Trem2promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions
AbstractGenome-wide association studies have reported that, amongst other microglial genes, variants inTREM2can profoundly increase the incidence of developing Alzheimer’s disease (AD). We have investigated the role of TREM2 in primary microglial cultures from wild type mice by using siRNA to decreaseTrem2expression, and in parallel from knock-in mice heterozygous or homozygous for theTrem2R47H AD risk variant. The prevailing phenotype ofTrem2R47H knock-in mice was decreased expression levels ofTrem2in microglia, which resulted in decreased density of microglia in the hippocampus. Overall, primary microglia with reducedTrem2expression, either by siRNA or from the R47H knock-in mice, displayed a similar phenotype. Comparison of the effects of decreasedTrem2expression under conditions of LPS pro-inflammatory or IL-4 anti-inflammatory stimulation revealed the importance ofTrem2in driving a number of the genes up-regulated in the anti-inflammatory phenotype. RNA-seq analysis showed that IL-4 induced the expression of a programme of genes includingArg1andAp1b1in microglia, which showed an attenuated response to IL-4 whenTrem2expression was decreased. Genes showing a similar expression profile toArg1were enriched for STAT6 transcription factor recognition elements in their promoter, andTrem2knockdown decreased levels of the transcription factor STAT6. LPS-induced pro-inflammatory stimulation suppressedTrem2expression, thus preventing TREM2’s anti-inflammatory drive. Given that anti-inflammatory signaling is associated with tissue repair, understanding the signaling mechanisms downstream ofTrem2in coordinating the pro- and anti-inflammatory balance of microglia, particularly mediating effects of the IL-4-regulated anti-inflammatory pathway, has important implications for fighting neurodegenerative disease.Graphical abstract