative diseases, including HIV-1-associated dementia. In this study, we show that genetic ablation of CCR5 prevents microglial activation and neuronal damage in a transgenic model of HIV-associated brain injury induced by a CXCR4-using viral envelope gp120. The CCR5 knockout (KO) also rescues spatial learning and memory in gp120-transgenic mice. However, the CCR5KO does not abrogate astrocytosis, indicating it can occur independently from neuronal injury and behavioral impairment. To characterize further the neuroprotective effect of CCR5 deficiency we performed a genome-wide gene expression analysis of brains from HIVgp120tg mice expressing or lacking CCR5 and nontransgenic controls. A comparison with a human brain microarray study reveals that brains of HIVgp120tg mice and HIV patients with neurocognitive impairment share numerous differentially regulated genes. Furthermore, brains of CCR5 wild-type and CCR5KO gp120tg mice express markers of an innate immune response. One of the most significantly upregulated factors is the acute phase protein lipocalin-2 (LCN2). Using cerebrocortical cell cultures, we find that LCN2 is neurotoxic in a CCR5-dependent fashion, whereas inhibition of CCR5 alone is not sufficient to abrogate neurotoxicity of a CXCR4-using gp120. However, the combination of pharmacologic CCR5 blockade and LCN2 protects neurons from toxicity of a CXCR4-using gp120, thus recapitulating the finding in CCR5-deficient gp120tg mouse brain. Our study provides evidence for an indirect pathologic role of CCR5 and a novel protective effect of LCN2 in combination with inhibition of CCR5 in HIV-associated brain injury.<br /> (Copyright © 2014 by The American Association of Immunologists, Inc.)
- Subjects :
- Acute-Phase Proteins biosynthesis
Animals
CCR5 Receptor Antagonists
Cells, Cultured
Disease Models, Animal
Gene Expression Profiling
Gliosis
Lipocalin-2
Lipocalins biosynthesis
Maze Learning
Memory
Mice
Mice, Knockout
Microglia pathology
Oncogene Proteins biosynthesis
Receptors, CCR5 biosynthesis
Receptors, CXCR4 metabolism
Signal Transduction genetics
AIDS Dementia Complex genetics
Acute-Phase Proteins metabolism
HIV Envelope Protein gp120 genetics
HIV-1
Lipocalins metabolism
Oncogene Proteins metabolism
Receptors, CCR5 genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1550-6606
- Volume :
- 193
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Journal of immunology (Baltimore, Md. : 1950)
- Publication Type :
- Academic Journal
- Accession number :
- 25031461
- Full Text :
- https://doi.org/10.4049/jimmunol.1302915