Dissect The Roles Of Soluble TREM2 In Microglia

Triggering receptor expressed on myeloid cells 2(TREM2)is an innate immune receptor expressed by microglia in the central nervous system(CNS).The R47H mutation was identified as a major risk factor for late-onset Alzheimer's disease(AD),which gives anodds ratio similar to that of carrying an apolipoprotein E(APOE)?4 allele.It has been shown that TREM2 regulates a variety of functions in microglia,including the inflammatory responses,phagocytosis,cell survival and apoptosis.However,the mechanism by which TREM2 mutations modulate AD pathogenesis remains unknown.A soluble form of TREM2(sTREM2)derived from proteolytic cleavage of the cell surface receptor is abundantly detected in the cerebrospinal fluid(CSF)and its level peaks in early stage of AD.Interestingly,the CSF levels of sTREM2 positively correlate with the amounts of total and phosphorylated tau.So far,the physiological and pathological functions of sTREM2 remain unknown.Here we show that sTREM2 promotes microglial survival and suppresses cellular apoptosis in wild-type(WT)and Trem2-knockout(Trem2-KO)primary microglia.Additionally,we found that sTREM2 stimulates the production of pro-inflammatory cytokines(IL-?,IL-6 and TNF-a)and induces changes in morphology that are associated with activation in WT and Trem2-KO microglia.Furthermore,sTREM2 promotes microglial survival in a PI3K/Akt-dependent manner and stimulates the production of inflammatory cytokines depending on NF-kB.Intriguingly,variants of sTREM2 carrying AD risk-associated mutations were less potent in both suppressing apoptosis and triggering inflammatory responses.Importantly,sTREM2 delivered to the hippocampi of both WT and Trem2-KO mice elevated the expression of inflammatory cytokines and induced morphological changes of microglia.Collectively,these data indicate that sTREM2 triggers microglial activation inducing inflammatory responses and promoting survival.This study has implications for the pathogenesis of AD and provides insights into targeting sTREM2 pathway for AD therapy.