Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China.
Liver Transpl. 2019 Jul;25(7):1074-1090. doi: 10.1002/lt.25470. Epub 2019 Jun 3.
Hyperglycemia aggravates hepatic ischemia/reperfusion injury (IRI), but the underlying mechanism for the aggravation remains elusive. Sphingosine-1-phosphate (S1P) and sphingosine-1-phosphate receptors (S1PRs) have been implicated in metabolic and inflammatory diseases. Here, we discuss whether and how S1P/S1PRs are involved in hyperglycemia-related liver IRI. For our in vivo experiment, we enrolled diabetic patients with benign hepatic disease who had liver resection, and we used streptozotocin (STZ)-induced hyperglycemic mice or normal mice to establish a liver IRI model. In vitro bone marrow-derived macrophages (BMDMs) were differentiated in high-glucose (HG; 30 mM) or low-glucose (LG; 5 mM) conditions for 7 days. The expression of S1P/S1PRs was analyzed in the liver and BMDMs. We investigated the functional and molecular mechanisms by which S1P/S1PRs may influence hyperglycemia-related liver IRI. S1P levels were higher in liver tissues from patients with diabetes mellitus and mice with STZ-induced diabetes. S1PR3, but not S1PR1 or S1PR2, was activated in liver tissues and Kupffer cells under hyperglycemic conditions. The S1PR3 antagonist CAY10444 attenuated hyperglycemia-related liver IRI based on hepatic biochemistry, histology, and inflammatory responses. Diabetic livers expressed higher levels of M1 markers but lower levels of M2 markers at baseline and after ischemia/reperfusion. Dual-immunofluorescence staining showed that hyperglycemia promoted M1 (CD68/CD86) differentiation and inhibited M2 (CD68/CD206) differentiation. Importantly, CAY10444 reversed hyperglycemia-modulated M1/M2 polarization. HG concentrations in vitro also triggered S1P/S1PR3 signaling, promoted M1 polarization, inhibited M2 polarization, and enhanced inflammatory responses compared with LG concentrations in BMDMs. In contrast, S1PR3 knockdown significantly retrieved hyperglycemia-modulated M1/M2 polarization and attenuated inflammation. In conclusion, our study reveals that hyperglycemia specifically triggers S1P/S1PR3 signaling and exacerbates liver IRI by facilitating M1 polarization and inhibiting M2 polarization, which may represent an effective therapeutic strategy for liver IRI in diabetes.
高血糖会加重肝缺血/再灌注损伤（IRI），但加重的潜在机制仍不清楚。鞘氨醇-1-磷酸（S1P）和鞘氨醇-1-磷酸受体（S1PRs）与代谢和炎症性疾病有关。在这里，我们讨论 S1P/S1PRs 是否以及如何参与与高血糖相关的肝 IRI。对于我们的体内实验，我们招募了患有良性肝脏疾病并接受肝切除术的糖尿病患者，并用链脲佐菌素（STZ）诱导的高血糖小鼠或正常小鼠建立肝 IRI 模型。在体外，骨髓来源的巨噬细胞（BMDMs）在高糖（HG；30 mM）或低糖（LG；5 mM）条件下分化 7 天。分析肝脏和 BMDMs 中 S1P/S1PRs 的表达。我们研究了 S1P/S1PRs 可能影响与高血糖相关的肝 IRI 的功能和分子机制。糖尿病患者的肝组织和 STZ 诱导的糖尿病小鼠的肝组织中 S1P 水平较高。在高血糖条件下，S1PR3 而不是 S1PR1 或 S1PR2 在肝组织和库普弗细胞中被激活。S1PR3 拮抗剂 CAY10444 基于肝生化、组织学和炎症反应减轻与高血糖相关的肝 IRI。糖尿病肝脏在基线和缺血/再灌注后表达更高水平的 M1 标志物但更低水平的 M2 标志物。双重免疫荧光染色显示，高血糖促进 M1（CD68/CD86）分化并抑制 M2（CD68/CD206）分化。重要的是，CAY10444 逆转了高血糖调节的 M1/M2 极化。与 LG 浓度相比，体外 HG 浓度也触发了 S1P/S1PR3 信号转导，促进了 M1 极化，抑制了 M2 极化，并增强了 BMDMs 的炎症反应。相反，S1PR3 敲低显著恢复了高血糖调节的 M1/M2 极化并减轻了炎症。总之，我们的研究表明，高血糖特异性触发 S1P/S1PR3 信号转导，并通过促进 M1 极化和抑制 M2 极化加重肝 IRI，这可能代表糖尿病肝 IRI 的一种有效治疗策略。
