MicroRNA-21 Targets the Vitamin D-dependent Antimicrobial Pathway in Leprosy

Nat Med. 2012 Jan 29;18(2):267-73. doi: 10.1038/nm.2584.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 25-Hydroxyvitamin D3 1-alpha-Hydroxylase / physiology
  • Antimicrobial Cationic Peptides / physiology*
  • Cells, Cultured
  • Humans
  • Interleukin-10 / physiology
  • Interleukin-1beta / physiology
  • Leprosy / immunology*
  • Leprosy, Lepromatous / immunology
  • Leprosy, Tuberculoid / immunology
  • MicroRNAs / immunology
  • MicroRNAs / physiology*
  • Monocytes / immunology
  • Monocytes / microbiology
  • Mycobacterium leprae / immunology
  • Signal Transduction / physiology
  • Toll-Like Receptor 1 / immunology
  • Toll-Like Receptor 2 / immunology
  • Vitamin D / physiology*
  • beta-Defensins / physiology

Substances

  • Antimicrobial Cationic Peptides
  • DEFB4A protein, human
  • Interleukin-1beta
  • MIRN21 microRNA, human
  • MicroRNAs
  • Toll-Like Receptor 1
  • Toll-Like Receptor 2
  • beta-Defensins
  • Interleukin-10
  • Vitamin D
  • 25-Hydroxyvitamin D3 1-alpha-Hydroxylase