TREM2 regulates microglial phagocytosis of synapses in innate immune tolerance

Increasing evidence indicates that innate immune cells also possess immunological memory. Microglia are brain-resident innate immune cells and execute inflammatory and phagocytic functions upon environmental stimu-lation, during which processes triggering receptor expressed on myeloid cells 2 (TREM2) plays an important regulatory role. However, although microglia are known to exhibit innate immune memory related to inflam-mation when subjected to continuous inflammatory stimuli, whether microglia exhibit innate immune memory related to phagocytosis and whether TREM2 participates in innate immune memory of microglia remain un-known. Herein, we treated WT and Trem2 KO mice with peripheral injection of lipopolysaccharides (LPS) to induce microglial activation or microglial immune tolerance. We found that Tnf alpha and Il-1 beta expression levels in the hippocampi were significantly elevated after 1xLPS and then dramatically decreased after 4xLPS in both WT and Trem2 KO mice; and their level changes were indistinguishable between WT and Trem2 KO mice. Moreover, 1xLPS significantly promoted microglial phagocytosis of synapses and caused microglial morphology changes resembling activated status in both WT and Trem2 KO mice. However, 4xLPS significantly reduced synapse phagocytosis and largely reversed morphology changes in WT microglia. While 4xLPS had no effect on reducing synapse phagocytosis in Trem2 KO microglia. RNA-seq analysis revealed that TREM2 deficiency reprogrammed complement and phagosome-related transcriptional landscape during immune tolerance. Our results demon-strate that microglia also exhibit immune tolerance related to phagocytosis of synapses and that TREM2 plays a crucial role in this process possibly through regulating complement system and phagosome-related gene expressions.