Microglia are resident macrophage-like cells in the central nervous system (CNS). The induction of microglial activation dampens neuroinflammation-related diseases by promoting microglial (re)polarization to the anti-inflammatory (M2) phenotype and can serve as a potential therapeutic approach. Mitochondrial respiration and metabolic reprogramming are required for the anti-inflammatory response of M2 macrophages. However, whether these mitochondrial-dependent pathways are involved in microglial (re)polarization to the anti-inflammatory (M2) phenotype under conditions of lipopolysaccharide (LPS)-induced neuroinflammation remains unclear. Moreover, the mechanisms that coordinate mitochondrial respiration and the functional reprogramming of microglial cells have not been fully elucidated. Rosmarinic acid (RA) possesses antioxidative and anti-inflammatory activities, and we previously reported that RA markedly suppresses LPS-stimulated M1 microglial activation in mice. In this study, we found that RA suppresses M1 microglial polarization and promotes microglial polarization to the M2 phenotype under conditions of neuroinflammation. We identified an increase in mitochondrial respiration and found that metabolic reprogramming is required for the RA-mediated promotion of microglial polarization to the M2 phenotype under LPS-induced neuroinflammation conditions. Hypoxia-inducible factor (HIF) subunits are the key effector molecules responsible for the effects of RA on the restoration of mitochondrial function, metabolic reprogramming, and phenotypic polarization to M2 microglia. The phosphoinositide-dependent protein kinase 1 (PDPK1)/Akt/mTOR pathway is involved in the RA-mediated regulation of HIF expression and increase in M2 marker expression. We propose that the inhibition of PDPK1/Akt/HIFs by RA might be a potential therapeutic approach for inhibiting neuroinflammation through the regulation of microglial M1/M2 polarization.

小胶质细胞是中枢神经系统 (CNS) 中的常驻巨噬细胞样细胞。小胶质细胞激活的诱导通过促进小胶质细胞（重新）极化到抗炎（M2）表型来抑制神经炎症相关疾病，并且可以作为一种潜在的治疗方法。M2 巨噬细胞的抗炎反应需要线粒体呼吸和代谢重编程。然而，在脂多糖 (LPS) 诱导的神经炎症条件下，这些线粒体依赖性通路是否参与小胶质细胞 (重新) 极化到抗炎 (M2) 表型仍不清楚。此外，协调线粒体呼吸和小胶质细胞功能重编程的机制尚未完全阐明。迷迭香酸 (RA) 具有抗氧化和抗炎活性，我们之前报道过 RA 显着抑制小鼠中 LPS 刺激的 M1 小胶质细胞活化。在这项研究中，我们发现 RA 在神经炎症条件下抑制 M1 小胶质细胞极化并促进小胶质细胞极化为 M2 表型。我们发现线粒体呼吸增加，并发现在 LPS 诱导的神经炎症条件下，RA 介导的小胶质细胞极化促进 M2 表型需要代谢重编程。缺氧诱导因子 (HIF) 亚基是负责 RA 对线粒体功能恢复、代谢重编程和 M2 小胶质细胞表型极化的影响的关键效应分子。磷酸肌醇依赖性蛋白激酶 1 (PDPK1)/Akt/mTOR 通路参与 RA 介导的 HIF 表达调节和 M2 标记物表达的增加。我们提出 RA 对 PDPK1/Akt/HIF 的抑制可能是通过调节小胶质细胞 M1/M2 极化来抑制神经炎症的潜在治疗方法。