Prokineticin-2 Exists A Immuneprotection In Sepsis Through Regulating The Function Of Macrophage

Objective: Sepsis is a life-threatening multiple organ dysfunction syndrome caused by host anti-infective immune dysfunction,with a high incidence,a dangerous condition,and a high mortality rate,but how does sepsis arise and the immune factors involved in its development process during sepsis have not clearly known yet.Prokineticin-2(PK2),as a new type of immunomodulatory factor in the prokineticin family,can be highly expressed in immune cells such as peripheral blood cells,dendritic cells and lymphocytes,with the ability to regulate nerve development,angiogenesis,and inflammation There are many biological effects such as sexual pain,but whether it is involved in sepsis-mediated immune disorders has not been reported.Therefore,this study aims to detect the expression of PK2 in patients with sepsis and septic mice,to explore the immune effect of PK2 in the regulation during sepsis,and to further explore the specific molecular mechanism of PK2 in the regulation of sepsis.Methods: Plasma samples from 47 adult sepsis patients and 30 adult healthy volunteers were collected from the First Affiliated Hospital of Chongqing Medical University,and 31 child sepsis and 20 child healthy volunteers were collected from Children's Hospital of Chongqing Medical University were measured by ELISA to detect the expression of PK2 in human plasma.Pathogen-free 6 to 8-week-old male C57BL/6 mice were anesthetized with a mixture of xylazine(4.5 mg/kg)and ketamine(90 mg/kg)intraperitoneally,and the classic surgery model-cecal ligation puncture(CLP)was used as a model of systemic sepsis syndrome.The expression of PK2 in mouse peripheral blood,peritoneal lavage fluid(PLF)of septic mice was detected by ELISA.The immune regulatory effect of PK2 during sepsis was assessed by survival rate test,bacterial load test,multiple organ histopathology score and biochemical markers of organ damage.The specific immune molecular mechanisms of PK2 in sepsis were explored by flow cytometry,phagocytosis assays and bacterial killing assays.Results: Compared with the normal healthy volunteers of adults and children,the expression of PK2 in plasma of adults and children with sepsis was significantly reduced.The expression of PK2 in the peripheral blood and PLF of septic mice constructed as a model of moderate to severe sepsis by CLP was time-dependent,that is,it increased transiently in the early stage,and gradually decreased with the progress of sepsis.After treatment with mouse recombinant PK2 protein,the survival rate of sepsis mice was significantly improved,and the bacterial load in blood,PLF,and spleen was significantly reduced.Lung histopathological damage was alleviated,and liver function-specific damage marker ALT was significantly reduced,suggesting that PK2 mainly acts an immunoprotective role during sepsis.Interestingly,the most difference in the production of cytokines and chemokines after recombinant PK2 administration during sepsis in vivo was IL-10.Flow cytometry analysis showed that PK2 treatment had no significant effect on the total number of inflammatory cells,the proportion of macrophages and neutrophils in PLF in sepsis mice.Phagocytosis assays and bacterial killing assays analysis found that PK2 can significantly promote the phagocytosis and bactericidal function of macrophages,suggesting that PK2 may play an important role during sepsis by enhancing the phagocytosis and killing functions of macrophages.Conclusion: PK2 acts an immunoprotective role during sepsis by enhancing the host bacteria's ability to clear bacteria and participating in the process of inflammation regulation.It shows that PK2 acts on natural immune cells such as macrophages,and enhances its phagocytic and bactericidal function;PK2 inhibits the body's release of a large number of anti-inflammatory factors IL-10,mediates host immune suppression state,and enhances host ability to clear bacteria.