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

Leprosy provides a model to investigate mechanisms of immune regulation in humans, given that the disease forms a clinical-immunological spectrum. Here, we identified 13 miRNAs that were differentially expressed in the lesions of subjects with progressive lepromatous (L-lep) vs. 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 vs. T-lep lesions. The most differentially expressed miRNA in L-lep lesions, hsa-mir-21, was upregulated in M. leprae-infected monocytes. Hsa-mir-21, by downregulating toll-like receptor 2/1 (TLR2/1)-induced CYP27B1 and IL1B as well as upregulating IL-10, inhibited gene expression of the 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.