p38 MAPK Is a Major Regulator of Amyloid Beta-Induced IL-6 Expression in Human Microglia.
p38 MAPK Is a Major Regulator of Amyloid Beta-Induced IL-6 Expression in Human Microglia.
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DOI：
10.1007/s12035-022-02909-0
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发表时间：
2022-09
影响因子：
5.1
通讯作者：
Wang, Gavin Y.
中科院分区：
文献类型：
--
作者：
Lin, Houmin;Dixon, Steven Grant;Hu, Wei;Hamlett, Eric D.;Jin, Junfei;Ergul, Adviye;Wang, Gavin Y.
淀粉样β蛋白(Aβ)斑块在大脑中的积累是阿尔茨海默病(AD)病理的一个特征。小胶质细胞激活介导的神经炎症参与了AD的发病机制，AD患者脑组织中IL-6的表达水平升高。然而，IL-6在人小胶质细胞中表达的调控机制尚不完全清楚。在这里，我们证明了Aβ1-40寡聚体(Aβ40)剂量依赖地刺激人小胶质细胞IL-6的表达。Aβ40可促进HMC3和THP-1细胞IL-6和肿瘤坏死因子α(肿瘤坏死因子α)mRNAs的转录。机制研究表明，Aβ40诱导的IL-6分泌增加与激活p38丝裂原活化蛋白激酶(P38MAPK)有关。BIRB796或SB202190抑制p38MAPK可阻断Aβ40诱导的IL-6分泌增加。通过对脑标本的分析，我们发现AD患者小胶质细胞中IL-6和磷酸化(活化形式)p38MAPK的免疫反应性明显高于年龄匹配的对照组。此外，我们的研究还证实了IL-6和磷酸化的p38MAPK在AD患者大脑皮质的小胶质细胞中的共存。综上所述，这些结果表明p38MAPK是Aβ诱导的人小胶质细胞产生IL-6的主要调节因子，提示靶向p38MAPK可能是一种减轻Aβ积聚引起的AD神经炎症的新途径。
The accumulation of amyloid beta (Aβ) plaques in the brain is a hallmark of Alzheimer’s disease (AD) pathology. Microglial activation-mediated neuroinflammation has been implicated in the pathogenesis of AD and the expression levels of interleukin-6 (IL-6) were increased in the brains of AD patients. However, the mechanisms by which IL-6 expression is regulated in human microglia are incompletely understood. Here, we show that Aβ1–40 oligomers (Aβ40) dose-dependently stimulate IL-6 expression in HMC3 human microglial cells. Treatment with Aβ40 promotes the transcription of IL-6 and tumor necrosis factor α (TNFα) mRNAs in both HMC3 and THP-1 cells. Mechanistic studies reveal that Aβ40-induced increase of IL-6 secretion is associated with the activation of p38 mitogen-activated protein kinase (p38 MAPK). Inhibition of p38 MAPK by BIRB 796 or SB202190 abrogates Aβ40-induced increase of IL-6 production. Through analyzing brain specimens, we found that the immunoreactivity for IL-6 and phosphorylated (the activated form) p38 MAPK were markedly higher in microglia of AD patients than in age-matched control subjects. Moreover, our studies identified the co-localization of IL-6 with phosphorylated p38 MAPK in microglia in the cortices of AD patients. Taken together, these results indicate that p38 MAPK is a major regulator of Aβ-induced IL-6 production in human microglia, which suggests that targeting p38 MAPK may represent a new approach to ameliorate Aβ accumulation-induced neuroinflammation in AD.
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