Modulating sphingosine 1-phosphate receptor signaling skews intrahepatic leukocytes and attenuates murine nonalcoholic steatohepatitis.
Modulating sphingosine 1-phosphate receptor signaling skews intrahepatic leukocytes and attenuates murine nonalcoholic steatohepatitis.
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DOI：
10.3389/fimmu.2023.1130184
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发表时间：
2023
影响因子：
7.3
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中科院分区：
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鞘磷脂1-磷酸（S1P）是一种与非酒精性脂肪性肝炎（NASH）相关的生物活性鞘脂。免疫细胞驱动的炎症是NASH进展的关键决定因素。巨噬细胞、单核细胞、NK细胞、T细胞、NKT细胞和B细胞从S1P1 - S1P5的5种受体中表达不同的S1P受体。我们之前已经证明非特异性S1P受体拮抗剂可以改善NASH并减轻肝巨噬细胞积聚。然而，S1P受体拮抗剂对NASH中其他免疫细胞群的影响尚不清楚。我们假设S1P受体特异性调节可能通过改变白细胞募集来改善NASH。采用高果糖、高饱和脂肪和高胆固醇（FFC）日粮喂养C57BL/6雄性小鼠24周，建立小鼠NASH模型。在喂养的最后4周，小鼠每天口服S1P1、4、5调节剂Etrasimod或S1P1调节剂Amiselimod。通过组织学和基因表达分析确定肝损伤和炎症。通过流式细胞术、免疫组织化学和mRNA表达分析肝内白细胞群。丙氨酸转氨酶（一种敏感的肝损伤循环标志物）在Etrasimod和Amiselimod治疗后降低。肝脏组织学显示伊特拉西莫治疗小鼠炎症灶减少。通过降低T细胞、B细胞和NKT细胞的频率，以及按比例增加CD11b+骨髓细胞、多形核细胞和双阴性T细胞，伊特西莫德治疗在ffc喂养和对照标准饲料（CD）喂养的小鼠中显著改变了肝内白细胞群。相比之下，用ffc喂养的阿米沙利莫处理的小鼠肝内白细胞的频率没有变化。与肝损伤和炎症的改善一致，经etrasimod处理的ffc喂养小鼠的肝巨噬细胞积聚和促炎标志物Lgals3和Mcp-1的基因表达减少。经Etrasimod处理的小鼠肝脏显示出非炎症（Marco）和脂质相关（Trem2）巨噬细胞标志物的增加。因此，在测试剂量下，Etrasimod对S1P1,4,5的调节比Amiselimod对S1P1的拮抗更有效，可能是由于白细胞运输和募集的改变。伊特拉西莫治疗可显著减轻小鼠NASH的肝损伤和炎症。
Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid associated with nonalcoholic steatohepatitis (NASH). Immune cell-driven inflammation is a key determinant of NASH progression. Macrophages, monocytes, NK cells, T cells, NKT cells, and B cells variably express S1P receptors from a repertoire of 5 receptors termed S1P1 – S1P5. We have previously demonstrated that non-specific S1P receptor antagonism ameliorates NASH and attenuates hepatic macrophage accumulation. However, the effect of S1P receptor antagonism on additional immune cell populations in NASH remains unknown. We hypothesized that S1P receptor specific modulation may ameliorate NASH by altering leukocyte recruitment. A murine NASH model was established by dietary feeding of C57BL/6 male mice with a diet high in fructose, saturated fat, and cholesterol (FFC) for 24 weeks. In the last 4 weeks of dietary feeding, the mice received the S1P1,4,5 modulator Etrasimod or the S1P1 modulator Amiselimod, daily by oral gavage. Liver injury and inflammation were determined by histological and gene expression analyses. Intrahepatic leukocyte populations were analyzed by flow cytometry, immunohistochemistry, and mRNA expression. Alanine aminotransferase, a sensitive circulating marker for liver injury, was reduced in response to Etrasimod and Amiselimod treatment. Liver histology showed a reduction in inflammatory foci in Etrasimod-treated mice. Etrasimod treatment substantially altered the intrahepatic leukocyte populations through a reduction in the frequency of T cells, B cells, and NKT cells and a proportional increase in CD11b+ myeloid cells, polymorphonuclear cells, and double negative T cells in FFC-fed and control standard chow diet (CD)-fed mice. In contrast, FFC-fed Amiselimod-treated mice showed no changes in the frequencies of intrahepatic leukocytes. Consistent with the improvement in liver injury and inflammation, hepatic macrophage accumulation and the gene expression of proinflammatory markers such as Lgals3 and Mcp-1 were decreased in Etrasimod-treated FFC-fed mice. Etrasimod treated mouse livers demonstrated an increase in non-inflammatory (Marco) and lipid associated (Trem2) macrophage markers. Thus, S1P1,4,5 modulation by Etrasimod is more effective than S1P1 antagonism by Amiselimod, at the dose tested, in ameliorating NASH, likely due to the alteration of leukocyte trafficking and recruitment. Etrasimod treatment results in a substantial attenuation of liver injury and inflammation in murine NASH.