Activation of the MAC1-ERK1/2-NOX2 Pathway Is Required for LPS-Induced Sustaining Reactive Microgliosis, Chronic Neuroinflammation and Neurodegeneration.
Activation of the MAC1-ERK1/2-NOX2 Pathway Is Required for LPS-Induced Sustaining Reactive Microgliosis, Chronic Neuroinflammation and Neurodegeneration.
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DOI：
10.3390/antiox11061202
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发表时间：
2022-06-20
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最近的研究表明，急性神经炎症的不恰当解决可能会导致持久的低度慢性神经炎症并导致进行性神经退行性变。然而，从急性向慢性神经炎症转变的分子机制仍不清楚。本研究的主要目的是寻找介导LPS引起的慢性神经炎症和导致的神经退行性变的潜在途径。使用从C57 BL/6 J，MAC 1缺陷和MyD 88缺陷小鼠制备的小胶质细胞培养物，初步研究表明TLR-4的活化不足以维持慢性神经炎症，尽管其在LPS引发的急性神经炎症中起着重要作用。与TLR-4相反，我们的研究表明，在MAC 1缺陷的神经元/神经胶质细胞培养物或LPS刺激的小鼠中，慢性神经炎症、氧化应激和黑质多巴胺能神经元的进行性丧失的强度显著降低。机制研究揭示了ERK 1/2激活在慢性神经炎症引起的神经变性中的重要作用，这通过在神经元-胶质细胞培养中使用ERK 1/2抑制剂来证明。综上所述，我们提出了MAC 1-NOX 2-ERK 1/2信号通路在低度慢性神经炎症的启动和维持中的关键作用。持续的ERK 1/2磷酸化和NOX 2激活在小胶质细胞中形成恶性前馈循环，以维持低度神经炎症并驱动神经退行性变。
Recent studies suggest that improper resolution of acute neuroinflammation may lead to long-lasting low-grade chronic neuroinflammation and drive progressive neurodegeneration. However, the molecular mechanism underlying the transition from acute to chronic neuroinflammation remains unclear. The main purpose of this study was to search for potential pathways mediating LPS-elicited chronic neuroinflammation and resultant neurodegeneration. Using microglia cultures prepared from C57BL/6J, MAC1-deficient, and MyD88-deficient mice, the initial study showed that activation of TLR-4 is not sufficient for maintaining chronic neuroinflammation despite its essential role in LPS-initiated acute neuroinflammation. Opposite to TLR-4, our studies showed significantly reduced intensity of chronic neuroinflammation, oxidative stress, and progressive loss of nigral dopaminergic neurons in MAC1-deficient neuron/glial cultures or mice stimulated with LPS. Mechanistic studies revealed the essential role ERK1/2 activation in chronic neuroinflammation-elicited neurodegeneration, which was demonstrated by using an ERK1/2 inhibitor in neuron-glial cultures. Taken together, we propose a key role of the MAC1-NOX2-ERK1/2 signaling pathway in the initiation and maintenance of low-grade chronic neuroinflammation. Continuing ERK1/2 phosphorylation and NOX2 activation form a vicious feedforward cycle in microglia to maintain the low-grade neuroinflammation and drive neurodegeneration.
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DOI：
10.1007/978-1-62703-520-0_21
发表时间：
2013
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Chen SH;Oyarzabal EA;Hong JS
通讯作者：
Hong JS
影响因子：
16.2
作者：
Burda JE;Sofroniew MV
通讯作者：
Sofroniew MV
影响因子：
12.8
作者：
Park, Beom Seok;Lee, Jie-Oh
通讯作者：
Lee, Jie-Oh
影响因子：
2.9
作者：
Abdelgawad, Mohamed;De Angelis, Francesco;Silecchia, Gianfranco
通讯作者：
Silecchia, Gianfranco
影响因子：
--
作者：
Okun E;Griffioen KJ;Lathia JD;Tang SC;Mattson MP;Arumugam TV
通讯作者：
Arumugam TV