Topical Simvastatin as Host-Directed Therapy against Severity of Cutaneous Leishmaniasis in Mice
Topical Simvastatin as Host-Directed Therapy against Severity of Cutaneous Leishmaniasis in Mice
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DOI：
10.1038/srep33458
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发表时间：
2016-09-16
影响因子：
4.6
通讯作者：
Brombacher, Frank
中科院分区：
文献类型：
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作者：
Parihar, Suraj P.;Hartley, Mary-Anne;Brombacher, Frank
我们最近证明，他汀类药物介导的保护对细胞内病原体，结核分枝杆菌和李斯特菌在小鼠。在这里，我们研究了免疫调节潜力的辛伐他汀作为局部或全身的主机导向的药物治疗，在控制炎症反应的实验小鼠模型的皮肤利什曼原虫引起的重大利什曼病（LV39）。在耳部感染模型中，直接在已建立的病变上局部应用辛伐他汀显著降低了耳部病变大小和溃疡所反映的疾病严重程度。在BALB/c和C57BL/6小鼠中，宿主保护作用还伴随着耳和引流淋巴结中寄生虫负荷的降低。这些小鼠接受低脂胆固醇饮食和全身性辛伐他汀预处理也可减少足垫肿胀，以及更稳健的足垫感染模型中的寄生虫负荷和溃疡/坏死，证明辛伐他汀对皮肤利什曼病的预防潜力。机械地，继L。在严重感染后，辛伐他汀处理的原代巨噬细胞的反应是胆固醇水平显著降低和过氧化氢产生增加。此外，辛伐他汀处理的巨噬细胞表现出增强的吞噬体成熟，如荧光显微镜和Western印迹分析中增加的LAMP-3表达所揭示的。这些结果表明，辛伐他汀治疗增强宿主对L。主要通过增加巨噬细胞吞噬体成熟和杀伤效应子功能。
We recently demonstrated that statins mediate protection against intracellular pathogens, Mycobacterium tuberculosis and Listeria monocytogenes in mice. Here, we investigated the immunomodulatory potential of simvastatin as a topical or systemic host-directed drug therapy in controlling inflammatory responses in an experimental mouse model of cutaneous leishmaniasis caused by Leishmania major (LV39). In an ear infection model, topical application of simvastatin directly on established lesions significantly reduced severity of the disease reflected by ear lesion size and ulceration. The host protective effect was further accompanied by decreased parasite burden in the ear and draining lymph nodes in both BALB/c and C57BL/6 mice. Pre-treatment of these mice on a low-fat cholesterol diet and systemic simvastatin also reduced footpad swelling, as well as parasite burdens and ulceration/necrosis in the more robust footpad infection model, demonstrating the prophylactic potential of simvastatin for cutaneous leishmaniasis. Mechanistically, following L. major infection, simvastatin-treated primary macrophages responded with significantly reduced cholesterol levels and increased production of hydrogen peroxide. Furthermore, simvastatin-treated macrophages displayed enhanced phagosome maturation, as revealed by increased LAMP-3 expression in fluorescent microscopy and Western blot analysis. These findings demonstrate that simvastatin treatment enhances host protection against L. major by increasing macrophage phagosome maturation and killing effector functions.