Abstract
Microglia and macrophages are the main non-neuronal subsets of myeloid origin in the brain, and are critical regulators in neurodegenerative disorders, where inflammation is a key factor. Since HIV infection results in neurological perturbations that are similar to those in aging, we examined microglial and infiltrating myeloid subsets in the search for changes that might resemble the ones in aging. For that, we used the SIV infection in rhesus macaques to model neuroAIDS. We found that Sirt-1, a molecule that impacts survival and health in many models, was decreased in cell preparations containing a majority of microglia and myeloid cells from the brain of infected macaques. The role of Sirt-1 in neuroAIDS is unknown. We hypothesized that Sirt-1 silencing functions are affected by SIV. Mapping of Sirt-1 binding patterns to chromatin revealed that the number of Sirt-1-bound genes was 29.6% increased in myeloid cells from infected animals with mild or no detectable neuropathology, but 51% was decreased in severe neuropathology, compared to controls. Importantly, Sirt-1-bound genes in controls largely participate in neuroinflammation. Promoters of type I IFN pathway genes IRF7, IRF1, IFIT1, and AIF1, showed Sirt-1 binding in controls, which was consistently lost after infection, together with higher transcription. Loss of Sirt-1 binding was also found in brains from old uninfected animals, suggesting a common regulation. The role of Sirt-1 in regulating these inflammatory markers was confirmed in two different in vitro models, where Sirt-1 blockage modulated IRF7, IRF1 and AIF1 levels both in human macrophage cell lines and in human blood-derived monocytes from various normal donors, stimulated with a TLR9 agonist. Our data suggests that Sirt-1-inflammatory gene silencing is disturbed by SIV infection, resembling aging in brains. These findings may impact our knowledge on the contribution of myeloid subsets to the neurological consequences of HIV infection, aggravated and overlapping with the aging process.
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Acknowledgements
The authors would like to thank Steven A. Totusek (University of Nebraska Medical Center, Omaha, NE) for the help on depositing the ChIP data into the Gene Expression Omnibus (GEO) system. We thank Dr. Douglas Galasko (Department of Neurosciences, University of California, San Diego - UCSD, and Director of the UCSD Shiley-Marcos Alzheimer's Disease Research Center (ADRC), for important discussions and critical guidance throughout the study. We want to deeply thank the NIH National Institute of Aging Non Human Primate Tissue Repository, at the Wisconsin National Primate Center, for the amazing resource it provides. We also want to thank Dr. Lindsay Whitton for the use of his microscope. This work has been funded by NIH/NIDA grant R01DA036164 and by NIH/NIA grant R21AG054240 to MCGM.
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NB prepared cells for ChIP procedures, analyzed the data, performed most PCRs, and helped write the manuscript.
LB performed all the in vitro assays, the PCRs related to those experiments, and helped write the methods session of the manuscript.
JAN performed cell fixations and participated in discussions.
BM provided paraffin sections from SIV-infected macaques and controls.
HSF was present in all the necropsies, provided samples from macaques, participated in all discussions, and proofread the manuscript.
MCGM designed the study, was present in necropsies, performed cell and tissue isolation, analyzed data, performed systems analysis, performed PCRs, obtained funding and wrote the manuscript.
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Bortell, N., Basova, L., Najera, J.A. et al. Sirtuin 1-Chromatin-Binding Dynamics Points to a Common Mechanism Regulating Inflammatory Targets in SIV Infection and in the Aging Brain. J Neuroimmune Pharmacol 13, 163–178 (2018). https://doi.org/10.1007/s11481-017-9772-3
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DOI: https://doi.org/10.1007/s11481-017-9772-3