肝脏sEH通过IL-6和肝-脑轴驱动应激诱导的神经炎症
Hepatic sEH drives stress-induced neuroinflammation via IL-6 and liver-brain axis.
摘要(中文译文)
已知束缚应激可导致重要器官损伤。既往研究表明，急性束缚应激（ARS）可引起小鼠显著的肝损伤。有趣的是，尽管肝脏在去除应激原后逐渐恢复，但应激诱导的行为异常在应激停止后可持续长达7天。可溶性环氧化物水解酶（sEH）在神经炎症和情绪障碍中发挥关键调控作用。然而，肝脏sEH上调是否以及如何参与ARS诱导的神经损伤仍不清楚。在ARS小鼠模型中，采用行为学测试评估神经功能损害。通过血流测定、代谢组学和血清ALT/AST水平评估肝功能。采用免疫组化（IHC）和蛋白质印迹检测肝脏sEH表达，并使用生化试剂盒定量EETs和IL-6。通过IHC评估下丘脑小胶质细胞活化和神经元损伤，并通过免疫荧光双染显示下丘脑神经元中IL-6的表达。束缚应激诱导小鼠出现行为异常。这些异常持续至少7天，并伴有肝血流减少、肝损伤和花生四烯酸代谢紊乱。应激显著上调肝脏sEH表达，降低环氧二十碳三烯酸（EETs），并增加白细胞介素-6（IL-6）。在下丘脑中，sEH表达升高，小胶质细胞呈现M1型活化（CD86+），并发生神经元丢失，同时下丘脑神经元内IL-6水平升高。使用sEH抑制剂TPPU治疗可显著改善应激诱导的行为异常、肝损伤、下丘脑神经炎症以及神经元内IL-6的异常升高。这些发现揭示，ARS通过肝脏sEH上调介导的肝-脑轴引起行为异常，其降低EETs并促进IL-6释放，导致下丘脑小胶质细胞活化及随后的神经元损伤。这些结果确定肝脏sEH为潜在治疗靶点，并强调肝-脑轴是ARS诱导的行为异常和神经损伤的关键介导因素。
Abstract
Restraint stress is known to induce damage to vital organs. Previous work indicates that acute restraint stress (ARS) causes significant hepatic injury in mice. Interestingly, while the liver gradually recovered following removal of the stressor, stress-induced behavioral abnormalities persisted for up to 7 days after stress cessation. Soluble epoxide hydrolase (sEH) plays a key regulatory role in neuroinflammation and mood disorders. However, whether and how hepatic sEH upregulation contributes to ARS-induced neurological damage remains unknown. In a mouse model of ARS, behavioral tests were used to assess neurological impairment. Hepatic function was evaluated by blood flow measurement, metabolomics, and serum ALT/AST levels. Hepatic sEH expression was examined by IHC and western blot, and EETs and IL‑6 were quantified with biochemical kits. Microglial activation and neuronal injury in the hypothalamus were assessed by IHC, and IL‑6 expression in hypothalamic neurons was visualized by immunofluorescence double staining. Restraint stress-induced behavioral abnormalities in mice. These abnormalities persisted for at least 7 days and were accompanied by reduced hepatic blood flow, liver injury, and perturbation of arachidonic acid metabolism. Stress markedly upregulated hepatic sEH expression, decreased epoxyeicosatrienoic acids (EETs), and increased interleukin-6 (IL-6). In the hypothalamus, sEH expression was elevated, microglia exhibited M1-type activation (CD86+), and neuronal loss occurred, while IL-6 levels within hypothalamic neurons was increased. Treatment with the sEH inhibitor TPPU significantly ameliorated stress-induced behavioral abnormalities, liver injury, hypothalamic neuroinflammation, and the abnormal intraneuronal increase of IL-6. These findings reveal that ARS elicits behavioral abnormalities via the liver-brain axis mediated by hepatic sEH upregulation, which reduces EETs and promotes IL-6 release, leading to hypothalamic microglial activation and subsequent neuronal injury. These results identify hepatic sEH as a potential therapeutic target and highlight the liver-brain axis as a critical mediator in ARS-induced behavioral abnormalities and neurological damage.
如何引用
AMA
Shuoqi Yang, Yan Song, Shangge Zhang, Chenyu Liu, Jinghui Cui, Dongmei Wang, et al. Hepatic sEH drives stress-induced neuroinflammation via IL-6 and liver-brain axis.. Frontiers in immunology. 2026; doi:10.3389/fimmu.2026.1895669.
APA
Shuoqi Yang, Yan Song, Shangge Zhang, Chenyu Liu, Jinghui Cui, Dongmei Wang, et al (2026). Hepatic sEH drives stress-induced neuroinflammation via IL-6 and liver-brain axis.. Frontiers in immunology. https://doi.org/10.3389/fimmu.2026.1895669
GB/T 7714
Shuoqi Yang, Yan Song, Shangge Zhang, Chenyu Liu, Jinghui Cui, Dongmei Wang, et al. Hepatic sEH drives stress-induced neuroinflammation via IL-6 and liver-brain axis.[J]. Frontiers in immunology, 2026 doi:10.3389/fimmu.2026.1895669.
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