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Triglyceride metabolism controls inflammation and APOE4 -associated disease states in microglia
Abstract:
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 but rather necessary for microglial activation. We discovered that both triglyceride biosynthesis and catabolism are needed for the transcription and secretion of proinflammatory cytokines and chemokines in response to extrinsic stimuli. Additionally, we reveal that triglyceride biosynthesis and catabolism are necessary for the activation-associated phagocytosis of multiple substrates including the disease-associated amyloid-beta peptide. In microglia harboring the Alzheimer's disease risk APOE4 genotype, triglyceride-rich lipid droplets accumulate even in the absence of any external stimuli. Inhibiting triglyceride biosynthesis in APOE4 microglia not only modifies the transcription of immune response genes but also attenuates disease-associated transcriptional states. This work establishes that triglyceride metabolism is necessary for microglia to respond to extrinsic activation. In APOE4 microglia, this metabolic process modulates both immune signaling and a disease-associated transcriptional state. Importantly, our work identifies metabolic pathways that can be used to tune microglial immunometabolism in APOE4- associated disease.
Insights
Microglia utilize triglyceride metabolism for activation and inflammatory responses. This metabolic process is crucial for microglia function, particularly in Alzheimer's disease risk genotypes like APOE4.
Area of Science:
- Neuroimmunology
- Cellular Metabolism
- Stem Cell Biology
Background:
- Microglia, the brain's immune cells, alter their state in response to stimuli.
- Lipid changes often accompany microglial state shifts, but their functional role is unclear.
- The Alzheimer's disease-associated APOE4 genotype influences microglial function.
Purpose of the Study:
- To investigate the functional significance of lipid metabolism in microglial activation.
- To determine the role of triglyceride metabolism in microglial responses to stimuli and disease-associated factors.
- To explore the impact of APOE4 genotype on microglial lipid metabolism and immune function.
Main Methods:
- Utilized human induced pluripotent stem cell-derived microglia.
- Investigated effects of lipopolysaccharide (LPS) treatment for extrinsic activation.
- Analyzed triglyceride biosynthesis and catabolism pathways.
- Assessed phagocytosis of amyloid-beta.
- Examined gene transcription and cytokine secretion.
- Studied microglia with the APOE4 genotype.
Main Results:
- Both extrinsic activation (LPS) and intrinsic triggers (APOE4) lead to triglyceride-rich lipid droplet accumulation in microglia.
- Lipid droplet accumulation is essential, not just concomitant, for microglial activation.
- Triglyceride biosynthesis and catabolism are required for pro-inflammatory cytokine/chemokine production and phagocytosis of amyloid-beta.
- APOE4 microglia accumulate lipid droplets even without external stimuli.
- Inhibiting triglyceride biosynthesis in APOE4 microglia alters immune gene expression and disease-associated transcriptional states.
Conclusions:
- Triglyceride metabolism is necessary for microglia to respond to extrinsic activation.
- In APOE4 microglia, triglyceride metabolism modulates immune signaling and disease-associated transcriptional states.
- Identified metabolic pathways for tuning microglial immunometabolism in APOE4-associated diseases.
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