Omega-3 polyunsaturated fatty acid supplementation attenuates microglial-induced inflammation by inhibiting the HMGB1/TLR4/NF-κB pathway following experimental traumatic brain injury.
Omega-3 polyunsaturated fatty acid supplementation attenuates microglial-induced inflammation by inhibiting the HMGB1/TLR4/NF-κB pathway following experimental traumatic brain injury.
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DOI：
10.1186/s12974-017-0917-3
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发表时间：
2017-07-24
影响因子：
9.3
通讯作者：
He H
中科院分区：
文献类型：
--
作者：
Chen X;Wu S;Chen C;Xie B;Fang Z;Hu W;Chen J;Fu H;He H
小胶质细胞的激活和随后中枢神经系统的炎症反应在创伤性脑损伤后继发性损伤中起重要作用。高迁移率族蛋白1(HMGB1)是晚期炎症反应的重要介质，它与晚期糖基化终产物跨膜受体(RAGE)和Toll样受体(TLRs)相互作用，激活下游信号通路，如核因子(NF)-κB信号通路，导致炎症反应的级联放大，与脑创伤后神经元损伤有关。Omega-3多不饱和脂肪酸(ω-3PUFA)是一种临床常用的免疫营养素，具有抗氧化和抗炎作用。然而，ω-3多不饱和脂肪酸对HMGB1表达及HMGB1介导的TLR4/NF-κB信号通路激活的影响尚不清楚。采用Feeney DM脑损伤模型制作大鼠脑损伤模型。采用改良的神经严重程度评分、脑含水量和尼氏染色来确定补充ω-3多不饱和脂肪酸的神经保护作用。用肿瘤坏死因子α、白介素1β、白介素6、干扰素γ和HMGB1等促炎蛋白标志物评价损伤部位小胶质细胞的活化，以评价补充ω-3多不饱和脂肪酸的神经炎性反应和抗炎作用。免疫荧光染色和免疫印迹分析检测HMGB1核转位、分泌及HMGB1介导的TLR4/NF-κB信号通路的激活，以评价ω-3多不饱和脂肪酸对脑创伤后神经炎性反应发生的影响。结果发现，补充ω-3多不饱和脂肪酸可抑制脑损伤后小胶质细胞的活化和炎症因子(肿瘤坏死因子-α、IL-1β、IL-6和干扰素-γ)的表达，减轻脑水肿，减少神经细胞凋亡，改善神经功能。我们进一步证实，补充ω-3多不饱和脂肪酸抑制了HMGB1核的移位和分泌，并减少了损伤区域神经元和小胶质细胞中HMGB1的表达。此外，补充ω-3PUFA通过调节HMGB1和TLR4/NF-κB信号通路，抑制小胶质细胞的激活和随后的炎症反应。本研究结果提示，小胶质细胞活化和随后的神经炎性反应以及相关的HMGB1/TLR4/NF-κB信号通路在脑外伤后继发性损伤中起重要作用。此外，补充ω-3多不饱和脂肪酸通过调节HMGB1核转位和分泌，以及HMGB1介导的TLR4/NF-κB信号通路的激活，抑制脑损伤诱导的小胶质细胞激活和随后的炎症反应，从而发挥神经保护作用。
Microglial activation and the subsequent inflammatory response in the central nervous system play important roles in secondary damage after traumatic brain injury (TBI). High-mobility group box 1 (HMGB1) protein, an important mediator in late inflammatory responses, interacts with transmembrane receptor for advanced glycation end products (RAGE) and toll-like receptors (TLRs) to activate downstream signaling pathways, such as the nuclear factor (NF)-κB signaling pathway, leading to a cascade amplification of inflammatory responses, which are related to neuronal damage after TBI. Omega-3 polyunsaturated fatty acid (ω-3 PUFA) is a commonly used clinical immunonutrient, which has antioxidative and anti-inflammatory effects. However, the effects of ω-3 PUFA on HMGB1 expression and HMGB1-mediated activation of the TLR4/NF-κB signaling pathway are not clear. The Feeney DM TBI model was adopted to induce brain injury in rats. Modified neurological severity scores, brain water content, and Nissl staining were employed to determine the neuroprotective effects of ω-3 PUFA supplementation. Assessment of microglial activation in lesioned sites and protein markers for proinflammatory, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, interferon (IFN)-γ, and HMGB1 were used to evaluate neuroinflammatory responses and anti-inflammation effects of ω-3 PUFA supplementation. Immunofluorescent staining and western blot analysis were used to detect HMGB1 nuclear translocation, secretion, and HMGB1-mediated activation of the TLR4/NF-κB signaling pathway to evaluate the effects of ω-3 PUFA supplementation and gain further insight into the mechanisms underlying the development of the neuroinflammatory response after TBI. It was found that ω-3 PUFA supplementation inhibited TBI-induced microglial activation and expression of inflammatory factors (TNF-α, IL-1β, IL-6, and IFN-γ), reduced brain edema, decreased neuronal apoptosis, and improved neurological functions after TBI. We further demonstrated that ω-3 PUFA supplementation inhibited HMGB1 nuclear translocation and secretion and decreased expression of HMGB1 in neurons and microglia in the lesioned areas. Moreover, ω-3 PUFA supplementation inhibited microglial activation and the subsequent inflammatory response by regulating HMGB1 and the TLR4/NF-κB signaling pathway. The results of this study suggest that microglial activation and the subsequent neuroinflammatory response as well as the related HMGB1/TLR4/NF-κB signaling pathway play essential roles in secondary injury after TBI. Furthermore, ω-3 PUFA supplementation inhibited TBI-induced microglial activation and the subsequent inflammatory response by regulating HMGB1 nuclear translocation and secretion and also HMGB1-mediated activation of the TLR4/NF-κB signaling pathway, leading to neuroprotective effects.
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