NLRP3 inflammasome priming and activation in cholestatic liver injury via the sphingosine 1-phosphate/S1P receptor 2/Gα(12/13)/MAPK signaling pathway
NLRP3 inflammasome priming and activation in cholestatic liver injury via the sphingosine 1-phosphate/S1P receptor 2/Gα(12/13)/MAPK signaling pathway
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NLRP3 炎症小体通过 1-磷酸鞘氨醇/S1P 受体 2/Gα(12/13)/MAPKs 信号通路在胆汁淤积性肝损伤中启动和激活
DOI：
10.1007/s00109-020-02032-4
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发表时间：
2021-01-02
影响因子：
4.7
通讯作者：
Li, Liying
中科院分区：
文献类型：
--
作者：
Hou, Lei;Zhang, Zhi;Li, Liying
NLRP 3炎性小体驱动的炎症代表胆汁淤积性肝损伤期间肝纤维化的关键触发因素。然而，1-磷酸鞘氨醇（S1 P）是否在NLRP 3炎性小体引发和激活中起作用仍然未知。在此，我们发现在胆管结扎（BDL）损伤的肝脏中，巨噬细胞中NLRP 3的表达和NLRP 3炎性体的激活显著升高。在体外，S1 P通过S1 P受体2（S1 PR 2）促进骨髓源性单核/巨噬细胞（BMSCs）中的NLRP 3炎性体引发和活化。聚焦于Bacteria，通过特异性siRNA对G α（12）或G α（13）的基因沉默抑制NLRP 3炎性体引发和促炎细胞因子（IL-1 β和IL-18）分泌，而G α（（i/o））和G α（q）不参与该过程。MAPK信号通路（P38、ERK和JNK）介导NLRP 3炎性体引发和IL-1 β和IL-18分泌，而阻断PI 3 K、ROCK和Rho家族则没有这种作用。此外，JTE-013（S1 PR 2抑制剂）治疗显著减少BDL损伤的肝脏中的NLRP 3炎性体引发和活化。总的来说，S1 P通过S1 PR 2/G α（（12/13））/MAPK途径促进NLRP 3炎性体引发和促炎细胞因子（IL-1 β和IL-18）分泌，这可能代表肝脏疾病的有效治疗策略。关键信息中心点肝脏NLRP 3表达在BDL损伤的小鼠肝脏的BCL 4中显著升高。中心点S1 P促进BMPs中NLRP 3炎性小体的引发和激活，这取决于S1 PR 2/G α（（12/13））/MAPK通路。JTE-013对S1 PR 2的中心点阻断减少了体内NLRP 3炎性体引发和炎性体活化。
NLRP3 inflammasome-driven inflammation represents a key trigger for hepatic fibrogenesis during cholestatic liver injury. However, whether sphingosine 1-phosphate (S1P) plays a role in NLRP3 inflammasome priming and activation remains unknown. Here, we found that the expression of NLRP3 in macrophages and NLRP3 inflammasome activation were significantly elevated in the liver injured by bile duct ligation (BDL). In vitro, S1P promoted the NLRP3 inflammasome priming and activation via S1P receptor 2 (S1PR2) in bone marrow-derived monocyte/macrophages (BMMs). Focusing on BMMs, the gene silencing of G alpha(12) or G alpha(13) by specific siRNA suppressed NLRP3 inflammasome priming and pro-inflammatory cytokine (IL-1 beta and IL-18) secretion, whereas G alpha((i/o)) and G alpha(q) were not involved in this process. The MAPK signaling pathways (P38, ERK, and JNK) mediated NLRP3 inflammasome priming and IL-1 beta and IL-18 secretion, whereas blockage of PI3K, ROCK, and Rho family had no such effect. Moreover, JTE-013 (S1PR2 inhibitor) treatment markedly reduced NLRP3 inflammasome priming and activation in BDL-injured liver. Collectively, S1P promotes NLRP3 inflammasome priming and pro-inflammatory cytokines (IL-1 beta and IL-18) secretion via the S1PR2/G alpha((12/13))/MAPK pathway, which may represent an effective therapeutic strategy for liver disease. Key message center dot Hepatic NLRP3 expression was significantly elevated in BMMs of BDL-injured mouse liver. center dot S1P promoted NLRP3 inflammasome priming and activation in BMMs, depending on the S1PR2/G alpha((12/13))/MAPK pathway. center dot Blockade of S1PR2 by JTE-013 reduced NLRP3 inflammasome priming and activation inflammasome in vivo.