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Triglyceride metabolism controls inflammation and APOE4 -associated disease states in microglia

Stephenson, Roxan A., Johnson, Kory R., Cheng, Linling, Yang, Linda G., Root, Jessica T., Gopalakrishnan, Jaanam, Shih, Han-Yu, Narayan, Priyanka S.·2024
DOI 10.1101/2024.04.11.589145

Preprint — published as 10.1016/j.celrep.2025.115961 · Paper page

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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.

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  • These results differ from recent experiments using similar methods in hiPSC (Stephenson et al., 2024), where inhibiting TG biosynthesis in E4 microglia blunted cytokine/chemokine release and attenuated the disease-associated transcriptional profile.

    “these results differ from recent experiments using similar methods in human induce pluripotent stem cells (hiPSC) (Stephenson et al., 2024), where inhibiting TG biosynthesis in E4 microglia blunted cytokine/chemokine release and attenuated the disease-associated transcriptional profile of these cells.”

    From APOE4 reshapes the lipid droplet proteome and modulates microglial inflammatory responses (2025) · cites this paper as Stephenson et al., 2024

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Metadata

Authors
Stephenson, R. A., Johnson, K. R., Cheng, L., Yang, L. G., Root, J. T., Gopalakrishnan, J., Shih, H.-Y., & Narayan, P. S.
ORCID
Publisher
openRxiv
Published
2024-04-13
DOI
10.1101/2024.04.11.589145
Cited by
13
References
0
Type
Preprint

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