TNFα-mediated necroptosis in brain endothelial cells as a potential mechanism of increased seizure susceptibility in mice following systemic inflammation

Journal of Neuroinflammation

Chih-Hung Liang¹  Yen-Ling Lai²  Hsuan-Ying Chen²  Ko-Hung Liu²  Shankung Lin²  Hung-Ming Wu³  Kuei-Sen Hsu⁴  Wan-Yu Huang⁵ 

[1] Department of Food Science, Tunghai University, Taichung City, Taiwan;Inflammation Research and Drug Development Center, Changhua Christian Hospital, Changhua, Taiwan;Inflammation Research and Drug Development Center, Changhua Christian Hospital, Changhua, Taiwan;Department of Neurology, Changhua Christian Hospital, Changhua City, Taiwan;Institute of Acupuncture, School of Chinese Medicine, China Medical University, Taichung City, Taiwan;Institute of Basic Medical Sciences Basic Medicine, College of Medicine, National Cheng-Kung University, Tainan, Taiwan;Institute of Basic Medical Sciences Basic Medicine, College of Medicine, National Cheng-Kung University, Tainan, Taiwan;Pediatrics of Kung-Ten General Hospital, Taichung City, Taiwan;

关键词: Systemic inflammation;    Sepsis;    Seizure susceptibility;    Kainic acid;    Necroptosis;    Astrocytic Kir4.1;    Endothelia;    Blood–brain barrier;    Vascular integrity;   

DOI  :  10.1186/s12974-022-02406-0

来源: Springer

【 摘 要 】

BackgroundSystemic inflammation is a potent contributor to increased seizure susceptibility. However, information regarding the effects of systemic inflammation on cerebral vascular integrity that influence neuron excitability is scarce. Necroptosis is closely associated with inflammation in various neurological diseases. In this study, necroptosis was hypothesized to be involved in the mechanism underlying sepsis-associated neuronal excitability in the cerebrovascular components (e.g., endothelia cells).MethodsLipopolysaccharide (LPS) was used to induce systemic inflammation. Kainic acid intraperitoneal injection was used to measure the susceptibility of the mice to seizure. The pharmacological inhibitors C87 and GSK872 were used to block the signaling of TNFα receptors and necroptosis. In order to determine the features of the sepsis-associated response in the cerebral vasculature and CNS, brain tissues of mice were obtained for assays of the necroptosis-related protein expression, and for immunofluorescence staining to identify morphological changes in the endothelia and glia. In addition, microdialysis assay was used to assess the changes in extracellular potassium and glutamate levels in the brain.ResultsSome noteworthy findings, such as increased seizure susceptibility and brain endothelial necroptosis, Kir4.1 dysfunction, and microglia activation were observed in mice following LPS injection. C87 treatment, a TNFα receptor inhibitor, showed considerable attenuation of increased kainic acid-induced seizure susceptibility, endothelial cell necroptosis, microglia activation and restoration of Kir4.1 protein expression in LPS-treated mice. Treatment with GSK872, a RIP3 inhibitor, such as C87, showed similar effects on these changes following LPS injection.ConclusionsThe findings of this study showed that TNFα-mediated necroptosis induced cerebrovascular endothelial damage, neuroinflammation and astrocyte Kir4.1 dysregulation, which may coalesce to contribute to the increased seizure susceptibility in LPS-treated mice. Pharmacologic inhibition targeting this necroptosis pathway may provide a promising therapeutic approach to the reduction of sepsis-associated brain endothelia cell injury, astrocyte ion channel dysfunction, and subsequent neuronal excitability.

【 授权许可】

CC BY