Triglyceride metabolism controls inflammation and microglial phenotypes associated with APOE4 [RNA-seq]

Microglia modulate their cell state in response to various stimuli. Changes to cellular lipids often accompany shifts in microglial cell state, but the functional significance of these metabolic changes remains poorly understood. In human induced pluripotent stem cell-derived microglia, we observed that both extrinsic activation (by lipopolysaccharide treatment) and intrinsic triggers (the Alzheimer’s disease-associated APOE4 genotype) result in accumulation of triglyceride-rich lipid droplets. We demonstrate that lipid droplet accumulation is not simply concomitant with changes in cell state. In fact, both triglyceride biosynthesis and catabolism are necessary for the activation-induced transcription and the secretion of inflammatory cytokines and chemokines as well as the changes in phagocytosis of many substrates including the amyloid-beta peptide. In microglia harboring the Alzheimer’s disease risk APOE4 genotype, inhibiting triglyceride biosynthesis modifies the transcription of immune response genes and attenuates disease-associated transcriptional states. In addition, this inhibition rescues microglial surveillance defects observed in slices from APOE4 humanized transgenic mice. Together, our findings establish that modulating triglyceride metabolism can be used to tune microglial immunometabolism in response to extrinsic activation and in APOE4-associated disease. Bulk RNA-Seq profiling of 25 human iPSC samples representing either APOE3 or APOE4 under no treatment condition or treatment with LPS, DGAT1 and DGAT2 inhibitor, or DGAT1 and DGAT2 inhibitor and LPS