Sirtuin 1-Chromatin-Binding Dynamics Points to a Common Mechanism Regulating Inflammatory Targets in SIV Infection and in the Aging Brain

Nikki Bortell, Liana Basova, Julia A. Najera, Brenda Morsey, Howard S Fox, Maria Cecilia Garibaldi Marcondes

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)163-178
Number of pages16
JournalJournal of Neuroimmune Pharmacology
Volume13
Issue number2
DOIs
StatePublished - Jun 1 2018

Fingerprint

Sirtuin 1
Chromatin
Brain
Microglia
Myeloid Cells
Infection
HIV Infections
Macrophages
Genes
Macaca
Gene Silencing
Macaca mulatta
Neurodegenerative Diseases
Monocytes
Inflammation
Cell Line
Survival
Health

Keywords

  • Aging
  • HIV
  • Microglia
  • Neuroinflammation
  • SIV
  • Sirtuin-1

ASJC Scopus subject areas

  • Neuroscience (miscellaneous)
  • Immunology and Allergy
  • Immunology
  • Pharmacology

Cite this

Sirtuin 1-Chromatin-Binding Dynamics Points to a Common Mechanism Regulating Inflammatory Targets in SIV Infection and in the Aging Brain. / Bortell, Nikki; Basova, Liana; Najera, Julia A.; Morsey, Brenda; Fox, Howard S; Marcondes, Maria Cecilia Garibaldi.

In: Journal of Neuroimmune Pharmacology, Vol. 13, No. 2, 01.06.2018, p. 163-178.

Research output: Contribution to journalArticle

Bortell, Nikki ; Basova, Liana ; Najera, Julia A. ; Morsey, Brenda ; Fox, Howard S ; Marcondes, Maria Cecilia Garibaldi. / Sirtuin 1-Chromatin-Binding Dynamics Points to a Common Mechanism Regulating Inflammatory Targets in SIV Infection and in the Aging Brain. In: Journal of Neuroimmune Pharmacology. 2018 ; Vol. 13, No. 2. pp. 163-178.
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