MS2 VLP-based delivery of microRNA-146a inhibits autoantibody production in lupus-prone mice.
MS2 VLP-based delivery of microRNA-146a inhibits autoantibody production in lupus-prone mice.
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DOI：
10.2147/ijn.s37990
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发表时间：
2012
影响因子：
8
通讯作者：
Wang L
中科院分区：
文献类型：
--
作者：
Pan Y;Jia T;Zhang Y;Zhang K;Zhang R;Li J;Wang L
系统性红斑狼疮（SLE）是一种慢性自身免疫性疾病，其特征是存在致病性自身抗体。近年来的研究表明microRNAs（miRNAs）在免疫调节中起重要作用，并可能参与SLE的发病机制。因此，研究miRNA在SLE中的潜在治疗应用是令人感兴趣的，这是迄今为止尚未彻底研究的概念。病毒样颗粒（Virus-like particles，VLP）是一种由病毒外壳蛋白包裹的重组纳米颗粒。在本文中，我们描述了一种新的通过噬菌体MS 2 VLP的miRNA递送方法，并研究了miR-146 a在BXSB狼疮易感小鼠中的治疗作用，miR-146 a是一种研究充分的SLE相关miRNA。使用大肠杆菌表达系统制备含有miR-146 a的VLP和对照VLP，然后在12天的时间内给予狼疮易感小鼠。采用酶联免疫吸附试验检测血清抗dsDNA抗体、抗核抗原自身抗体（ANA）、总IgG和总IgM水平。通过qRT-PCR分析miR-146 a的表达。SLE相关的细胞因子以及一些toll样受体信号通路分子也进行了测量。用MS 2-miR 146 a VLP治疗对狼疮易感BXSB小鼠显示出深远的影响，包括成熟miR-146 a水平的增加，这导致自身抗体和总IgG的表达显著降低。值得注意的是，这些小鼠还表现出促炎细胞因子水平的降低，包括IFN-α（IFN-α）、白细胞介素-1 β（IL-1β）和白细胞介素-6（IL-6）。此外，我们发现，Toll样受体途径参与了这种调节。恢复miR-146 a的丢失在消除自身抗体的产生和改善狼疮易感小鼠中的SLE进展方面是有效的。因此，通过基于MS 2 VLP的递送系统诱导失调的miRNA可能导致新的疗法。
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the presence of pathogenic autoantibodies. Recent studies suggest that microRNAs (miRNAs) play an essential role in immunoregulation and may be involved in the pathogenesis of SLE. Therefore, it was of interest to investigate the potential therapeutic application of miRNAs in SLE, a concept that has not been thoroughly investigated thus far. Virus-like particles (VLPs) are a type of recombinant nanoparticle enveloped by certain proteins derived from the outer coat of a virus. Herein, we describe a novel miRNA-delivery approach via bacteriophage MS2 VLPs and investigate the therapeutic effects of miR-146a, a well-studied and SLE-related miRNA, in BXSB lupus-prone mice. VLPs containing miR-146a, and the control VLPs, were prepared using an Escherichia coli expression system and then administered to lupus-prone mice over a 12-day period. We performed an enzyme-linked immunosorbent assay to evaluate the anti-dsDNA antibody, autoantibody to nuclear antigen (ANA), total IgG and total IgM levels in serum. The expression of miR-146a was analyzed by qRT-PCR. SLE-related cytokines as well as some toll-like receptor signaling pathway molecules were also measured. Treatment with MS2-miR146a VLP showed profound effects on lupus-prone BXSB mice, including an increased level of mature miR-146a, which led to a significant reduction in the expression of autoantibodies and total IgG. Remarkably, these mice also exhibited reduced levels of proinflammatorycytokines, including IFN-Interferon-α (IFN-α), Interleukin-1β (Il-1β) and Interleukin-6 (Il-6). Moreover, we showed that the toll-like receptor pathway was involved in this regulation. Restoring the loss of miR-146a was effective in eliminating the production of autoantibodies and ameliorating SLE progression in lupus-prone mice. Thus, the induction of dysregulated miRNAs by an MS2 VLP-based delivery system may lead to novel therapies.