α-亚麻酸通过与 GPR120-β- arrestin2 结合抑制 NF-κB/NLRP3 通路减轻小鼠精神分裂症中小胶质细胞介导的神经炎症。
α-linolenic acid mitigates microglia-mediated neuroinflammation of schizophrenia in mice by suppressing the NF-κB/NLRP3 pathway via binding GPR120-β-arrestin 2.
机构信息
School of Basic Medical Sciences, Ningxia Medical University, Yinchuan 750004 Ningxia, China.
Clinical Medical College, Ningxia Medical University, Yinchuan 750004, Ningxia, China.
出版信息
Int Immunopharmacol. 2024 Dec 5;142(Pt A):113047. doi: 10.1016/j.intimp.2024.113047. Epub 2024 Sep 4.
BACKGROUND
Schizophrenia (SCZ) is a heterogeneous psychiatric disorder that is poorly treated by current therapies. Emerging evidence indicates that SCZ is closely correlated with a persistent neuroinflammation. α-linolenic acid (ALA) is highly concentrated in the brain and represents a modulator of the immune system by decreasing the inflammatory response in chronic metabolic diseases. This study was first designed to investigate the potential role of dietary ALA on cognitive function and neuroinflammation in mice with SCZ.
METHODS
In vivo, after 2 weeks of modeling, mice were treated with dietary ALA treatment for 6 weeks. In vitro, inflammation model was created using lipopolysaccharide as an inducer in BV2 microglial cells.
RESULTS
Our results demonstrated that ALA alleviated cognitive impairment and enhanced synaptic plasticity in mice with SCZ. Moreover, ALA mitigated systematic and cerebral inflammation through elevating IL-10 and inhibiting IL-1β, IL-6, IL-18 and TNF-α. Furthermore, ALA notably inhibited microglia and pro-inflammatory monocytes, as well as microglial activation andpolarization. Mechanistically, ALA up-regulated the expressions of G protein coupled receptor (GPR) 120 and associated β-inhibitor protein 2 (β-arrestin2), accompanied by observable weakened levels of transforming growth factor-β activated kinase 1 (TAK1), NF-κB p65, cysteine proteinase-1 (caspase-1), pro-caspase-1, associated speck-like protein (ASC) and NLRP3. In vitro, ALA directly restrained the inflammation of microglia by decreasing the levels of pro-inflammatory factors and regulating microglial polarization via GPR120-NF-κB/NLRP3inflammasome signaling pathway, whereas AH7614 definitely eliminated this anti-inflammatory effect of ALA.
CONCLUSION
Dietary ALA ameliorates microglia-mediated neuroinflammation by suppressing the NF-κB/NLRP3 pathway via binding GPR120-β-arrestin2.
背景
精神分裂症（SCZ）是一种异质性精神疾病，目前的治疗方法效果不佳。新出现的证据表明，SCZ 与持续的神经炎症密切相关。α-亚麻酸（ALA）在大脑中高度集中，通过降低慢性代谢疾病中的炎症反应，代表免疫系统的调节剂。本研究旨在首次研究饮食 ALA 对 SCZ 小鼠认知功能和神经炎症的潜在作用。
方法
在体内，建模 2 周后，用饮食 ALA 治疗 6 周。在体外，使用脂多糖作为诱导剂在 BV2 小胶质细胞中创建炎症模型。
结果
我们的结果表明，ALA 减轻了 SCZ 小鼠的认知障碍并增强了突触可塑性。此外，ALA 通过提高 IL-10 并抑制 IL-1β、IL-6、IL-18 和 TNF-α来减轻全身和大脑炎症。此外，ALA 明显抑制小胶质细胞和促炎单核细胞以及小胶质细胞的激活和极化。从机制上讲，ALA 上调 G 蛋白偶联受体（GPR）120 和相关的β抑制剂蛋白 2（β-arrestin2）的表达，同时观察到转化生长因子-β激活激酶 1（TAK1）、NF-κB p65、半胱氨酸蛋白酶-1（caspase-1）、原胱天蛋白酶-1、相关斑点样蛋白（ASC）和 NLRP3 的水平减弱。在体外，ALA 通过降低促炎因子的水平并通过 GPR120-NF-κB/NLRP3 炎症小体信号通路调节小胶质细胞极化来直接抑制小胶质细胞的炎症，而 AH7614 则肯定消除了 ALA 的这种抗炎作用。
结论
饮食 ALA 通过与 GPR120-β-arrestin2 结合抑制 NF-κB/NLRP3 通路来改善小胶质细胞介导的神经炎症。
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