Uric acid inhibits HMGB1-TLR4-NF- k B signaling to alleviate oxygen- glucose deprivation/reoxygenation injury of microglia
Uric acid inhibits HMGB1-TLR4-NF- k B signaling to alleviate oxygen- glucose deprivation/reoxygenation injury of microglia
复制标题
尿酸抑制HMGB1-TLR4-NF-k B信号传导减轻小胶质细胞氧糖剥夺/复氧损伤
DOI：
10.1016/j.bbrc.2020.12.097
复制
发表时间：
2020
影响因子：
3.1
通讯作者：
Jidong Cheng
中科院分区：
文献类型：
--
作者：
Qiang Wang;Hairong Zhao;Yuan Gao;Jiaming Lu;De Xie;Wei Yu;Furong He;Weidong Liu;Ichiro Hisatome;Tetsuya Yamamoto;Wei Wang;Jidong Cheng
越来越多的证据表明急性缺血性卒中（AIS）后的缺血-再灌注损伤中存在炎症。小胶质细胞仍然是脑炎症的主要发起者和参与者。新出现的证据表明，尿酸有希望治疗AIS，但其明确的机制仍然难以捉摸。在这里，我们观察到，尿酸降低脑梗死的严重程度，并在小鼠大脑中动脉闭塞/再灌注模型中减弱大脑皮层中小胶质细胞的激活。因此，我们推测尿酸可能通过直接干扰小胶质细胞的炎症反应而发挥作用。首先，我们研究了HMGB 1-TLR 4-NF-κB信号通路在氧糖剥夺再灌注（OGD/R）损伤BV 2细胞中的作用。抑制信号传导显著减少了BV 2细胞中由OGD/R引起的促炎细胞因子肿瘤坏死因子α（TNF-α）、白细胞介素1β（IL 1 β）和IL 6的释放。第二，尿酸减弱了由OGD/R诱导的BV 2细胞活力和乳酸脱氢酶释放的降低。最后，尿酸通过抑制HMGB 1-TLR 4-NF-κB信号转导，减少了BV 2细胞中OGD/R引起的促炎细胞因子TNF-α、IL 1 β和IL 6的释放，这一作用可被尿酸通道抑制剂丙磺舒逆转。尿酸通过抑制HMGB 1-TLR 4-NF-κB信号通路，抑制ODG/R诱导的炎症因子释放和细胞活力下降，从而减轻小胶质细胞损伤。这可能是尿酸保护小鼠免受大脑中动脉闭塞/再灌注脑损伤的分子机制的一部分。
Mounting evidence has implicated inflammation in ischemia–reperfusion injury following acute ischemic stroke (AIS). Microglia remain the primary initiator and participant of brain inflammation. Emerging evidence has indicated that uric acid has promise for the treatment of AIS, but its explicit mechanisms remain elusive. Here, we observed that uric acid reduced the severity of cerebral infarction and attenuated the activation of microglia in the cerebral cortex in a mouse middle cerebral-artery occlusion/reperfusion model. Thus, we speculated that uric acid may play a role by directly interfering with the inflammatory response of microglia. First, we investigated whether the HMGB1-TLR4-NF-κB signaling plays a role in oxygen glucose deprivation and reperfusion (OGD/R) injury of BV2 cells. Inhibition of the signaling significantly reduced the release of the proinflammatory cytokines tumor necrosis factor α (TNF-α), interleukin 1β (IL1β), and IL6 caused by OGD/R in BV2 cells. Second, uric acid weakened the decreased cell viability and lactate dehydrogenase release induced by OGD/R in BV2 cells. Finally, uric acid reduced the release of the proinflammatory cytokines TNF-α, IL1β, and IL6 caused by OGD/R in BV2 cells by dampening HMGB1-TLR4-NF-κB signaling, which was reversed by probenecid treatment, an inhibitor of the uric acid channel. Hence, uric acid halted the release of inflammatory factors and the decreased cell viability induced by ODG/R via inhibiting the microglia HMGB1-TLR4-NF-κB signaling, thereby alleviating the damage to microglia. This may be part of the molecular mechanisms by which uric acid protects mice against the brain damage of middle cerebral-artery occlusion/reperfusion.