1. Academic Validation
  2. Uric acid inhibits HMGB1-TLR4-NF-κB signaling to alleviate oxygen-glucose deprivation/reoxygenation injury of microglia

Uric acid inhibits HMGB1-TLR4-NF-κB signaling to alleviate oxygen-glucose deprivation/reoxygenation injury of microglia

  • Biochem Biophys Res Commun. 2021 Feb 12;540:22-28. doi: 10.1016/j.bbrc.2020.12.097.
Qiang Wang 1 Hairong Zhao 1 Yuan Gao 1 Jiaming Lu 1 De Xie 1 Wei Yu 1 Furong He 1 Weidong Liu 1 Ichiro Hisatome 2 Tetsuya Yamamoto 3 Wei Wang 4 Jidong Cheng 5
Affiliations

Affiliations

  • 1 Department of Endocrinology, Xiang'an Hospital of Xiamen University, Xiamen, Fujian, China.
  • 2 Division of Regenerative Medicine and Therapeutics, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Sciences, Tottori University, Yonago, Japan.
  • 3 Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
  • 4 Department of Endocrinology, Xiang'an Hospital of Xiamen University, Xiamen, Fujian, China; Xiamen Key Laboratory of Translational Medicine for Nucleic Acid Metabolism and Regulation, Xiamen, Fujian, China. Electronic address: wwei19742007@hotmail.com.
  • 5 Department of Endocrinology, Xiang'an Hospital of Xiamen University, Xiamen, Fujian, China; Xiamen Key Laboratory of Translational Medicine for Nucleic Acid Metabolism and Regulation, Xiamen, Fujian, China. Electronic address: jidongcheng36@hotmail.com.
Abstract

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.

Keywords

HMGB1-TLR4-NF-κB signaling; Microglia; Oxygen-glucose deprivation; Uric acid.

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