Macrophage Sphingosine 1-Phosphate Receptor 2 Blockade Attenuates Liver Inflammation and Fibrogenesis Triggered by NLRP3 Inflammasome
Macrophage Sphingosine 1-Phosphate Receptor 2 Blockade Attenuates Liver Inflammation and Fibrogenesis Triggered by NLRP3 Inflammasome
复制标题
巨噬细胞鞘氨醇1-磷酸受体2阻断剂减轻NLRP 3炎性小体引发的肝脏炎症和纤维化
DOI：
10.3389/fimmu.2020.01149
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发表时间：
2020-06-26
影响因子：
7.3
通讯作者：
Li, Liying
中科院分区：
文献类型：
--
作者：
Hou, Lei;Yang, Le;Li, Liying
NLR家族pyrin domain containing 3（NLRP 3）炎性小体伴随慢性肝损伤，并且是炎症驱动的肝纤维化的关键介质。1-磷酸鞘氨醇（S1 P）/S1 P受体（S1 PR）信号通路通过影响骨髓源性单核/巨噬细胞（BMM）活化参与肝纤维化。然而，S1 P/S1 PR信号转导与BERN 1中NLRP 3炎性小体之间的关系尚不清楚。在这里，我们发现显着升高的基因表达的NLRP 3炎性体成分（NLRP 3，前白细胞介素-1 β，和前白细胞介素-18）和激活的NLRP 3炎性体显着升高，在小鼠慢性肝损伤诱导的胆管结扎手术，蛋氨酸胆碱缺乏和高脂肪饮食，或四氯化碳腹腔注射。此外，S1 P的限速合成酶鞘氨醇激酶1（SphK 1）的表达增加与患者和小鼠模型肝脏中的NLRP 3炎性小体组分呈正相关。流式细胞术分析和免疫荧光染色显示，Bcl 4在小鼠炎症肝脏中贡献了显著比例的NLRP 3（+）细胞，而不是Kupffer细胞、树突状细胞、内皮细胞、T细胞和肝细胞。聚焦于巨噬细胞，S1 P以剂量依赖性方式促进NLRP 3炎性体引发和活化。通过JTE-013（S1 PR（2）拮抗剂）或S1 PR（2）-siRNA阻断S1 PR（2）可抑制S1 P诱导的NLRP 3炎性体引发和炎性细胞因子（白细胞介素-1 β和白细胞介素-18）分泌，而阻断S1 PR（1）或S1 PR（3）则没有effect.in体内，β 1，3-d-葡聚糖包封的siRNA颗粒（GeRP）递送系统能够特异性沉默巨噬细胞中的基因。用S1 PR（2）siRNA-GeRPs治疗显著减少了NLRP 3炎性体引发和活化，并减轻了肝脏炎症和纤维化。总之，结论表明靶向巨噬细胞S1 PR（2）通过下调NLRP 3炎性体延缓肝脏炎症和纤维化，这可能代表慢性肝损伤的有效治疗策略。
NLR family pyrin domain containing 3 (NLRP3) inflammasome accompanies chronic liver injury and is a critical mediator of inflammation-driven liver fibrosis. Sphingosine 1-phosphate (S1P)/S1P Receptor (S1PR) signaling participates in liver fibrogenesis by affecting bone marrow (BM)-derived monocytes/macrophage (BMM) activation. However, the relationship between S1P/S1PR signaling and NLRP3 inflammasome in BMMs remains unclear. Here, we found significantly elevated gene expression of NLRP3 inflammasome components (NLRP3, pro-interleukin-1 beta, and pro-interleukin-18) and the activation of NLRP3 inflammasome significantly elevated during murine chronic liver injury induced by a bile duct ligation operation, a methionine-choline-deficient and high-fat diet, or carbon tetrachloride intraperitoneal injection. Moreover, the increased expression of sphingosine kinase 1 (SphK1), the rate-limiting synthetic enzyme of S1P, was positively correlated with NLRP3 inflammasome components in both patients and mouse model livers. Flow cytometry analysis and immunofluorescence staining showed BMMs contributed to the significant proportion of NLRP3(+)cells in murine inflammatory livers, but not Kupffer cells, dendritic cells, endothelial cells, T cells, and hepatocytes. Focusing on macrophages, S1P promoted NLRP3 inflammasome priming and activation in a dose-dependent manner. Blockade of S1PR(2)by JTE-013 (antagonist of S1PR(2)) or S1PR(2)-siRNA inhibited S1P-induced NLRP3 inflammasome priming and inflammatory cytokine (interleukin-1 beta and interleukin-18) secretion, whereas blockade of S1PR(1)or S1PR(3)had no such effect.in vivo, a beta 1,3-d-glucan-encapsulated siRNA particle (GeRP) delivery system is capable of silencing genes in macrophages specifically. Treatment with S1PR(2)siRNA-GeRPs markedly reduced NLRP3 inflammasome priming and activation and attenuated liver inflammation and fibrosis. Together, the conclusions indicated that targeting macrophage S1PR(2)retarded liver inflammation and fibrogenesis via downregulating NLRP3 inflammasome, which may represent an effective therapeutic strategy for chronic liver injury.