Study On The Role Of TREM2 Regulating NLRP3 Inflammasome In The Pathogenesis Of PD

Objective: This study aimed to explore the potential neuroinflammatory mechanism of TREM2 in regulating the NLRP3 inflammasome in Parkinson’s disease(PD).Methods: In vivo experiment,Adeno-associated virus(AAV)was used to interfere with the expression of TREM2 in the substantia nigra of C57/BL mice.Then1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)and probenecid were injected intraperitoneally in mice in older to establish classic PD mouse model.After the model was completed,the behavior of mice was detected by the pole test and the traction test to evaluate the movement disorder of mice.The expression level of TREM2 in mouse midbrain was detected by q PCR.Immunohistochemistry was used to detect TH staining of the substantia nigra to observe the effect of decreased expression of TREM2 on dopaminergic neurons of mice which were induced chronically by MPTP.The expression difference of NLRP3 inflammasome and its components in the midbrain of mice was detected by western blot to observe the regulatory effect of TREM2 on NLRP3 inflammasome in vivo experiments.In vitro experiment,Lentivirus was used to interfere with the expression of TREM2 in BV2 microglia,then LPS and ATP were used to stimulate inflammation to construct a cellular inflammation model.The expression differences of NLRP3 inflammasome and its components were detected by q PCR and western blot to further clarify the regulatory effect of TREM2 on NLRP3 inflammasome in microglia.The upstream NF-κB pathway of NLRP3 inflammasome was detected to explore the potential role of TREM2 in the regulation of NLRP3 inflammasome.Results:(1)In the mouse model induced chronically by MPTP,the expression of TREM2,NLRP3 inflammasome and its components increased,and AAV-TREM2-sh RNA decreased the expression of TREM2 in the midbrain of PD mice.(2)The decreased expression of TREM2 can aggravate the motor injury of mice which was induced chronically by MPTP.(3)Reducing the expression of TREM2 in mice aggravated the TH staining positive neuronal damage in the substantia nigra of mice induced chronically by MPTP.(4)After the expression of TREM2 decreased,NLRP3 inflammasome and its components were significantly increased in the substantia nigra induced by MPTP in mice.(5)After interfering with the expression of TREM2 in BV2 microglia,the expression level of NLRP3 inflammasome and its components increased significantly.(6)The decrease of TREM2 expression in BV2 microglia induced the increase of phosphorylated protein p P65 in NF-κB pathway.Activation of NLRP3 inflammasome was reduced after intervention of BV2 microglia with NF-κB inhibitor.(7)Decreased expression of TREM2 in BV2 microglia resulted in an increase in the expression level of TLR4/My D88 which are the downstream of NF-κB.Conclusion: This study proved for the first time that during the pathogenesis of PD,TREM2 may inhibit the activation of NLRP3 inflammasome through the TLR4/My D88/NF-κB pathway,thereby alleviating the damage of dopaminergic neurons caused by PD neuroinflammation.TREM2 may have an important neuroprotective effect in PD.