TREM2 Interacts With CSF1R But Is Not Necessary For CSF1R-mediated Microglia Survival

Colony-stimulating factor-1 receptor(CSF1R)and Triggering receptor expressed on myeloid-2(TREM2)are primarily expressed in microglia,the innate immune cells of the central nervous system(CNS).Mutations in CSF1R or TREM2 lead to adultonset dementia characterized by microgliopathy,a phenotype of microglial dysfunction.CSF1R and TREM2 are crucial in maintaining the development and survival of myloid cells.However,whether these two receptors interact with each other needs to be revealed.Besides,what’s the functional significance and mechanism of CSF1R binding to TREM2 remains elusive.Here,we identified that CSF1R interacted with TREM2 by coimmunoprecipitation analysis.Then we constructed extracellular fragments and intracellular fragments containing transmembrane domain of CSF1R or TREM2,determining that CSF1R and TREM2 interacted with each other on the cell surface and the transmembrane domain.Subsequently,we found that Csflr knockdown impaired the viability of microglia and increased the Trem2 mRNA level;in contrast,the expression of CSF1R in Trem2 knockout microglia was significantly upregulated.Furthermore,we found that CSF1 stimulation increased the expression of β-catenin in wild-type microglia,but there was no significant change in Trem2 knockout microglia.Interestingly,the phosphorylation of CSF1R and Akt in Trem2-deficient microglia was activated by CSF1,the specific ligand of CSF1R.Given the important role of CSF1R and Akt signaling in cellular survival,we finally verified that the treatment of CSF1 improved the survival of Trem2 knockout microglia both in vivo and in vitro.Taken together,our data demonstrate that CSF1R and TREM2 not only interact with each other but also mutually modulate their expression in microglia.Moreover,our results indicate that CSF1/CSF1R signaling is a potential target for TREM2 lossof-function neurodegenerative disease.