PLCG2 Regulates Divergent Microglial Functions via TREM2-Dependent and -Independent Signaling

We use genetically engineered human iPSC-derived microglia-like cells (iMG) to show that TREM2 signals through PLC?2 to mediate cell survival, phagocytosis, and lipid metabolism following myelin challenge. Loss of TREM2 or PLC?2 signaling leads to a shared signature of transcriptional dysregulation that underlies these phenotypes. However, PLC?2 also signals downstream of Toll-like receptors to mediate inflammatory responses in a TREM2-independent manner. Therefore, PLC?2 activity regulates divergent microglial functions via distinct TREM2-dependent and -independent signaling and may be involved in the transition to a microglial state associated with neurodegenerative disease. Overall design: Comparison of microglia differentiated from induced pluripotent stem cells (iPSCs) carrying homozyous deletions in theTREM2 or PLCG2 loci or the parental control line. A subset of samples were challenged with Zymosan particles.