抗STAT1多酚杨梅素抑制M1小胶质细胞活化并抵消神经元死亡,The FEBS Journal

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抗STAT1多酚杨梅素抑制M1小胶质细胞活化并抵消神经元死亡
The FEBS Journal ( IF 5.5 ) Pub Date : 2020-09-27 , DOI: 10.1111/febs.15577
Diana Boriero ₁ , Alessandra Carcereri de Prati ₁ , Lorenzo Antonini ₂ , Rino Ragno ₂ , Kazuo Sohji ₃ , Sofia Mariotto ₁ , Elena Butturini ₁

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小胶质细胞向M1促炎表型的激活代表了神经系统疾病的最早事件之一。因此，减少小胶质细胞活化应抑制神经炎症，从而延迟神经变性的进展。最近，我们指出了STAT1信号在缺氧诱导的M1激活中的作用，并提出STAT1作为预防和治疗神经退行性变的合适分子靶标。杨梅素（MYR）是一种天然类黄酮，具有与STAT1蛋白本身的直接相互作用相关的特定抗STAT1活性。在这里，我们研究了MYR的抗炎作用及其在体外保护神经元免于死亡的能力。使用暴露于缺氧激活的小胶质细胞BV2细胞的条件培养基中的成神经细胞样SH‐SY5Y细胞建立神经毒性模型。我们证明MYR预处理能够通过抑制STAT1信号来关闭低氧诱导的M1小胶质细胞极化。分子机制的分析表明，MYR与STAT1的直接相互作用损害了其S-谷胱甘肽化和磷酸化。此外，用MYR预处理的低氧激活小胶质细胞的条件培养基处理SH-SY5Y细胞，神经元活力显着降低。我们的数据表明，MYR代表了神经退行性疾病中神经炎症的预防和治疗的有前途的候选者。

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The anti‐STAT1 polyphenol myricetin inhibits M1 microglia activation and counteracts neuronal death

Microglia activation toward M1 pro‐inflammatory phenotype represents one of the earliest events of neurological disorders. Therefore, reducing microglia activation should inhibit neuroinflammation, thereby delaying the progression of neurodegeneration. Recently, we pointed out the role of STAT1 signaling in hypoxia‐induced M1 activation and proposed STAT1 as a suitable molecular target for the prevention and treatment of neurodegeneration. Myricetin (MYR) is a natural flavonoid that exhibits a specific anti‐STAT1 activity correlated with its direct interaction with STAT1 protein itself. Herein, we investigated the anti‐inflammatory effect of MYR and its ability to protect neurons from death in an in vitro model of neurotoxicity using the neuroblast‐like SH‐SY5Y cells that were exposed to conditioned media from hypoxia‐activated microglia BV2 cells. We demonstrate that MYR pretreatment is able to switch off hypoxia‐induced M1 microglia polarization through the inhibition of STAT1 signaling. The analysis of the molecular mechanism suggests that the direct interaction of MYR with STAT1 impairs its S‐glutathionylation and phosphorylation. Moreover, treatment of SH‐SY5Y cells with conditioned medium from hypoxia‐activated microglia pretreated with MYR produced a significant reduction in neuronal viability. Our data indicate that MYR may represent a promising candidate for prevention and treatment of neuroinflammation in neurodegenerative disorders.

更新日期：2020-09-27

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