James Graham Brown Cancer Center, Department of Microbiology & Immunology, University of Louisville, KY 40202, USA.
Department of Physiology, University of Louisville School of Medicine, Louisville, KY 40202, USA.
Theranostics. 2022 Jan 1;12(3):1220-1246. doi: 10.7150/thno.65427. eCollection 2022.
Obesity is becoming a global epidemic and reversing the pathological processes underlying obesity and metabolic co-morbidities is challenging. Obesity induced chronic inflammation including brain inflammation is a hallmark of obesity via the gut-brain axis. The objective of this study was to develop garlic exosome-like nanoparticles (GaELNs) that inhibit systemic as well as brain inflammatory activity and reverse a HFD induced obesity in mice. GELNs were isolated and administrated orally into HFD fed mice. GaELNs were fluorescent labeled for monitoring their trafficking route after oral administration and quantified the number particles in several tissues. The brain inflammation was determined by measuring inflammatory cytokines by ELISA and real-time PCR. Mitochondrial membrane permeability of microglial cells was determined using JC-10 fluorescence dye. The apoptotic cell death was quantified by TUNEL assay. The brain metabolites were identified and quantified by LC-MS analysis. Memory function of the mice was determined by several memory functional analysis. The effect of GaELNs on glucose and insulin response of the mice was determined by glucose and insulin tolerance tests. c-Myc localization and interaction with BASP1 and calmodulin was determined by confocal microscopy. Our results show that GaELNs is preferentially taken up microglial cells and inhibits the brain inflammation in HFD mice. GaELN phosphatidic acid (PA) (36:4) is required for the uptake of GaELNs via interaction with microglial BASP1. Formation of the GaELNs/BASP1 complex is required for inhibition of c-Myc mediated expression of STING. GaELN PA binds to BASP1, leading to inhibition of c-Myc expression and activity through competitively binding to CaM with c-Myc transcription factor. Inhibition of STING activity leads to reducing the expression of an array of inflammatory cytokines including IFN-γ and TNF-α. IFN-γ induces the expression of IDO1, which in turn the metabolites generated as IDO1 dependent manner activate the AHR pathway that contributes to developing obesity. The metabolites derived from the GaELNs treated microglial cells promote neuronal differentiation and inhibit mitochondrial mediated neuronal cell death. GaELNs treated HFD mice showed improved memory function and increased glucose tolerance and insulin sensitivity in these mice. : Collectively, these results demonstrate how nanoparticles from a healthy diet can inhibit unhealthy high-fat diet induced brain inflammation and reveal a link between brain microglia/diet to brain inflammatory disease outcomes via diet-derived exosome-like nanoparticles.
肥胖正在成为全球性的流行病，而逆转肥胖和代谢合并症的病理过程具有挑战性。肥胖诱导的慢性炎症，包括大脑炎症，是通过肠道-大脑轴导致肥胖的标志。本研究的目的是开发大蒜外体样纳米颗粒（GaELNs），以抑制全身和大脑炎症活性，并逆转高脂肪饮食（HFD）诱导的肥胖。GELNs 被分离并口服给予 HFD 喂养的小鼠。用荧光标记 GaELNs，以监测其口服给药后的转运途径，并定量几种组织中的颗粒数。通过 ELISA 和实时 PCR 测量炎症细胞因子来确定脑炎症。使用 JC-10 荧光染料测定小胶质细胞的线粒体膜通透性。通过 TUNEL 测定法定量细胞凋亡。通过 LC-MS 分析鉴定和定量脑代谢物。通过几种记忆功能分析确定小鼠的记忆功能。通过葡萄糖和胰岛素耐量试验确定 GaELNs 对小鼠葡萄糖和胰岛素反应的影响。通过共聚焦显微镜确定 c-Myc 定位及其与 BASP1 和钙调蛋白的相互作用。我们的结果表明，GaELNs 优先被小胶质细胞摄取，并抑制 HFD 小鼠的大脑炎症。GaELN 磷脂酸（PA）（36:4）通过与小胶质细胞 BASP1 的相互作用，是 GaELNs 摄取所必需的。GaELNs/BASP1 复合物的形成是抑制 c-Myc 介导的 STING 表达所必需的。GaELN PA 与 BASP1 结合，通过与钙调蛋白竞争性结合抑制 c-Myc 转录因子的表达和活性。抑制 STING 活性导致一系列炎症细胞因子（包括 IFN-γ 和 TNF-α）的表达减少。IFN-γ 诱导 IDO1 的表达，反过来，IDO1 依赖性方式产生的代谢物激活 AHR 途径，有助于肥胖的发展。来自用 GaELNs 处理的小胶质细胞的代谢物促进神经元分化并抑制线粒体介导的神经元细胞死亡。用 GaELNs 处理的 HFD 小鼠表现出改善的记忆功能，并增加了这些小鼠的葡萄糖耐量和胰岛素敏感性。总之，这些结果表明来自健康饮食的纳米颗粒如何抑制不健康的高脂肪饮食诱导的大脑炎症，并通过饮食衍生的外体样纳米颗粒揭示了大脑小胶质细胞/饮食与大脑炎症性疾病结果之间的联系。
