title: MicroRNA-21 targets the vitamin D-dependent antimicrobial pathway in leprosy.
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.
authors.affiliation: Orthopaedic Hospital Research Center, University of California-Los Angeles, Los Angeles, California, USA. ptliu@mednet.ucla.edu
authors.forename: Philip T
authors.initials: PT
authors.lastname: Liu
authors.forename: Matthew
authors.initials: M
authors.lastname: Wheelwright
authors.forename: Rosane
authors.initials: R
authors.lastname: Teles
authors.forename: Evangelia
authors.initials: E
authors.lastname: Komisopoulou
authors.forename: Kristina
authors.initials: K
authors.lastname: Edfeldt
authors.forename: Benjamin
authors.initials: B
authors.lastname: Ferguson
authors.forename: Manali D
authors.initials: MD
authors.lastname: Mehta
authors.forename: Aria
authors.initials: A
authors.lastname: Vazirnia
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Rea
authors.forename: Euzenir N
authors.initials: EN
authors.lastname: Sarno
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Graeber
authors.forename: Robert L
authors.initials: RL
authors.lastname: Modlin
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000502:physiology; D023181:Antimicrobial Cationic Peptides / Q000502:physiology*; D002478:Cells, Cultured; D006801:Humans; D016753:Interleukin-10 / Q000502:physiology; D053583:Interleukin-1beta / Q000502:physiology; D007918:Leprosy / Q000276:immunology*; D015440:Leprosy, Lepromatous / Q000276:immunology; D015441:Leprosy, Tuberculoid / Q000276:immunology; D035683:MicroRNAs / Q000276:immunology / Q000502:physiology*; D009000:Monocytes / Q000276:immunology / Q000382:microbiology; D009166:Mycobacterium leprae / Q000276:immunology; D015398:Signal Transduction / Q000502:physiology; D051194:Toll-Like Receptor 1 / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000276:immunology; D014807:Vitamin D / Q000502:physiology*; D023083:beta-Defensins / Q000502:physiology
chemical_list: D023181:Antimicrobial Cationic Peptides; C106641:DEFB4A protein, human; D053583:Interleukin-1beta; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D023083:beta-Defensins; D016753:Interleukin-10; D014807:Vitamin D; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase