关键词： BDNF, Brain-derived neurotrophic factor CNS, Central nervous system DAMPs, Danger-associated molecular patterns HO-1,Heme oxygenase-1, Hp,Haptoglobin Hematoma clearance ICH, Intracerebral hemorrhage IFNγ,Interferon-gamma, IL-1β,Interleukin 1β Intracerebral hemorrhage MMP, Matrix metalloproteasesNF-κB,Nuclear factor-kappa light chain enhancer of activated B cells Microglial phenotype NO, Nitric oxide Nrf2 Nrf2, Nuclear factor erythroid 2-related factor 2 PPAR-ɤ, Peroxidase proliferator-activated receptor gamma Phagocytosis TLR4, Toll-like receptor 4 TNFα, Tumor necrosis factor-α Trem1, Triggering receptors I expressed on myeloid cells Trem2, Triggering receptors II expressed on myeloid cells

来  源：   DOI：10.1016/j.heliyon.2023.e13777   PDF(Pubmed)

Abstract：
Activated microglia are divided into pro-inflammatory and anti-inflammatory functional states. In anti-inflammatory state, activated microglia contribute to phagocytosis, neural repair and anti-inflammation. Nrf2 as a major endogenous regulator in hematoma clearance after intracerebral hemorrhage (ICH) has received much attention. This study aims to investigate the mechanism underlying Nrf2-mediated regulation of microglial phenotype and phagocytosis in hematoma clearance after ICH. In vitro experiments, BV-2 cells were assigned to normal group and administration group (Nrf2-siRNA, Nrf2 agonists Monascin and Xuezhikang). In vivo experiments, mice were divided into 5 groups: sham, ICH + vehicle, ICH + Nrf2-/-, ICH + Monascin and ICH + Xuezhikang. In vitro and in vivo, 72 h after administration of Monascin and Xuezhikang, the expression of Nrf2, inflammatory-associated factors such as Trem1, TNF-α and CD80, anti-inflammatory, neural repair and phagocytic associated factors such as Trem2, CD206 and BDNF were analyzed by the Western blot method. In vitro, fluorescent latex beads or erythrocytes were uptaken by BV-2 cells in order to study microglial phagocytic ability. In vivo, hemoglobin levels reflect the hematoma volume. In this study, Nrf2 agonists (Monascin and Xuezhikang) upregulated the expression of Trem2, CD206 and BDNF while decreased the expression of Trem1, TNF-α and CD80 both in vivo and in vitro. At the same time, after Monascin and Xuezhikang treatment, the phagocytic capacity of microglia increased in vitro, neurological deficits improved and hematoma volume lessened in vivo. These results were reversed in the Nrf2-siRNA or the Nrf2-/- mice. All these results indicated that Nrf2 enhanced hematoma clearance and neural repair, improved neurological outcomes through enhancing microglial phagocytosis and alleviating neuroinflammation.
摘要：
活化的小胶质细胞分为促炎和抗炎功能状态。在抗炎状态下，活化的小胶质细胞有助于吞噬作用，神经修复和抗炎。Nrf2作为脑出血（ICH）后血肿清除的主要内源性调节因子备受关注。本研究旨在探讨Nrf2介导的小胶质细胞表型和吞噬作用在脑出血后血肿清除中的作用机制。体外实验,将BV-2细胞分为正常组和给药组(Nrf2-siRNA,Nrf2激动剂Monascin和血脂康）。体内实验,将小鼠分为5组：假手术，ICH+车辆,ICH+Nrf2-/-，ICH+Monascin和ICH+血脂康。在体外和体内，Monascin和血脂康给药后72小时，Nrf2、炎症相关因子Trem1、TNF-α和CD80的表达,通过Westernblot方法分析神经修复和吞噬相关因子如Trem2，CD206和BDNF。体外，BV-2细胞摄取荧光乳胶珠或红细胞，以研究小胶质细胞的吞噬能力。在体内,血红蛋白水平反映血肿体积。在这项研究中,Nrf2激动剂（Monascin和血脂康）在体内和体外均上调Trem2，CD206和BDNF的表达，而在体内和体外均降低Trem1，TNF-α和CD80的表达。同时,经过Monascin和血脂康治疗，小胶质细胞的吞噬能力在体外增加，体内神经功能缺损改善，血肿体积减少。这些结果在Nrf2-siRNA或Nrf2-/-小鼠中逆转。所有这些结果表明Nrf2增强血肿清除和神经修复，通过增强小胶质细胞吞噬作用和减轻神经炎症改善神经系统预后。
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