Omega-3 polyunsaturated fatty acid attenuates the inflammatory response by modulating microglia polarization through SIRT1-mediated deacetylation of the HMGB1/NF-κB pathway following experimental traumatic brain injury.
Omega-3 polyunsaturated fatty acid attenuates the inflammatory response by modulating microglia polarization through SIRT1-mediated deacetylation of the HMGB1/NF-κB pathway following experimental traumatic brain injury.
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Omega-3多不饱和脂肪酸通过sirt1介导的HMGB1/NF-κB途径去乙酰化调节小胶质细胞极化，从而减轻实验性脑损伤后的炎症反应。
DOI：
10.1186/s12974-018-1151-3
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发表时间：
2018-04-20
影响因子：
9.3
通讯作者：
Li Y
中科院分区：
文献类型：
--
作者：
Chen X;Chen C;Fan S;Wu S;Yang F;Fang Z;Fu H;Li Y
小胶质细胞极化和随后的神经炎症反应是创伤性脑损伤（TBI）诱导的继发性损伤的促成因素。高移动的族蛋白1（HMGB 1）介导NF-κB通路的激活，被认为在晚期神经炎症反应中起关键作用。HMGB 1/NF-κB通路的激活与HMGB 1乙酰化密切相关，HMGB 1乙酰化受沉默调节蛋白（SIRT）家族的调节。众所周知，欧米茄-3多不饱和脂肪酸（ω-3 PUFA）具有抗氧化和抗炎作用。我们先前研究表明ω-3 PUFA通过调节HMGB 1/NF-κB信号通路抑制TBI诱导的小胶质细胞活化和随后的神经炎症反应。然而，尚没有研究阐明ω-3 PUFA是否以HMGB 1依赖SIRT 1的去乙酰化方式影响HMGB 1/NF-κB通路，从而调节小胶质细胞极化和随后的神经炎症反应。采用Feeney DM TBI模型建立大鼠脑损伤模型。采用改良神经功能评分、转棒试验、脑含水量和尼氏染色等方法检测补充ω-3 PUFA的神经保护作用。采用小胶质细胞极化和促炎标志物（如肿瘤坏死因子（TNF）-α、白细胞介素（IL）-1β、IL-6和HMGB 1）评估神经炎症反应和补充ω-3 PUFA的抗炎作用。采用免疫荧光染色和western blot检测HMGB 1的核转位、分泌和HMGB 1/NF-κB信号通路的激活情况，评价ω-3 PUFA对HMGB 1的影响。评估SIRT 1脱乙酰酶活性对HMGB 1乙酰化的影响以及HMGB 1和SIRT 1之间的相互作用，以评估ω-3 PUFA的抗炎作用，以及这些作用是否依赖于SIRT 1-HMGB 1/NF-κB轴，以进一步了解TBI后神经炎症反应发展的潜在机制。我们的研究结果表明，ω-3 PUFA补充促进了从M1小胶质细胞表型向M2小胶质细胞表型的转变，并抑制了小胶质细胞活化，从而减少了TBI诱导的炎症因子。此外，发现ω-3 PUFA介导的HMGB 1乙酰化及其胞外分泌的下调可能是由于SIRT 1活性增加。我们还发现，ω-3 PUFA处理抑制HMGB 1乙酰化，并通过提高TBI后SIRT 1活性诱导SIRT 1和HMGB 1之间的直接相互作用。这些事件导致抑制HMGB 1核质易位/细胞外分泌，并减轻TBI诱导的小胶质细胞活化后HMGB 1介导的NF-κB通路活化，从而抑制随后的炎症反应。本研究的结果表明，ω-3 PUFA补充剂通过SIRT 1介导的HMGB 1/NF-κB通路的去乙酰化调节小胶质细胞极化来减轻炎症反应，从而导致实验性创伤性脑损伤后的神经保护作用。
Microglial polarization and the subsequent neuroinflammatory response are contributing factors for traumatic brain injury (TBI)-induced secondary injury. High mobile group box 1 (HMGB1) mediates the activation of the NF-κB pathway, and it is considered to be pivotal in the late neuroinflammatory response. Activation of the HMGB1/NF-κB pathway is closely related to HMGB1 acetylation, which is regulated by the sirtuin (SIRT) family of proteins. Omega-3 polyunsaturated fatty acids (ω-3 PUFA) are known to have antioxidative and anti-inflammatory effects. We previously demonstrated that ω-3 PUFA inhibited TBI-induced microglial activation and the subsequent neuroinflammatory response by regulating the HMGB1/NF-κB signaling pathway. However, no studies have elucidated if ω-3 PUFA affects the HMGB1/NF-κB pathway in a HMGB1 deacetylation of dependent SIRT1 manner, thus regulating microglial polarization and the subsequent neuroinflammatory response. The Feeney DM TBI model was adopted to induce brain injury in rats. Modified neurological severity scores, rotarod test, brain water content, and Nissl staining were employed to determine the neuroprotective effects of ω-3 PUFA supplementation. Assessment of microglia polarization and pro-inflammatory markers, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and HMGB1, were used to evaluate the neuroinflammatory responses and the anti-inflammatory effects of ω-3 PUFA supplementation. Immunofluorescent staining and western blot analysis were used to detect HMGB1 nuclear translocation, secretion, and HMGB1/NF-κB signaling pathway activation to evaluate the effects of ω-3 PUFA supplementation. The impact of SIRT1 deacetylase activity on HMGB1 acetylation and the interaction between HMGB1 and SIRT1 were assessed to evaluate anti-inflammation effects of ω-3 PUFAs, and also, whether these effects were dependent on a SIRT1-HMGB1/NF-κB axis to gain further insight into the mechanisms underlying the development of the neuroinflammatory response after TBI. The results of our study showed that ω-3 PUFA supplementation promoted a shift from the M1 microglial phenotype to the M2 microglial phenotype and inhibited microglial activation, thus reducing TBI-induced inflammatory factors. In addition, ω-3 PUFA-mediated downregulation of HMGB1 acetylation and its extracellular secretion was found to be likely due to increased SIRT1 activity. We also found that treatment with ω-3 PUFA inhibited HMGB1 acetylation and induced direct interactions between SIRT1 and HMGB1 by elevating SIRT1 activity following TBI. These events lead to inhibition of HMGB1 nucleocytoplasmic translocation/extracellular secretion and alleviated HMGB1-mediated activation of the NF-κB pathway following TBI-induced microglial activation, thus inhibiting the subsequent inflammatory response. The results of this study suggest that ω-3 PUFA supplementation attenuates the inflammatory response by modulating microglial polarization through SIRT1-mediated deacetylation of the HMGB1/NF-κB pathway, leading to neuroprotective effects following experimental traumatic brain injury.
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