MicroRNA 223 3p Negatively Regulates the NLRP3 Inflammasome in Acute and Chronic Liver Injury
MicroRNA 223 3p Negatively Regulates the NLRP3 Inflammasome in Acute and Chronic Liver Injury
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DOI：
10.1016/j.ymthe.2019.09.013
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发表时间：
2020-02-05
影响因子：
12.4
通讯作者：
Feldstein, Ariel E.
中科院分区：
文献类型：
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作者：
Calvente, Carolina Jimenez;Del Pilar, Hana;Feldstein, Ariel E.
粒细胞特异性 microRNA-223 (miR-223) 最近已成为 NOD 样受体 3 (NLRP3) 表达的负调节因子，而 NOD 样受体 3 (NLRP3) 是纤维化非酒精性脂肪性肝炎 (NASH) 等慢性肝损伤以及包括急性肝炎等其他肝脏疾病的关键因素。在这项研究中，我们评估了合成的 miR-223 类似物 miR-223 3p 在脂多糖 (LPS)/D-GalN 诱导的内毒素急性肝炎 (EAH) 或长期高脂肪、果糖和胆固醇 (FFC) 饮食喂养导致的纤维化 NASH 的小鼠模型中的治疗效果。 miR-223 3p 改善了 EAH 中单核细胞、中性粒细胞和早期活化巨噬细胞的浸润，并下调促炎细胞因子 Il6 和 Il12 以及趋化因子 Ccl2、Ccl3、Cxcl1 和 Cxcl2 的转录表达。在纤维化 NASH 中，用 miR-223 3p 治疗可显着减轻纤维化发展和肝星状细胞 (HSC) 的激活。 miR-223 3p 通过损害 EAH 和纤维化 NASH 中裂解的白细胞介素 1 β (IL-1 β)、成熟 IL-1 β 和 NLRP3 的合成以及 caspase-1 p10 的激活来破坏 NLRP3 炎症小体的激活。我们的数据揭示了 miR-223 3p 作为一种转录后方法，通过沉默 NLRP3 炎性体的激活来治疗急性和慢性肝炎。
The granulocyte-specific microRNA-223 (miR-223) has recently emerged as a negative regulator of NOD-like receptor 3 (NLRP3) expression, a central key player in chronic hepatic injuries such as fibrotic nonalcoholic steatohepatitis (NASH), as well as in other liver conditions including acute hepatitis. In this study, we evaluated the therapeutic effect of the synthetic miR-223 analog miR-223 3p in a murine model of lipopolysaccharide (LPS)/D-GalN-induced endotoxin acute hepatitis (EAH) or fibrotic NASH resultant of long-term feeding with a high-fat, fructose, and cholesterol (FFC) diet. miR-223 3p ameliorated the infiltration of monocytes, neutrophils, and early activated macrophages and downregulated the transcriptional expression of the pro-inflammatory cytokines Il6 and Il12 and the chemokines Ccl2, Ccl3, Cxcl1, and Cxcl2 in EAH. In fibrotic NASH, treatment with miR-223 3p led to a remarkable mitigation of fibrosis development and activation of hepatic stellate cells (HSCs). miR-223 3p disrupted the activation of the NLRP3 inflammasome by impairing the synthesis of cleaved interleukin-1 beta (IL-1 beta), mature IL-1 beta, and NLRP3, and the activation of caspase-1 p10 in both EAH and fibrotic NASH. Our data enlightens miR-223 3p as a post-transcriptional approach to treat acute and chronic hepatitis by silencing the activation of the NLRP3 inflammasome.