Necroptosis of macrophage is a key pathological feature in biliary atresia via GDCA/S1PR2/ZBP1/p-MLKL axis.
Necroptosis of macrophage is a key pathological feature in biliary atresia via GDCA/S1PR2/ZBP1/p-MLKL axis.
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DOI：
10.1038/s41419-023-05615-4
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发表时间：
2023-03-01
影响因子：
9
通讯作者：
Li, Liying
中科院分区：
文献类型：
--
作者：
Yang, Shen;Chang, Na;Li, Weiyang;Yang, Ting;Xue, Renmin;Liu, Jing;Zhang, Li;Yao, Xingfeng;Chen, Yajun;Wang, Huanmin;Yang, Lin;Huang, Jinshi;Li, Liying
胆道闭锁（BA）是一种严重的炎症性纤维化新生儿胆管病，其特征是肝外胆管进行性阻塞，导致胆汁淤积和进行性肝功能衰竭。胆汁淤积可能在炎症和纤维化病理过程中起重要作用，但其具体机制尚不清楚。z - dna结合蛋白1 (ZBP1)/磷酸化-混合谱系激酶结构域样伪激酶（p-MLKL）介导的坏死性坏死是炎症和纤维化疾病的重要致病因子，但其在BA中的功能尚不清楚。在此，我们旨在确定巨噬细胞坏死在BA病理中的作用，并探讨其具体的分子机制。我们发现BA肝存在坏死性上睑下垂，发生在肝巨噬细胞中。该过程由ZBP1/p-MLKL介导，BA肝中ZBP1表达上调与肝纤维化及预后相关。同样，在胆管结扎（BDL）诱导的小鼠胆汁淤积性肝损伤模型中，也观察到ZBP1/p-MLKL介导的巨噬细胞坏死。在体外，偶联胆汁酸-糖脱氧胆酸盐（GDCA）通过鞘氨醇1-磷酸受体2 （S1PR2）上调小鼠骨髓源性单核细胞/巨噬细胞（BMDMs）中ZBP1的表达，而ZBP1的诱导是增强坏死性上闭的先决条件。最后，在体内选择性敲除巨噬细胞S1pr2后，BDL小鼠中ZBP1/p- mlkl介导的坏死下垂减少，进一步的胶原沉积明显减弱。此外，巨噬细胞Zbp1或Mlkl特异性敲低也减轻了bdl诱导的肝损伤/纤维化。综上所述，GDCA/S1PR2/ZBP1/p-MLKL介导的巨噬细胞坏死在BA肝纤维化的发病机制中起着至关重要的作用，靶向这一过程可能是BA的潜在治疗策略。
Biliary atresia (BA) is a severe inflammatory and fibrosing neonatal cholangiopathy disease characterized by progressive obstruction of extrahepatic bile ducts, resulting in cholestasis and progressive hepatic failure. Cholestasis may play an important role in the inflammatory and fibrotic pathological processes, but its specific mechanism is still unclear. Necroptosis mediated by Z-DNA-binding protein 1 (ZBP1)/phosphorylated-mixed lineage kinase domain-like pseudokinase (p-MLKL) is a prominent pathogenic factor in inflammatory and fibrotic diseases, but its function in BA remains unclear. Here, we aim to determine the effect of macrophage necroptosis in the BA pathology, and to explore the specific molecular mechanism. We found that necroptosis existed in BA livers, which was occurred in liver macrophages. Furthermore, this process was mediated by ZBP1/p-MLKL, and the upregulated expression of ZBP1 in BA livers was correlated with liver fibrosis and prognosis. Similarly, in the bile duct ligation (BDL) induced mouse cholestatic liver injury model, macrophage necroptosis mediated by ZBP1/p-MLKL was also observed. In vitro, conjugated bile acid-glycodeoxycholate (GDCA) upregulated ZBP1 expression in mouse bone marrow-derived monocyte/macrophages (BMDMs) through sphingosine 1-phosphate receptor 2 (S1PR2), and the induction of ZBP1 was a prerequisite for the enhanced necroptosis. Finally, after selectively knocking down of macrophage S1pr2 in vivo, ZBP1/p-MLKL-mediated necroptosis was decreased, and further collagen deposition was markedly attenuated in BDL mice. Furthermore, macrophage Zbp1 or Mlkl specific knockdown also alleviated BDL-induced liver injury/fibrosis. In conclusion, GDCA/S1PR2/ZBP1/p-MLKL mediated macrophage necroptosis plays vital role in the pathogenesis of BA liver fibrosis, and targeting this process may represent a potential therapeutic strategy for BA.
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