Pathogen-associated molecular patterns (PAMPs) have the capacity to couple inflammatory gene expression to changes in macrophage metabolism, both of which influence subsequent inflammatory activities. Similar to their microbial counterparts, several self-encoded damage-associated molecular patterns (DAMPs) induce inflammatory gene expression. However, whether this symmetry in host responses between PAMPs and DAMPs extends to metabolic shifts is unclear. Here, we report that the self-encoded oxidized phospholipid oxPAPC alters the metabolism of macrophages exposed to lipopolysaccharide. While cells activated by lipopolysaccharide rely exclusively on glycolysis, macrophages exposed to oxPAPC also use mitochondrial respiration, feed the Krebs cycle with glutamine, and favor the accumulation of oxaloacetate in the cytoplasm. This metabolite potentiates interleukin-1β production, resulting in hyperinflammation. Similar metabolic adaptions occur in vivo in hypercholesterolemic mice and human subjects. Drugs that interfere with oxPAPC-driven metabolic changes reduce atherosclerotic plaque formation in mice, thereby underscoring the importance of DAMP-mediated activities in pathophysiological conditions.
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The data that support the findings of this study are available from the corresponding author upon request. Uncropped raw immunoblot images can be found in the ‘Source data’ section of the Supplementary Information. Participant-level phenotype and genotype data from the FHS are accessible from the US National Center for Biotechnology Information database of Genotypes and Phenotypes at https://dbgap.ncbi.nlm.nih.gov/ to approved scientific investigators pursuing research questions that are consistent with the informed consent agreements provided by individual research participants. The FHS expression data are available from the database of Genotypes and Phenotypes at https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000363.v3.p6.
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We thank F. Granucci, J. C. Kagan and L. R. Marek for discussions, help and support. R.S. thanks the UCLA QCBio Collaboratory community, directed by M. Pellegrini. I.Z. is supported by National Institutes of Health (NIH) grants 1R01AI121066, 1R01DK115217 and NIAID-DAIT-NIHAI201700100. J.R.S. is supported by NIH grant 1R15HL121770-01A1. The FHS is funded by NIH contracts N01-HC-25195 and HHSN268201500001I. The laboratory work for the FHS investigation was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, NIH, and by a Director’s Challenge Award, NIH (principal investigator: D.L.). This study utilized the computational resources of the Biowulf system at the NIH in Bethesda, Maryland (http://hpc.nih.gov). M.M.M. is supported by NIH grant K99HL136875. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
I.Z., M.D.G. and Boston Children’s Hospital have filed an international patent application (US patent application number 62/851,561) that relates to the metabolic activity of oxPAPC.
Peer review information Zoltan Fehervari was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.
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Schematic depicting oxPAPC activities. oxPAPC is a mixture of oxidized phospholipids that induce an hyperinflammatory state in phagocytes upon LPS encounter and/or during atherosclerosis development. Moieties such as POVPC or PGPC contained in oxPAPC drive the formation of hyperactive cells that are characterized by inflammasome activation in the absence of pyroptosis. In contrast to POVPC or PGPC, PEIPC engages a hypermetabolic state in phagocytes that favors IL-1β accumulation and that is characterized by: i) the simultaneous activation of OXPHOS and aerobic glycolysis; ii) glutamine utilization to feed the TCA cycle; iii) oxaloacetate (OAA) accumulation in the cytoplasm to potentiate HIF-1α activation.
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Di Gioia, M., Spreafico, R., Springstead, J.R. et al. Endogenous oxidized phospholipids reprogram cellular metabolism and boost hyperinflammation. Nat Immunol 21, 42–53 (2020). https://doi.org/10.1038/s41590-019-0539-2
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