Institute for Immunology and School of Medicine, Tsinghua University, Beijing, 100084, China.
Tsinghua-Peking Center for Life Sciences, Beijing, 10084, China.
Cell Mol Immunol. 2021 Jul;18(7):1751-1760. doi: 10.1038/s41423-020-0363-5. Epub 2020 Feb 3.
MicroRNAs (miRNAs) have been widely implicated in immune regulation, but evidence for the coordinated function of paralogous miRNA clusters remains scarce. Here, by using genetically modified mice with individual or combined cluster deficiencies, we found that three paralogous clusters of the miR-1792 family of miRNAs collectively suppressed IL-12 production in macrophages. Accordingly, miR-1792 family miRNAs deficiencies resulted in heightened production of IL-12 and thus enhanced the host defense against intracellular pathogen Listeria monocytogenes in vivo. Mechanistically, different members of the miR-1792 family of miRNAs acted on a common target, PTEN, to inhibit IL-12 expression by modulating the PI3K-Akt-GSK3 pathway. In addition, the expression of miR-1792 family miRNAs was collectively inhibited by the transcription factor RBP-J, and RBP-J-associated macrophage functional defects were genetically rescued by deleting three clusters of miR-1792 family miRNAs on a RBP-J null background. Thus, our results illustrated key roles of three clusters of miR-1792 family miRNAs in cooperatively controlling IL-12-mediated immune responses and identified miR-17~92 family miRNAs as functional targets of RBP-J in macrophages.
微小 RNA（miRNA）广泛参与免疫调节，但关于旁系 miRNA 簇协同功能的证据仍然很少。在这里，我们通过使用单个或组合簇缺失的基因修饰小鼠，发现 miR-1792 家族的三个旁系 miRNA 簇共同抑制巨噬细胞中 IL-12 的产生。因此，miR-1792 家族 miRNA 缺陷导致 IL-12 的产生增加，从而增强了宿主对细胞内病原体李斯特菌的防御。从机制上讲，miR-1792 家族的不同成员作用于一个共同的靶点，PTEN，通过调节 PI3K-Akt-GSK3 通路来抑制 IL-12 的表达。此外，miR-1792 家族 miRNA 的表达被转录因子 RBP-J 共同抑制，并且在 RBP-J 缺失背景上缺失三个 miR-1792 家族 miRNA 簇可以遗传拯救 RBP-J 相关巨噬细胞功能缺陷。因此，我们的结果说明了 miR-1792 家族的三个簇在协同控制 IL-12 介导的免疫反应中的关键作用，并确定 miR-17~92 家族 miRNA 是巨噬细胞中 RBP-J 的功能靶点。
