Park7 interacts with p47phox to direct NADPH oxidase-dependent ROS production and protect against sepsis
Park7 interacts with p47phox to direct NADPH oxidase-dependent ROS production and protect against sepsis
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DOI：
10.1038/cr.2015.63
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发表时间：
2015-06-01
期刊：
影响因子：
44.1
通讯作者：
Gao, Wei-Qiang
中科院分区：
文献类型：
--
作者：
Liu, Wenjun;Wu, Hailong;Gao, Wei-Qiang
不适当的炎症反应导致败血症期间的死亡。NADPH氧化酶产生的活性氧（ROS）可通过toll样受体（TLRs）调节炎症反应。帕金森病（常染色体隐性，早发）7 （Park7）通过消除ROS具有细胞保护作用。然而，Park7是否可以调节脓毒症的炎症反应和死亡率尚不清楚。在这里，我们发现，与野生型小鼠相比，Park7（-/-）小鼠在脓毒症模型中死亡率和细菌负担显著增加，全身和局部炎症明显减少，巨噬细胞吞噬和细菌杀伤能力显著受损。令人惊讶的是，LPS和phorbol12 -肉肉酸酯-13-乙酸刺激未能诱导Park7（-/-）巨噬细胞和缺乏Park7的RAW264.7细胞产生ROS和促炎细胞因子。通过其c端，Park7与NADPH氧化酶的亚基p47phox结合，促进NADPH氧化酶依赖性ROS的产生。在lps诱导的脓毒症中，恢复Park7的表达可恢复ROS的产生并提高存活率。总之，我们的研究表明，Park7通过控制巨噬细胞活化、NADPH氧化酶活化和炎症反应，对脓毒症具有保护作用。
Inappropriate inflammation responses contribute to mortality during sepsis. Through Toll-like receptors (TLRs), reactive oxygen species (ROS) produced by NADPH oxidase could modulate the inflammation responses. Parkinson disease (autosomal recessive, early onset) 7 (Park7) has a cytoprotective role by eliminating ROS. However, whether Park7 could modulate inflammation responses and mortality in sepsis is unclear. Here, we show that, compared with wild-type mice, Park7(-/-) mice had significantly increased mortality and bacterial burdens in sepsis model along with markedly decreased systemic and local inflammation, and drastically impaired macrophage phagocytosis and bacterial killing abilities. Surprisingly, LPS and phorbol-12-myristate-13-acetate stimulation failed to induce ROS and proinflammatory cytokine production in Park7(-/-) macrophages and Park7-deficient RAW264.7 cells. Through its C-terminus, Park7 binds to p47phox, a subunit of the NADPH oxidase, to promote NADPH oxidase-dependent production of ROS. Restoration of Park7 expression rescues ROS production and improves survival in LPS-induced sepsis. Together, our study shows that Park7 has a protective role against sepsis by controlling macrophage activation, NADPH oxidase activation and inflammation responses.