Uncoupling Protein 2 Negatively Regulates Mitochondrial Reactive Oxygen Species Generation and Induces Phosphatase-Mediated Anti-Inflammatory Response in Experimental Visceral Leishmaniasis
Uncoupling Protein 2 Negatively Regulates Mitochondrial Reactive Oxygen Species Generation and Induces Phosphatase-Mediated Anti-Inflammatory Response in Experimental Visceral Leishmaniasis
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DOI：
10.4049/jimmunol.1004237
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发表时间：
2011-08-01
影响因子：
4.4
通讯作者：
Das, Pijush K.
中科院分区：
文献类型：
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作者：
Ball, Writoban Basu;Kar, Susanta;Das, Pijush K.
为了在宿主巨噬细胞内成功驻留和繁殖，利什曼原虫寄生虫会损害活性氧（ROS）的产生，而活性氧是宿主抵御任何入侵病原体的主要防御机制。线粒体解偶联蛋白与线粒体 ROS 生成相关，线粒体是总细胞 ROS 生成的主要贡献者。在本研究中，我们证明杜氏利什曼原虫感染与解偶联蛋白 2 (UCP2) 的强烈上调有关，解偶联蛋白 2 (UCP2) 是位于线粒体内膜的线粒体 ROS 生成的负调节因子。小干扰RNA介导的沉默对巨噬细胞UCP2的功能性敲除与线粒体ROS生成增加、寄生虫存活率降低以及明显促炎细胞因子反应的诱导有关。 UCP2 敲低细胞中促炎细胞因子反应的诱导是 p38 和 ERK1/2 MAPK 激活的直接结果，这是由 ROS 介导的蛋白酪氨酸磷酸酶 (PTP) 抑制引起的。施用 ROS 猝灭剂 N-乙酰基-L-半胱氨酸可消除 UCP2 敲低的感染细胞中的 PTP 抑制，这表明 ROS 在灭活 PTP 中发挥着作用。短发夹RNA介导的UCP2体内沉默导致含有Src同源2结构域的酪氨酸磷酸酶1和PTP-1B活性和宿主保护性促炎细胞因子反应降低，从而有效清除寄生虫。据我们所知，这项研究首次揭示了利什曼原虫感染期间宿主 UCP2 表达的诱导，从而下调线粒体 ROS 的产生，从而可能阻止 ROS 介导的 PTP 失活，从而抑制巨噬细胞的防御机制。免疫学杂志，2011，187：1322-1332。
To reside and multiply successfully within the host macrophages, Leishmania parasites impair the generation of reactive oxygen species (ROS), which are a major host defense mechanism against any invading pathogen. Mitochondrial uncoupling proteins are associated with mitochondrial ROS generation, which is the major contributor of total cellular ROS generation. In the present study we have demonstrated that Leishmania donovani infection is associated with strong upregulation of uncoupling protein 2 (UCP2), a negative regulator of mitochondrial ROS generation located at the inner membrane of mitochondria. Functional knockdown of macrophage UCP2 by small interfering RNA-mediated silencing was associated with increased mitochondrial ROS generation, lower parasite survival, and induction of marked proinflammatory cytokine response. Induction of proinflammatory cytokine response in UCP2 knocked-down cells was a direct consequence of p38 and ERK1/2 MAPK activation, which resulted from ROS-mediated inhibition of protein tyrosine phosphatases (PTPs). Administration of ROS quencher, N-acetyl-L-cysteine, abrogated PTP inhibition in UCP2 knocked-down infected cells, implying a role of ROS in inactivating PTP. Short hairpin RNA-mediated in vivo silencing of UCP2 resulted in decreased Src homology 2 domain-containing tyrosine phosphatase 1 and PTP-1B activity and host-protective proinflammatory cytokine response resulting in effective parasite clearance. To our knowledge, this study, for the first time, reveals the induction of host UCP2 expression during Leishmania infection to downregulate mitochondrial ROS generation, thereby possibly preventing ROS-mediated PTP inactivation to suppress macrophage defense mechanisms. The Journal of Immunology, 2011, 187: 1322-1332.