Park7 interacts with p47phox to direct NADPH oxidase- dependent ROS production and protect against sepsis

• Published in: Cell research 2015-05, Vol.25 (6), p.691-706
• Main Authors: Liu, Wenjun, Wu, Hailong, Chen, Lili, Wen, Yankai, Kong, Xiaoni, Gao, Wei-Qiang
• Format: Article
• Language: English
• Subjects: 631/80/86; 692/420/256/1980; 692/420/2780/262/2106/2108; 692/699/375/1718; Biomedical and Life Sciences; Cell Biology; Life Sciences; Mortality; NADPH氧化酶; Original; original-article; RAW264.7细胞; ROS; Toll样受体; 巨噬细胞; 炎性细胞因子; 炎症反应; 防止感染
• ISSN: 1001-0602; 1748-7838
• DOI: 10.1038/cr.2015.63

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 （autosomai recessive, early onset） 7 （Park7） has a cytoprotective role by eliminating ROS. However, wheth- er 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 produc- tion 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, NA- DPH oxidase activation and inflammation responses.