Endogenous oxidized phospholipids reprogram cellular metabolism and boost hyperinflammation
- 1 January 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Immunology
- Vol. 21 (1), 42-+
- https://doi.org/10.1038/s41590-019-0539-2
Abstract
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-1 beta 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.Funding Information
- U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (1R01AI121066)
- U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK115217)
This publication has 58 references indexed in Scilit:
- The TLR4 antagonist Eritoran protects mice from lethal influenza infectionNature, 2013
- A positive/negative ion–switching, targeted mass spectrometry–based metabolomics platform for bodily fluids, cells, and fresh and fixed tissueNature Protocols, 2012
- Interleukin-1 in the pathogenesis and treatment of inflammatory diseasesBlood, 2011
- Oxidized Phospholipids Are More Potent Antagonists of Lipopolysaccharide than Inducers of InflammationThe Journal of Immunology, 2010
- Oxidized Low-Density Lipoprotein and AtherosclerosisArteriosclerosis, Thrombosis, and Vascular Biology, 2010
- Regulation of Adaptive Immunity by the Innate Immune SystemScience, 2010
- The role of oxidized phospholipids in atherosclerosisJournal of Lipid Research, 2009
- Exploration, normalization, and summaries of high density oligonucleotide array probe level dataBiostatistics, 2003
- Points of control in inflammationNature, 2002
- Tolerance, Danger, and the Extended FamilyAnnual Review of Immunology, 1994