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MicroRNA-21 targets the vitamin D–dependent antimicrobial pathway in leprosy

Nature Medicine volume 18, pages 267–273 (2012)Cite this article

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Abstract

Leprosy provides a model to investigate mechanisms of immune regulation in humans, given that the disease forms a spectrum of clinical presentations that correlate with host immune responses. Here we identified 13 miRNAs that were differentially expressed in the lesions of subjects with progressive lepromatous (L-lep) versus the self-limited tuberculoid (T-lep) disease. Bioinformatic analysis revealed a significant enrichment of L-lep–specific miRNAs that preferentially target key immune genes downregulated in L-lep versus T-lep lesions. The most differentially expressed miRNA in L-lep lesions, hsa-mir-21, was upregulated in Mycobacterium leprae–infected monocytes. By directly downregulating Toll-like receptor 2/1 heterodimer (TLR2/1)-induced CYP27B1 and IL1B expression as well as indirectly upregulating interleukin-10 (IL-10), hsa-mir-21 inhibited expression of the genes encoding two vitamin D–dependent antimicrobial peptides, CAMP and DEFB4A. Conversely, knockdown of hsa-mir-21 in M. leprae–infected monocytes enhanced expression of CAMP and DEFB4A and restored TLR2/1-mediated antimicrobial activity against M. leprae. Therefore, the ability of M. leprae to upregulate hsa-mir-21 targets multiple genes associated with the immunologically localized disease form, providing an effective mechanism to escape from the vitamin D–dependent antimicrobial pathway.

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Figure 1: MiRNA expression and targeting profile in leprosy.
Figure 2: Expression of hsa-mir-21 in leprosy.
Figure 3: Regulation of hsa-mir-21 levels in primary human monocytes by M. leprae.
Figure 4: The ability of hsa-mir-21 to regulate the innate immune response in human monocytes.
Figure 5: Role of hsa-mir-21 expression during M. leprae infection.
Figure 6: Role of hsa-mir-21 in TLR2/1-mediated antimicrobial activity.

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Acknowledgements

We would like to thank G. Cheng, R. O'Connell, J. Krahenbuhl, R. Lahiri and B. Bloom for their helpful discussions. The live M. leprae was provided by the US National Hansen's Disease Programs through the generous support of the American Leprosy Missions and Society of St. Lazarus of Jerusalem. This work was supported by US National Institutes of Health grants AI 022553, AI 047868, AR 040312 and AI 073539. P.T.L. is supported by US National Institutes of Health K22 Career Development Award AI 85025. K.E. is supported by a postdoctoral grant from the Wenner-Gren Foundations (Sweden). We would like to thank M. Schibler and the University of California–Los Angeles, California NanoSystems Institute, Advanced Light Microscopy Core Facility for their assistance with the confocal studies.

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Authors and Affiliations

  1. Orthopaedic Hospital Research Center, University of California–Los Angeles, Los Angeles, California, USA

    Philip T Liu

  2. Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California–Los Angeles, Los Angeles, California, USA

    Philip T Liu, Matthew Wheelwright, Rosane Teles, Kristina Edfeldt, Benjamin Ferguson & Robert L Modlin

  3. Crump Institute for Molecular Imaging, University of California–Los Angeles, Los Angeles, California, USA

    Evangelia Komisopoulou & Thomas G Graeber

  4. Department of Molecular and Medical Pharmacology, University of California–Los Angeles, Los Angeles, California, USA

    Evangelia Komisopoulou & Thomas G Graeber

  5. Department of Microbiology, Immunology and Molecular Genetics, University of California–Los Angeles, Los Angeles, California, USA

    Manali D Mehta, Aria Vazirnia & Robert L Modlin

  6. Department of Dermatology, University of Southern California School of Medicine, Los Angeles, California, USA

    Thomas H Rea

  7. Leprosy Laboratory Institute Oswaldo Cruz, Rio de Janeiro, Brazil

    Euzenir N Sarno

  8. Institute for Molecular Medicine, University of California–Los Angeles, Los Angeles, California, USA

    Thomas G Graeber

  9. Jonsson Comprehensive Cancer Center, University of California–Los Angeles, Los Angeles, California, USA

    Thomas G Graeber

  10. California NanoSystems Institute, University of California–Los Angeles, Los Angeles, California, USA

    Thomas G Graeber

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Contributions

P.T.L. performed the experiments, supervised the project, analyzed the data and wrote the manuscript. M.W. performed the in situ hybridization experiments and a portion of the M. leprae infection, antimicrobial and monocyte transfection experiments. R.T. performed the microarray experiments. E.K. performed the bioinformatics analysis of the microarray data. K.E. performed the IL-10–related experiments. B.F. performed a portion of the M. leprae infection, antimicrobial and monocyte transfection experiments. M.D.M. performed a portion of the M. leprae infection and ligands experiments. A.V. performed a portion of the monocyte transfection experiments. T.H.R. and E.N.S. diagnosed patients with leprosy collected skin biopsy specimens. T.G.G. designed, supervised and performed bioinformatics analysis. R.L.M. supervised the project and wrote the manuscript.

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Correspondence to Philip T Liu.

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The authors declare no competing financial interests.

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Supplementary Figures 1–12, Supplementary Table 1, Supplementary Note and Supplementary Methods (PDF 782 kb)

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Liu, P., Wheelwright, M., Teles, R. et al. MicroRNA-21 targets the vitamin D–dependent antimicrobial pathway in leprosy. Nat Med 18, 267–273 (2012). https://doi.org/10.1038/nm.2584

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