The Novel MyD88 Inhibitor TJ-M2010-5 Protects Against Hepatic Ischemia-reperfusion Injury by Suppressing Pyroptosis in Mice.
The Novel MyD88 Inhibitor TJ-M2010-5 Protects Against Hepatic Ischemia-reperfusion Injury by Suppressing Pyroptosis in Mice.
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DOI：
10.1097/tp.0000000000004317
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发表时间：
2023-02-01
期刊：
影响因子：
6.2
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中科院分区：
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.随着医疗技术的发展和手术经验的增加，接受肝移植的患者数量也在增加。然而，肝缺血再灌注损伤（IRI）的发生限制了患者肝功能的恢复。Toll样受体4（TLR 4）/髓样分化因子88（MyD 88）信号通路和细胞凋亡在肝IRI的发生发展中起重要作用。.采用BALB/c小鼠建立了节段性（70%）热肝IRI小鼠模型。使用脂多糖和ATP处理的骨髓源性巨噬细胞在体外探索了肝脏IRI小鼠模型中的炎症机制。该体外炎症模型用于模拟肝IRI中的炎症和焦亡。.我们发现，MyD 88抑制剂通过下调TLR 4/MyD 88信号通路，在小鼠模型中提供对部分热肝IRI的保护。此外，TJ-M2010-5（一种新型MyD 88抑制剂，下文称为TJ-5）减少了肝IRI引起的肝巨噬细胞消耗和细胞凋亡诱导。TJ-5处理通过减少活化的B细胞的核因子κ轻链增强子的核转位、减少高迁移率族蛋白盒-1的释放和促进脂多糖-高迁移率族蛋白盒-1复合物的内吞作用来抑制骨髓源性巨噬细胞中的焦亡。. MyD 88的抑制可以通过减少肝脏先天免疫细胞中的焦亡来保护肝脏免受部分热肝IRI。这些结果揭示了部分热肝IRI中炎症发展和诱导细胞热凋亡的潜在机制。
. With the development of medical technology and increased surgical experience, the number of patients receiving liver transplants has increased. However, restoration of liver function in patients is limited by the occurrence of hepatic ischemia-reperfusion injury (IRI). Previous studies have reported that the Toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88) signaling pathway and pyroptosis play critical roles in the development of hepatic IRI. . A mouse model of segmental (70%) warm hepatic IRI was established using BALB/c mice in vivo. The mechanism underlying inflammation in mouse models of hepatic IRI was explored in vitro using lipopolysaccharide- and ATP-treated bone marrow-derived macrophages. This in vitro inflammation model was used to simulate inflammation and pyroptosis in hepatic IRI. . We found that a MyD88 inhibitor conferred protection against partial warm hepatic IRI in mouse models by downregulating the TLR4/MyD88 signaling pathway. Moreover, TJ-M2010-5 (a novel MyD88 inhibitor, hereafter named TJ-5) reduced hepatic macrophage depletion and pyroptosis induction by hepatic IRI. TJ-5 treatment inhibited pyroptosis in bone marrow-derived macrophages by reducing the nuclear translocation of nuclear factor kappa-light-chain-enhancer of activated B cells, decreasing the release of high-mobility group box-1, and promoting endocytosis of lipopolysaccharide-high-mobility group box-1 complexes. . Inhibition of MyD88 may protect the liver from partial warm hepatic IRI by reducing pyroptosis in hepatic innate immune cells. These results reveal the mechanism underlying the development of inflammation in partially warm hepatic IRI and the induction of cell pyroptosis.