Orthopaedic Hospital Research Center, University of California-Los Angeles, Los Angeles, California, USA.
Nat Med. 2012 Jan 29;18(2):267-73. doi: 10.1038/nm.2584.
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.
麻风病为研究人类免疫调节机制提供了一个模型，因为该病表现出一系列与宿主免疫反应相关的临床特征。在此，我们鉴定出 13 种在进展期瘤型麻风（L 型麻风）和自限性结核样型麻风（T 型麻风）患者皮损中差异表达的 microRNA。生物信息学分析显示，L 型麻风特异性 microRNA 显著富集，这些 microRNA 优先靶向在 L 型麻风皮损中下调的关键免疫基因。在 L 型麻风皮损中表达最差异的 microRNA，hsa-mir-21，在麻风分枝杆菌感染的单核细胞中上调。hsa-mir-21 通过直接下调 Toll 样受体 2/1 异二聚体（TLR2/1）诱导的 CYP27B1 和 IL1B 表达，以及间接上调白细胞介素 10（IL-10），抑制编码两种维生素 D 依赖性抗菌肽 CAMP 和 DEFB4A 的基因表达。相反，在麻风分枝杆菌感染的单核细胞中敲低 hsa-mir-21，增强了 CAMP 和 DEFB4A 的表达，并恢复了 TLR2/1 介导的对麻风分枝杆菌的抗菌活性。因此，麻风分枝杆菌上调 hsa-mir-21 的能力靶向多个与免疫定位疾病形式相关的基因，为逃避维生素 D 依赖性抗菌途径提供了有效的机制。
