Mechanism Of Park7 In Innate Immune Regulation Of Sepsis

Sepsis(systemic inflammatory response syndrome or SIRS)is a fatal whole-body inflammation which is usually caused by severe infections.Up to date,sepsis is still a difficult and complicated disease resulting 40%-70%patients died because of septic shock and multiple organ dysfunction.There are over 1 million sepsis patients per year in US and everyday nearly 500 sepsis patients die.The mortality of sepsis has been higher than that caused by prostate cancer,breast cancer and HIV infection.Early stage of sepsis is characterized by extravagant inflammatory reactions and massive expressions of proinflammatory cytokines,which are autodestructive to distant organs.However,clinical researches point out that most of the sepsis patients die in the late stage with insufficient responses due to immune tolerance.Sepsis patients at the late stage are marked by impaired activation of immune cells and low epressions of proinflammatory cytokines which may propagate further lethal infections.Therefore,understanding the pathophysiology of immunosuppression of sepsis will be mandatory for discovering novel therapeutic options.Park7 was first identified in Parkinson disease.Loss-of-function mutations of Park7 are considered as causal factors for the early onset of Parkinson disease.Subsequent work demonstrated that,as an oncogene,Park7 was related to the progression of multiple human cancers,such as lung cancer,breast cancer,gastric cancer and liver cancer.Additionally,Park7 can also be a sensor of oxidative stress,protecting neuron cells and myocardial cells from overactive oxidative stress caused cell death.ROS,as byproducts of the metabolism of oxygen under normal conditions,play important roles in many signaling transductions and macrophages'bactericidal activity.However,under pathogenesis,levels of ROS increase dramatically which may result in damage to cells and could be associated with pathogenesis of many diseases.Given the antioxidant feature of Park7 and that oxidative stress is tightly related to inflammatory responses and the survival in experimental sepsis,here,we attempt to explore whether Park7 has any influence in regulating innate immune response and how it works with the ROS.Classical sepsis model CLP(cecal ligation puncture)and exposure of lipopolysaccharide(LPS)and infection with Pseudomonas were used to construct sepsis in both WT mice and Park7^-/-mice.Studies found that mice with Park7 deficiency showed higher mortality,but had reduced infiltrated inflammatory cells and decreased expressions of proinflammatory cytokines and chemokines.Park7^-/-mice exhibited immunosuppression in both CLP and LPS induced sepsis.In addition,Park7^-/-and Park7-KD macrophages produced litter ROS in LPS and PMA stimulation,comparing with WT and Park7-NT macrophages.Notably,forced expression of Park7 restored activation of macrophages characterizing with recovered production of ROS and increased expressions of proinflammatory cytokines.Further investigation indicated that Park7 functioned as a modulator in regulating ROS levels by binding to one of the subunits of NADPH oxidase-p47phox through its C terminus.The interaction of Park7 and p47phox facilitated phosphorylation and translocation of p47phox from the cytoplasm to cellular membrane which in turn resulted in the activation of NADPH oxidase.More importantly,mice transferred with Park7-restored macrophages showed significantly improved survival along with decreased bacterial burdens and reinforced proinflammatory responses in LPS induced sepsis.This provides a possibility that agents that can induce Park7 expression may have clinical value to treat sepsis in late stage.All these findings lead to a conclusion that Park7 plays a protective role against sepsis by controlling macrophages activation,NADPH oxidase-dependent ROS production and inflammation responses.