背景:大气颗粒物(PM)暴露诱导的神经炎症在介导神经系统损害中至关重要。然而,有效的干预措施有待发展。
结果:在这项研究中,我们研究了补充β-烟酰胺单核苷酸(NMN)对PM暴露后神经系统损伤的影响以及脂质代谢的空间调节机制。将120只C57BL/6雄性小鼠暴露于真实环境PM下11天(亚急性)或16周(亚慢性)。NMN补充将小鼠脑中烟酰胺腺嘌呤二核苷酸(NAD+)的水平提高了2.04倍。这种增强有效地减少了神经炎症,各个脑区激活的小胶质细胞水平显著下降,从29.29%到85.96%不等。全脑脂质组学分析显示,NMN干预导致亚急性PM暴露后大脑中神经酰胺(Cer)和溶血磷脂水平降低,亚慢性PM暴露后,甘油三酯(TG)和甘油磷脂(GP)逆转,赋予小鼠抗神经炎症反应,改善免疫功能,和增强膜的稳定性。此外,我们证明海马和下丘脑可能是对PM暴露和NMN补充反应最敏感的脑区.特别是,TG的改变(60:10,56:2,60:7),二酰基甘油(DG,42:6),和溶血磷脂酰胆碱(LPC,18:3)是最深刻的,与功能注释的变化和包括氧化应激在内的途径的扰动相关,炎症,空间转录组学分析揭示了膜的不稳定性。
结论:这项研究表明,NMN干预通过调节空间脂质代谢有效地减少了PM暴露后海马和下丘脑的神经炎症。针对脂质稳态改善的策略可以提供针对与空气污染物暴露相关的脑损伤的显著保护。
BACKGROUND: Atmospheric particulate matter (PM) exposure-induced neuroinflammation is critical in mediating nervous system impairment. However, effective intervention is yet to be developed.
RESULTS: In this study, we examine the effect of β-nicotinamide mononucleotide (NMN) supplementation on nervous system damage upon PM exposure and the mechanism of spatial regulation of lipid metabolism. 120 C57BL/6 male mice were exposed to real ambient PM for 11 days (subacute) or 16 weeks (sub-chronic). NMN supplementation boosted the level of nicotinamide adenine dinucleotide (NAD+) in the mouse brain by 2.04 times. This augmentation effectively reduced neuroinflammation, as evidenced by a marked decrease in activated microglia levels across various brain regions, ranging from 29.29 to 85.96%. Whole brain lipidomics analysis revealed that NMN intervention resulted in an less increased levels of ceramide (Cer) and lysophospholipid in the brain following subacute PM exposure, and reversed triglyceride (TG) and glycerophospholipids (GP) following sub-chronic PM exposure, which conferred mice with anti-neuroinflammation response, improved immune function, and enhanced membrane stability. In addition, we demonstrated that the hippocampus and hypothalamus might be the most sensitive brain regions in response to PM exposure and NMN supplementation. Particularly, the alteration of TG (60:10, 56:2, 60:7), diacylglycerol (DG, 42:6), and lysophosphatidylcholine (LPC, 18:3) are the most profound, which correlated with the changes in functional annotation and perturbation of pathways including oxidative stress, inflammation, and membrane instability unveiled by spatial transcriptomic analysis.
CONCLUSIONS: This study demonstrates that NMN intervention effectively reduces neuroinflammation in the hippocampus and hypothalamus after PM exposure by modulating spatial lipid metabolism. Strategies targeting the improvement of lipid homeostasis may provide significant protection against brain injury associated with air pollutant exposure.