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

Abstract

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 p47 phox , 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, NA-DPH oxidase activation and inflammation responses.

Endogenous Hydrogen Sulfide Ameliorates NOX4 Induced Oxidative Stress in LPS-Stimulated Macrophages and Mice

“…Nox4 was constitutively active, the elevated Nox4 expression directly translated to increase ROS production [32]. Increasing evidences demonstrated that Nox4 played a detrimental role in process of inflammatory diseases, including sepsis [3,30,33]. Here, our results clearly showed that Nox4 was significantly increased in LPSinduced septic mice, which was accompanied by increased inflammatory mediators and inflammatory cytokines production.…”

“…Meanwhile, NADPH oxidase-dependent ROS played a detrimental role in lethal innate immune response in sepsis [4,30]. The role of oxidative stress in septic pathogenesis has been well appreciated [3,4]; however, the mechanisms by which oxidative stress contributed to pathogenesis were not well defined. There were at least seven isoforms of NADPH oxidase that have been identified, termed Nox1-Nox5, DUOX1, and DUOX2, and most of them were detected in immune cells, including macrophages [31].…”

Swiprosin-1 deficiency impairs macrophage immune response of septic mice

“…Interestingly, a similar phenomenon was also seen in Park7 -/-mice and Stat2 -/-mice. In Park7 -/-mice, the increased mortality was mainly associated with aggravated lung injury and immunosuppression, along with the impaired bactericidal ability of macrophages (23). Here, we also found that swiprosin-1 deletion caused severe lung and kidney injury and immune paralysis, including impaired bacterial clearance and decreased HLA-DR in the macrophages.…”

NADPH oxidase in brain injury and neurodegenerative disorders

“…Other PD-related genes have been reported to affect NOX activation. DJ-1/Park7 can bind to p47phox to alter NOX activation [222, 223], and silencing of DJ-1 has been shown to increase NOX4 expression and ROS production [224]. In addition, NOX has been implicated as a potential mechanism underlying neuronal vulnerability associated with PINK1 dysfunction [225].…”