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Three paralogous clusters of the miR-17~92 family of microRNAs restrain IL-12-mediated immune defense

Cellular & Molecular Immunology volume 18, pages 1751–1760 (2021)Cite this article

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Abstract

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-17~92 family of miRNAs collectively suppressed IL-12 production in macrophages. Accordingly, miR-17~92 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-17~92 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-17~92 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-17~92 family miRNAs on a RBP-J null background. Thus, our results illustrated key roles of three clusters of miR-17~92 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.

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Data availability

The small RNA-seq and RNA-seq data sets were deposited in the National Center for Biotechnology Information Gene Expression Omnibus under accession numbers GSE103220, GSE129613, and GSE133844.

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Acknowledgements

We thank B. Zhang (Tsinghua University) for advice and help with the small RNA-seq analysis. We thank Y. Zhang (University of Maryland) for help with the RNA-seq analysis. We thank C. Dong (Tsinghua University) for providing Listeria monocytogenes. We thank W. Guo (Zhejiang University) for providing mir-106a~363−/− and mir-106b~25−/− mice. This research was supported by the Ministry of Science and Technology of China National Key Research Projects (2015CB943201 to X.H. and 2015CB943200 to L.W.), National Natural Science Foundation of China grants (31821003, 31725010, 81571580, 91642115, and 81661130161 to X.H. and 31330027 to L.W.), funds from Tsinghua-Peking Center for Life Sciences (X.H., L.W., and X.Z.), funds from the Institute for Immunology at Tsinghua University (X.H. and L.W.), and funds from the National Institutes of Health (B.Z.).

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Authors and Affiliations

  1. Institute for Immunology and School of Medicine, Tsinghua University, Beijing, 100084, China

    Xiang Zhang, Li Wu & Xiaoyu Hu

  2. Tsinghua-Peking Center for Life Sciences, Beijing, 10084, China

    Xiang Zhang, Li Wu & Xiaoyu Hu

  3. Beijing Key Laboratory for Immunological Research on Chronic Diseases, Beijing, 100084, China

    Xiang Zhang, Li Wu & Xiaoyu Hu

  4. Department of Clinical Medicine, School of Medicine, Trinity College Dublin, Dublin, Ireland

    Sinead M. Smith

  5. Department of Immunology, Beijing Key Laboratory for Cancer Invasion and Metastasis, Advanced Innovation Center for Human Brain Protection, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China

    Xi Wang

  6. Arthritis and Tissue Degeneration Program and the David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY, 10021, USA

    Baohong Zhao

  7. Department of Medicine, Weill Cornell Medical College, New York, NY, 10021, USA

    Baohong Zhao

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  1. Xiang Zhang
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Contributions

X.Z. designed the research, performed the experiments, analyzed the data, and wrote the paper; S.S. performed small RNA-seq experiments; B.Z. contributed to the small RNA-seq experiments and provided advice on the experiments; X.W. provided advice and key reagents; L.W. provided miR-106a~363−/−, miR-106b~25−/− and mir-17~92flox/flox mice and contributed to paper preparation; X.H. conceptualized the project, designed the research, supervised the experiments, and wrote the paper.

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Correspondence to Xiaoyu Hu.

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Zhang, X., Smith, S.M., Wang, X. et al. Three paralogous clusters of the miR-17~92 family of microRNAs restrain IL-12-mediated immune defense. Cell Mol Immunol 18, 1751–1760 (2021). https://doi.org/10.1038/s41423-020-0363-5

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