School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China.
Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
Molecules. 2023 Jun 1;28(11):4501. doi: 10.3390/molecules28114501.
The activation of the microglia plays an important role in the neuroinflammation induced by different stimulations associated with Alzheimer's disease (AD). Different stimulations, such as pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs) and cytokines, trigger a consequence of activation in the microglia with diverse changes of the microglial cell type response in AD. The activation of the microglia is often accompanied by metabolic changes in response to PAMPs, DAMPs and cytokines in AD. Actually, we do not know the distinct differences on the energetic metabolism of microglia when subject to these stimuli. This research assessed the changes of the cell type response and energetic metabolism in mouse-derived immortalized cells (BV-2 cells) induced by a PAMP (LPS), DAMPs (Aβ and ATP) and a cytokine (IL-4) in mouse-derived immortalized cells (BV-2 cells) and whether the microglial cell type response was improved by targeting the metabolism. We uncovered that LPS, a proinflammatory stimulation of PAMPs, modified the morphology from irregular to fusiform, with stronger cell viability, fusion rates and phagocytosis in the microglia accompanied by a metabolic shift to the promotion of glycolysis and the inhibition of oxidative phosphorylation (OXPHOS). Aβ and ATP, which are two known kinds of DAMPs that trigger microglial sterile activation, induced the morphology from irregular to amoebic, and significantly decreased others in the microglia, accompanied by boosting or reducing both glycolysis and OXPHOS. Monotonous pathological changes and energetic metabolism of microglia were observed under IL-4 exposure. Further, the inhibition of glycolysis transformed the LPS-induced proinflammatory morphology and decreased the enhancement of LPS-induced cell viability, the fusion rate and phagocytosis. However, the promotion of glycolysis exerted a minimal effect on the changes of morphology, the fusion rate, cell viability and phagocytosis induced by ATP. Our study reveals that microglia induced diverse pathological changes accompanied by various changes in the energetic metabolism in response to PAMPs, DAMPs and cytokines, and it may be a potential application of targeting the cellular metabolism to interfere with the microglia-mediated pathological changes in AD.
小胶质细胞的激活在与阿尔茨海默病（AD）相关的不同刺激引起的神经炎症中起着重要作用。不同的刺激，如病原体相关分子模式（PAMPs）、损伤相关分子模式（DAMPs）和细胞因子，触发小胶质细胞的激活后果，导致 AD 中小胶质细胞类型反应的不同变化。小胶质细胞的激活通常伴随着代谢变化，以应对 AD 中的 PAMPs、DAMPs 和细胞因子。实际上，我们不知道小胶质细胞在受到这些刺激时在能量代谢方面的明显差异。这项研究评估了 PAMP（LPS）、DAMPs（Aβ 和 ATP）和细胞因子（IL-4）在诱导小鼠来源的永生化细胞（BV-2 细胞）中的细胞类型反应和能量代谢的变化，以及小胶质细胞的细胞类型反应是否通过靶向代谢得到改善。我们发现，LPS 作为一种促炎的 PAMP 刺激，将形态从不规则改变为梭形，小胶质细胞的活力、融合率和吞噬作用增强，同时代谢向促进糖酵解和抑制氧化磷酸化（OXPHOS）转变。Aβ 和 ATP 是两种已知的触发小胶质细胞无菌激活的 DAMPs，诱导形态从不规则改变为阿米巴状，并显著降低小胶质细胞中的其他物质，同时促进或降低糖酵解和 OXPHOS。在 IL-4 暴露下，观察到小胶质细胞的单一病理变化和能量代谢。此外，抑制糖酵解改变了 LPS 诱导的促炎形态，降低了 LPS 诱导的细胞活力、融合率和吞噬作用的增强。然而，促进糖酵解对 ATP 诱导的形态变化、融合率、细胞活力和吞噬作用的影响很小。我们的研究表明，小胶质细胞在应对 PAMPs、DAMPs 和细胞因子时，会引起不同的病理变化，同时伴随着能量代谢的变化，这可能是一种通过靶向细胞代谢来干扰 AD 中小胶质细胞介导的病理变化的潜在应用。
