Department of Biology, University of Rome Tor Vergata, Rome, 00133, Italy.
UniCamillus-Saint Camillus International University of Health and Medical Sciences, Rome, 00131, Italy.
Cell Commun Signal. 2024 Nov 25;22(1):564. doi: 10.1186/s12964-024-01947-6.
Microglia play a crucial role in brain development and repair by facilitating processes such as synaptic pruning and debris clearance. They can be activated in response to various stimuli, leading to either pro-inflammatory or anti-inflammatory responses associated with specific metabolic alterations. The imbalances between microglia activation states contribute to chronic neuroinflammation, a hallmark of neurodegenerative diseases. N-acetylaspartate (NAA) is a brain metabolite predominantly produced by neurons and is crucial for central nervous system health. Alterations in NAA metabolism are observed in disorders such as Multiple Sclerosis and Canavan disease. While NAA's role in oligodendrocytes and astrocytes has been investigated, its impact on microglial function remains less understood.
The murine BV2 microglial cell line and primary microglia were used as experimental models. Cells were treated with exogenous NAA and stimulated with LPS/IFN-γ to reproduce the pro-inflammatory phenomenon. HPLC and immunofluorescence analysis were used to study lipid metabolism following NAA treatment. Automated fluorescence microscopy was used to analyze phagocytic activity. The effects on the pro-inflammatory response were evaluated by analysis of protein/mRNA expression and ChIP assay of typical inflammatory markers.
NAA treatment promotes an increase in both lipid synthesis and degradation, and enhances the phagocytic activity of BV2 cells, thus fostering surveillant microglia characteristics. Importantly, NAA decreases the pro-inflammatory state induced by LPS/IFN-γ via the activation of histone deacetylases (HDACs). These findings were validated in primary microglial cells, highlighting the impact on cellular metabolism and inflammatory responses.
The study highlighted the role of NAA in reinforcing the oxidative metabolism of surveillant microglial cells and, most importantly, in buffering the inflammatory processes characterizing reactive microglia. These results suggest that the decreased levels of NAA observed in neurodegenerative disorders can contribute to chronic neuroinflammation.
小胶质细胞在脑发育和修复中起着至关重要的作用，通过促进突触修剪和碎片清除等过程。它们可以响应各种刺激而被激活，导致与特定代谢改变相关的促炎或抗炎反应。小胶质细胞激活状态的失衡导致慢性神经炎症，这是神经退行性疾病的一个标志。N-乙酰天冬氨酸（NAA）是一种主要由神经元产生的脑代谢物，对中枢神经系统的健康至关重要。在多发性硬化症和 Canavan 病等疾病中观察到 NAA 代谢的改变。虽然已经研究了 NAA 在少突胶质细胞和星形胶质细胞中的作用，但它对小胶质细胞功能的影响仍知之甚少。
使用鼠 BV2 小胶质细胞系和原代小胶质细胞作为实验模型。用外源性 NAA 处理细胞，并以 LPS/IFN-γ 刺激以重现促炎现象。使用 HPLC 和免疫荧光分析研究 NAA 处理后脂质代谢的变化。使用自动荧光显微镜分析吞噬活性。通过分析蛋白质/信使 RNA 表达和典型炎症标志物的 ChIP 测定来评估对促炎反应的影响。
NAA 处理促进了脂质合成和降解的增加，并增强了 BV2 细胞的吞噬活性，从而促进了监视小胶质细胞的特征。重要的是，NAA 通过激活组蛋白去乙酰化酶（HDACs）降低了 LPS/IFN-γ 诱导的促炎状态。这些发现在原代小胶质细胞中得到了验证，突出了其对细胞代谢和炎症反应的影响。
该研究强调了 NAA 在增强监视小胶质细胞的氧化代谢中的作用，最重要的是，在缓冲表征反应性小胶质细胞的炎症过程中。这些结果表明，神经退行性疾病中观察到的 NAA 水平降低可能导致慢性神经炎症。
