Molecular and Cellular Neurosciences Department, The Scripps Research Institute, La Jolla, CA, USA.
San Diego Biomedical Research Institute, 10865 Road to Cure, Suite 100, San Diego, CA, 92121, USA.
J Neuroimmune Pharmacol. 2018 Jun;13(2):163-178. doi: 10.1007/s11481-017-9772-3. Epub 2017 Dec 26.
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.
小胶质细胞和巨噬细胞是大脑中主要的骨髓源性非神经元亚群，是神经退行性疾病中炎症的关键调节因子。由于 HIV 感染导致的神经紊乱与衰老相似，我们研究了小胶质细胞和浸润性骨髓细胞亚群，以寻找可能与衰老相似的变化。为此，我们使用 SIV 感染恒河猴来模拟神经艾滋病。我们发现，Sirt-1 是一种在许多模型中影响生存和健康的分子，在感染恒河猴大脑中含有大多数小胶质细胞和骨髓细胞的细胞制剂中减少。Sirt-1 在神经艾滋病中的作用尚不清楚。我们假设 Sirt-1 沉默功能受 SIV 影响。将 Sirt-1 结合模式映射到染色质上，结果表明，在轻度或无明显神经病理学的感染动物的骨髓细胞中，Sirt-1 结合的基因数量增加了 29.6%，而在严重神经病理学的动物中，与对照组相比，减少了 51%。重要的是，对照组中 Sirt-1 结合的基因主要参与神经炎症。I 型 IFN 途径基因 IRF7、IRF1、IFIT1 和 AIF1 的启动子在对照组中显示出 Sirt-1 结合，这种结合在感染后一致丢失，同时转录增加。在未感染的老年动物的大脑中也发现了 Sirt-1 结合的丢失，这表明存在共同的调节。在两种不同的体外模型中，Sirt-1 阻断通过 TLR9 激动剂刺激人巨噬细胞系和来自不同正常供体的人血源性单核细胞，证实了 Sirt-1 在调节这些炎症标志物中的作用。我们的数据表明，Sirt-1-炎症基因沉默被 SIV 感染扰乱，类似于大脑中的衰老。这些发现可能会影响我们对骨髓细胞亚群对 HIV 感染的神经后果的贡献的认识，这种影响因衰老过程而加重和重叠。
