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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.

References

  1. Huntzinger, E. & Izaurralde, E. Gene silencing by microRNAs: contributions of translational repression and mRNA decay. Nat. Rev. 12, 99–110 (2011).

    CAS  Google Scholar 

  2. Krol, J., Loedige, I. & Filipowicz, W. The widespread regulation of microRNA biogenesis, function and decay. Nat. Rev. 11, 597–610 (2010).

    CAS  Google Scholar 

  3. Ha, M. & Kim, V. N. Regulation of microRNA biogenesis. Nat. Rev. 15, 509–524 (2014).

    CAS  Google Scholar 

  4. Altuvia, Y. et al. Clustering and conservation patterns of human microRNAs. Nucleic Acids Res. 33, 2697–2706 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Kozomara A., Griffiths-Jones S. miRBase: annotating high confidence microRNAs using deep sequencing data. Nucleic Acids Res. 42, D68–D73 (2014).

  6. Ventura, A. et al. Targeted deletion reveals essential and overlapping functions of the miR-17~92 family of miRNA clusters. Cell 132, 875–886 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Mendell, J. T. miRiad roles for the miR-17~92 cluster in development and disease. Cell 133, 217–222 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Mogilyansky, E. & Rigoutsos, I. The miR-17/92 cluster: a comprehensive update on its genomics, genetics, functions and increasingly important and numerous roles in health and disease. Cell Death Differ. 20, 1603–1614 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Xiao, C. et al. Lymphoproliferative disease and autoimmunity in mice with increased miR-17~92 expression in lymphocytes. Nat. Immunol. 9, 405–414 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Kang, S. G. et al. MicroRNAs of the miR-17~92 family are critical regulators of TFH differentiation. Nat. Immunol. 14, 849–857 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Lai, M. et al. Regulation of B-cell development and tolerance by different members of the miR-17~92 family microRNAs. Nat. Commun. 7, 12207 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Benhamou, D. et al. A c-Myc/miR17-92/Pten axis controls PI3K-mediated positive and negative selection in B cell development and reconstitutes CD19 deficiency. Cell Rep. 16, 419–431. (2016).

    CAS  PubMed  Google Scholar 

  13. Fontana, L. et al. MicroRNAs 17-5p–20a–106a control monocytopoiesis through AML1 targeting and M-CSF receptor upregulation. Nat. Cell Biol. 9, 775 (2007).

    CAS  PubMed  Google Scholar 

  14. Fedeli, M. et al. miR-17∼92 family clusters control iNKT cell ontogenesis via modulation of TGF-β signaling. Proc. Natl Acad. Sci. 113, E8286–E8295 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Labi, V., Schoeler, K. & Melamed, D. miR-17∼92 in lymphocyte development and lymphomagenesis. Cancer Lett. 446, 73–80 (2019).

    CAS  PubMed  Google Scholar 

  16. Trinchieri, G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat. Rev. 3, 133–146 (2003).

    CAS  Google Scholar 

  17. Serbina, N. V., Jia, T., Hohl, T. M. & Pamer, E. G. Monocyte-mediated defense against microbial pathogens. Annu. Rev. Immunol. 26, 421–452. (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Teng, M. W. L. et al. IL-12 and IL-23 cytokines: from discovery to targeted therapies for immune-mediated inflammatory diseases. Nat. Med. 21, 719–729 (2015).

    CAS  PubMed  Google Scholar 

  19. Ramirez-Carrozzi, V. R. et al. A unifying model for the selective regulation of inducible transcription by CpG islands and nucleosome remodeling. Cell 138, 114–128 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Jin, J. et al. Epigenetic regulation of the expression of Il12 and Il23 and autoimmune inflammation by the deubiquitinase Trabid. Nat. Immunol. 17, 259–268 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Goriely, S., Neurath, M. F. & Goldman, M. How microorganisms tip the balance between interleukin-12 family members. Nat. Rev. 8, 81–86 (2008).

    CAS  Google Scholar 

  22. Lyakh, L., Trinchieri, G., Provezza, L., Carra, G. & Gerosa, F. Regulation of interleukin-12/interleukin-23 production and the T-helper 17 response in humans. Immunol. Rev. 226, 112–131. (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Pamer, E. G. Immune responses to Listeria monocytogenes. Nat. Rev. 4, 812–823 (2004).

    CAS  Google Scholar 

  24. Shi, C. et al. Bone marrow mesenchymal stem and progenitor cells induce monocyte emigration in response to circulating toll-like receptor ligands. Immunity 34, 590–601 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Liu, J. & Cao, X. Cellular and molecular regulation of innate inflammatory responses. Cell. Mol. Immunol. 13, 711–721. (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Hu, X. et al. IFN-gamma suppresses IL-10 production and synergizes with TLR2 by regulating GSK3 and CREB/AP-1 proteins. Immunity 24, 563–574. (2006).

    CAS  PubMed  Google Scholar 

  27. Martin, M., Rehani, K., Jope, R. S. & Michalek, S. M. Toll-like receptor-mediated cytokine production is differentially regulated by glycogen synthase kinase 3. Nat. Immunol. 6, 777–784. (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Cohen, P. & Frame, S. The renaissance of GSK3. Nat. Rev. 2, 769–776 (2001).

    CAS  Google Scholar 

  29. Beurel, E., Michalek, S. M. & Jope, R. S. Innate and adaptive immune responses regulated by glycogen synthase kinase-3 (GSK3). Trends Immunol. 31, 24–31 (2010).

    CAS  PubMed  Google Scholar 

  30. Song, M. S., Salmena, L. & Pandolfi, P. P. The functions and regulation of the PTEN tumour suppressor. Nat. Rev. 13, 283–296 (2012).

    CAS  Google Scholar 

  31. Agarwal, V., Bell, G. W., Nam, J.-W. & Bartel, D. P. Predicting effective microRNA target sites in mammalian mRNAs. eLife 4, e05005 (2015).

    PubMed Central  Google Scholar 

  32. Tanigaki, K. & Honjo, T. Two opposing roles of RBP-J in Notch signaling. Curr. Top. Dev. Biol. 92, 231–252. (2010).

    CAS  PubMed  Google Scholar 

  33. Kopan, R. & Ilagan, M. X. The canonical Notch signaling pathway: unfolding the activation mechanism. Cell 137, 216–233 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Yuan, J. S., Kousis, P. C., Suliman, S., Visan, I. & Guidos, C. J. Functions of notch signaling in the immune system: consensus and controversies. Annu. Rev. Immunol. 28, 343–365 (2010).

    PubMed  Google Scholar 

  35. Shang, Y., Smith, S. & Hu, X. Role of Notch signaling in regulating innate immunity and inflammation in health and disease. Protein Cell 7, 159–174 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Radtke, F., Fasnacht, N. & MacDonald, H. R. Notch Signaling in the immune system. Immunity 32, 14–27 (2010).

    CAS  PubMed  Google Scholar 

  37. Xu, H. et al. Notch-RBP-J signaling regulates the transcription factor IRF8 to promote inflammatory macrophage polarization. Nat. Immunol. 13, 642–650 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Lindsay, M. A. microRNAs and the immune response. Trends Immunol. 29, 343–351. (2008).

    CAS  PubMed  Google Scholar 

  39. Fuziwara C. S., Kimura E. T. Insights into regulation of the miR-17-92 cluster of miRNAs in cancer. Front. Med. 2 64 (2015).

  40. O’Donnell, K. A., Wentzel, E. A., Zeller, K. I., Dang, C. V. & Mendell, J. T. c-Myc-regulated microRNAs modulate E2F1 expression. Nature 435, 839–843 (2005).

    PubMed  Google Scholar 

  41. Novotny, G. W. et al. Translational repression of E2F1 mRNA in carcinoma in situ and normal testis correlates with expression of the miR-17-92 cluster. Cell Death Differ. 14, 879 (2007).

    CAS  PubMed  Google Scholar 

  42. Hu, X. et al. Integrated regulation of Toll-like receptor responses by Notch and interferon-γ pathways. Immunity 29, 691–703 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Chung, Y. et al. T cells and T cell tumors efficiently generate antigen-specific cytotoxic T cell immunity when modified with an NKT ligand. OncoImmunology 1, 141–151. (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Seregin, S. S., Chen, G. Y. & Laouar, Y. Dissecting CD8+ NKT cell responses to Listeria infection reveals a component of innate resistance. J. Immunol. 195, 1112–1120 (2015).

    CAS  PubMed  Google Scholar 

  45. Ji, L. et al. Slc6a8-mediated creatine uptake and accumulation reprogram macrophage polarization via regulating cytokine responses. Immunity 51, 272–284.e7 (2019).

    CAS  PubMed  Google Scholar 

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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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