FC-99 ameliorates sepsis-induced liver dysfunction by modulating monocyte/macrophage differentiation via Let-7a related monocytes apoptosis.
FC-99 ameliorates sepsis-induced liver dysfunction by modulating monocyte/macrophage differentiation via Let-7a related monocytes apoptosis.
复制标题
FC-99 通过 Let-7a 相关单核细胞凋亡调节单核细胞/巨噬细胞分化，改善脓毒症引起的肝功能障碍
DOI：
10.18632/oncotarget.24127
复制
发表时间：
2018-03-13
期刊：
影响因子：
--
通讯作者：
Dou H
中科院分区：
文献类型：
--
作者：
Zhao Y;Zhu H;Wang H;Ding L;Xu L;Chen D;Shen S;Hou Y;Dou H
肝脏是脓毒症相关损伤的重要靶点，导致炎症发病机制、多器官功能障碍和高死亡率。单核细胞衍生的巨噬细胞转化是肝脏炎症的关键事件。N1-[（4-甲氧基）甲基]-4-甲基-1，2-苯二胺（FC-99）先前显示出对实验性脓毒症的治疗潜力。然而，这种保护作用的潜在机制仍然不清楚。FC-99治疗减轻了脓毒症小鼠的肝功能障碍，伴有外周血中促炎Ly 6Chi单核细胞和肝脏中CD 11b +F4/80 lo单核细胞衍生的巨噬细胞数量减少。这些作用归因于FC-99诱导的CD 11b+细胞凋亡。在PMA分化的THP-1细胞中，FC-99抑制CD 11b、CD 14和caspase 3的表达，并导致高比例的Annexin V+细胞。此外，let-7a-5 p表达在CLP刺激后被废除，而FC-99处理后恢复。TargetScan分析和荧光素酶检测表明let-7a-5 p靶向抗凋亡蛋白BCL-XL。FC-99抑制BCL-XL以诱导单核细胞凋亡，导致单核细胞向巨噬细胞分化受损。FC-99给药后，通过盲肠结扎穿刺术建立小鼠急性肝衰竭模型，采集血液和肝组织，测定单核/巨噬细胞亚群和细胞凋亡诱导情况。用FC-99预处理人急性单核细胞白血病细胞系（THP-1），然后用佛波醇-12-肉豆蔻酸酯-13-乙酸酯（PMA）刺激，以诱导单核细胞向巨噬细胞分化。通过微阵列、qRT-PCR验证、TargetScan算法和荧光素酶报告分析进行FC-99的靶标和机制分析。FC-99通过恢复let-7a-5 p水平对CLP诱导的肝功能障碍表现出潜在的治疗作用。
The liver is a vital target for sepsis-related injury, leading to inflammatory pathogenesis, multiple organ dysfunction and high mortality rates. Monocyte-derived macrophage transformations are key events in hepatic inflammation. N1-[(4-methoxy)methyl]-4-methyl-1,2-benzenediamine (FC-99) previously displayed therapeutic potential on experimental sepsis. However, the underlying mechanism of this protective effect is still not clear. FC-99 treatment attenuated the liver dysfunction in septic mice that was accompanied with reduced numbers of pro-inflammatory Ly6Chi monocytes in the peripheral blood and CD11b+F4/80lo monocyte-derived macrophages in the liver. These effects were attributed to the FC-99-induced apoptosis of CD11b+ cells. In PMA-differentiated THP-1 cells, FC-99 repressed the expression of CD11b, CD14 and caspase3 and resulted in a high proportion of Annexin V+ cells. Moreover, let-7a-5p expression was abrogated upon CLP stimulation in vivo, whereas it was restored by FC-99 treatment. TargetScan analysis and luciferase assays indicated that the anti-apoptotic protein BCL-XL was targeted by let-7a-5p. BCL-XL was inhibited by FC-99 in order to induce monocyte apoptosis, leading to the impaired monocyte-to-macrophage differentiation. Murine acute liver failure was generated by caecal ligation puncture surgery after FC-99 administration; Blood samples and liver tissues were collected to determine the monocyte/macrophage subsets and the induction of apoptosis. Human acute monocytic leukemia cell line (THP-1) cells were pretreated with FC-99 followed by phorbol-12-myristate-13-acetate (PMA) stimulation, in order to induce monocyte-to-macrophage differentiation. The target of FC-99 and the mechanistic analyses were conducted by microarrays, qRT-PCR validation, TargetScan algorithms and a luciferase report assay. FC-99 exhibits potential therapeutic effects on CLP-induced liver dysfunction by restoring let-7a-5p levels.