Prolonged activation of microglia leads to excessive release of proinflammatory mediators, which are detrimental to brain health. Therefore, there are significant efforts to identify pathways mediating microglial activation. Recent studies have demonstrated that fatty acid-binding protein 4 (FABP4), a lipid binding protein, is a critical player in macrophage–mediated inflammation. Given that we have previously identified FABP4 in microglia, the aim of this study was to assess whether FABP4 activity contributed to inflammation, metabolism and immune function (i.e. immunometabolism) in immortalised mouse microglia (BV-2 cells) using the proinflammatory stimulus lipopolysaccharide (LPS) to induce general microglial activation. Microglial FABP4 expression was significantly increased following exposure to LPS, an outcome associated with a significant increase in microglial proliferation rate. LPS-stimulated BV-2 microglia demonstrated a significant increase in the production of reactive oxygen species (ROS) and tumour necrosis factor-alpha (TNF-α), phosphorylation of c-Jun N-terminal kinase (JNK), increased expression of Toll-like receptor 4 (TLR4), and reduced expression of uncoupling protein 2 (UCP2), all of which were reversed following FABP4 genetic silencing and chemical inhibition with BMS309403. The oxidation rate of ³H-oleic acid and microglial uptake of ³H-2-deoxy-D-glucose were modulated with LPS activation, processes which were restored with genetic and chemical inhibition of FABP4. This is the first study to report on the critical role of FABP4 in mediating the deleterious effects of LPS on microglial immunometabolism, suggesting that FABP4 may present as a novel therapeutic target to alleviate microglia-mediated neuroinflammation, a commonly reported factor in multiple neurodegenerative diseases.

Graphical Abstract

中文翻译：

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脂肪酸结合蛋白 4 对于小胶质细胞对脂多糖的炎症和代谢反应至关重要

小胶质细胞的长时间激活会导致促炎介质的过度释放，这不利于大脑健康。因此，人们付出了巨大的努力来确定介导小胶质细胞激活的途径。最近的研究表明，脂肪酸结合蛋白 4 (FABP4)（一种脂质结合蛋白）在巨噬细胞介导的炎症中发挥着关键作用。鉴于我们之前已在小胶质细胞中鉴定出 FABP4，本研究的目的是使用促炎刺激脂多糖 (LPS) 评估 FABP4 活性是否有助于永生化小鼠小胶质细胞（BV-2 细胞）中的炎症、代谢和免疫功能（即免疫代谢） ）诱导一般小胶质细胞激活。暴露于 LPS 后，小胶质细胞 FABP4 表达显着增加，这一结果与小胶质细胞增殖率显着增加相关。LPS 刺激的 BV-2 小胶质细胞表现出活性氧 (ROS) 和肿瘤坏死因子-α (TNF-α) 的产生显着增加、c-Jun N 末端激酶 (JNK) 磷酸化、Toll 表达增加样受体 4 (TLR4) 和解偶联蛋白 2 (UCP2) 表达减少，所有这些在 FABP4 基因沉默和 BMS309403 化学抑制后均被逆转。^{LPS 激活可调节3} H-油酸的氧化速率和小胶质细胞对³ H-2-脱氧-D-葡萄糖的摄取，这些过程可通过 FABP4 的遗传和化学抑制来恢复。这是第一项报道 FABP4 在介导 LPS 对小胶质细胞免疫代谢有害影响中的关键作用的研究，表明 FABP4 可能作为减轻小胶质细胞介导的神经炎症的新治疗靶点，而小胶质细胞介导的神经炎症是多种神经退行性疾病中常见的因素。

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