Department of Anesthesiology, Nanfang Hospital, Southern Medical University; The key Laboratory of Precision Anesthesia & perioperative Organ Protection, Guangzhou, Guangdong, 510515, China.
Biomed Pharmacother. 2024 Aug;177:117092. doi: 10.1016/j.biopha.2024.117092. Epub 2024 Jul 7.
Sepsis-associated encephalopathy (SAE) is a disease characterized by neuroinflammation and cognitive dysfunction caused by systemic infection. Inflammation-induced microglial activation is closely associated with neuroinflammation in SAE. It is widely understood that melatonin has strong anti-inflammatory and immunomodulatory properties beneficial for sepsis-related brain damage. However, the mechanism of melatonin action in SAE has not been fully elucidated.
The SAE cell model and SAE mouse model were induced by lipopolysaccharide (LPS). Behavioral tests were performed to analyze cognitive function. Microglial markers and M1/M2 markers were measured by immunofluorescence. Mitophagy was assessed by western blot, mt-Keima and transmission electron microscopy experiments. Immunoprecipitation and co-immunoprecipitation assays investigated the interactions between AMP-activated protein kinase α2 (AMPKα2) and PTEN-induced putative kinase 1 (PINK1).
Melatonin suppresses LPS-induced microglia M1 polarization by enhancing mitophagy, thereby attenuating LPS-induced neuroinflammation and behavioral deficits. However, inhibition or knockdown of AMPKα2 can inhibit the enhancement of melatonin on mitophagy, then weaken its promotion of microglia polarization towards M2 phenotype, and eliminate its protective effect on brain function. Furthermore, melatonin enhances mitophagy through activating AMPKα2, promotes PINK1 Ser495 site phosphorylation, and ultimately regulates microglial polarization from M1 to M2.
Our findings demonstrate that melatonin facilitates microglia polarization towards M2 phenotype to alleviate LPS-induced neuroinflammation, primarily through AMPKα2-mediated enhancement of mitophagy.
脓毒症相关性脑病（SAE）是一种以全身感染引起的神经炎症和认知功能障碍为特征的疾病。炎症诱导的小胶质细胞激活与 SAE 中的神经炎症密切相关。人们普遍认为，褪黑素具有强大的抗炎和免疫调节特性，有利于脓毒症相关的脑损伤。然而，褪黑素在 SAE 中的作用机制尚未完全阐明。
通过脂多糖（LPS）诱导 SAE 细胞模型和 SAE 小鼠模型。通过行为测试分析认知功能。通过免疫荧光测定小胶质细胞标志物和 M1/M2 标志物。通过 Western blot、mt-Keima 和透射电子显微镜实验评估自噬。免疫沉淀和共免疫沉淀实验研究 AMP 激活蛋白激酶α2（AMPKα2）和 PTEN 诱导的假定激酶 1（PINK1）之间的相互作用。
褪黑素通过增强自噬来抑制 LPS 诱导的小胶质细胞 M1 极化，从而减轻 LPS 诱导的神经炎症和行为缺陷。然而，AMPKα2 的抑制或敲低可抑制褪黑素对自噬的增强作用，继而减弱其对小胶质细胞向 M2 表型极化的促进作用，并消除其对脑功能的保护作用。此外，褪黑素通过激活 AMPKα2 增强自噬，促进 PINK1 Ser495 位点磷酸化，最终调节小胶质细胞从 M1 向 M2 的极化。
我们的研究结果表明，褪黑素促进小胶质细胞向 M2 表型极化，从而减轻 LPS 诱导的神经炎症，主要通过 AMPKα2 介导的自噬增强。
