Macrophages sensing oxidized DAMPs reprogram their metabolism to support redox homeostasis and inflammation through a TLR2-Syk-ceramide dependent mechanism
| Autor: | Vlad Serbulea, Thurl E. Harris, Katelyn W. Ahern, Clint M Upchurch, Dory E. DeWeese, Paxton Voigt, Akshaya K. Meher, Norbert Leitinger, Gael F. P. Bories |
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| Rok vydání: | 2018 |
| Předmět: |
Vascular Endothelial Growth Factor A
0301 basic medicine lcsh:Internal medicine Ceramide NF-E2-Related Factor 2 Interleukin-1beta Syk Inflammation Oxidative phosphorylation Bioenergetics Biology Pentose phosphate pathway Ceramides Pentose Phosphate Pathway Mice Oxidized phospholipids 03 medical and health sciences chemistry.chemical_compound medicine Animals Homeostasis Syk Kinase Macrophage lcsh:RC31-1245 Molecular Biology Cells Cultured Tissue homeostasis Glucose Transporter Type 1 030102 biochemistry & molecular biology Macrophages Spleen tyrosine kinase Cellular metabolism Cell Biology Hypoxia-Inducible Factor 1 alpha Subunit Glutathione Toll-Like Receptor 2 Cell biology Mice Inbred C57BL Oxidative Stress Glucose 030104 developmental biology chemistry Biochemistry Anaerobic glycolysis Original Article medicine.symptom Redox homeostasis Signal Transduction |
| Zdroj: | Molecular Metabolism Molecular Metabolism, Vol 7, Iss, Pp 23-34 (2018) |
| ISSN: | 2212-8778 |
| Popis: | Objective Macrophages control tissue homeostasis and inflammation by sensing and responding to environmental cues. However, the metabolic adaptation of macrophages to oxidative tissue damage and its translation into inflammatory mechanisms remains enigmatic. Methods Here we identify the critical regulatory pathways that are induced by endogenous oxidation-derived DAMPs (oxidized phospholipids, OxPL) in vitro, leading to formation of a unique redox-regulatory metabolic phenotype (Mox), which is strikingly different from conventional classical or alternative macrophage activation. Results Unexpectedly, metabolomic analyses demonstrated that Mox heavily rely on glucose metabolism and the pentose phosphate pathway (PPP) to support GSH production and Nrf2-dependent antioxidant gene expression. While the metabolic adaptation of macrophages to OxPL involved transient suppression of aerobic glycolysis, it also led to upregulation of inflammatory gene expression. In contrast to classically activated (M1) macrophages, Hif1α mediated expression of OxPL-induced Glut1 and VEGF but was dispensable for Il1β expression. Mechanistically, we show that OxPL suppress mitochondrial respiration via TLR2-dependent ceramide production, redirecting TCA metabolites to GSH synthesis. Finally, we identify spleen tyrosine kinase (Syk) as a critical downstream signaling mediator that translates OxPL-induced effects into ceramide production and inflammatory gene regulation. Conclusions Together, these data demonstrate the metabolic and bioenergetic requirements that enable macrophages to translate tissue oxidation status into either antioxidant or inflammatory responses via sensing OxPL. Targeting dysregulated redox homeostasis in macrophages could therefore lead to novel therapies to treat chronic inflammation. Highlights • Mox macrophages have a unique metabolism compared to M1 and M2, characterized by suppressed respiration and aerobic glycolysis. • Oxidized phospholipids (OxPL) redirect glucose metabolism and TCA metabolites to GSH synthesis in macrophages. • Macrophages sensing OxPL upregulate sets of genes via Hif1α and Nrf2. • OxPL induce inflammatory gene expression and inhibit respiration in macrophages via a TLR2-Syk-ceramide mechanism. |
| Databáze: | OpenAIRE |
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