Immunity (Cambridge, Mass.), 2015-07, Vol.43 (1), p.80-91
2015
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- Autor(en) / Beteiligte
- Titel
- Orphan Nuclear Receptor ERRα Controls Macrophage Metabolic Signaling and A20 Expression to Negatively Regulate TLR-Induced Inflammation
- Ist Teil von
- Immunity (Cambridge, Mass.), 2015-07, Vol.43 (1), p.80-91
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2015
- Quelle
- Access via ScienceDirect (Elsevier)
- Beschreibungen/Notizen
- The orphan nuclear receptor estrogen-related receptor α (ERRα; NR3B1) is a key metabolic regulator, but its function in regulating inflammation remains largely unknown. Here, we demonstrate that ERRα negatively regulates Toll-like receptor (TLR)-induced inflammation by promoting Tnfaip3 transcription and fine-tuning of metabolic reprogramming in macrophages. ERRα-deficient (Esrra–/–) mice showed increased susceptibility to endotoxin-induced septic shock, leading to more severe pro-inflammatory responses than control mice. ERRα regulated macrophage inflammatory responses by directly binding the promoter region of Tnfaip3, a deubiquitinating enzyme in TLR signaling. In addition, Esrra–/– macrophages showed an increased glycolysis, but impaired mitochondrial respiratory function and biogenesis. Further, ERRα was required for the regulation of NF-κB signaling by controlling p65 acetylation via maintenance of NAD+ levels and sirtuin 1 activation. These findings unravel a previously unappreciated role for ERRα as a negative regulator of TLR-induced inflammatory responses through inducing Tnfaip3 transcription and controlling the metabolic reprogramming. [Display omitted] •ERRα deficiency leads to excessive systemic and macrophage inflammatory responses•ERRα negatively regulates TLR4 signaling through transcriptional activation of A20•ERRα regulates metabolic reprogramming during TLR-induced inflammation•Loss of ERRα promotes NF-κB signaling through p65 acetylation via SIRT1 inhibition The orphan nuclear receptor ERRα is well known for its regulation of energy metabolism and mitochondrial biogenesis. Jo and colleagues show that ERRα also negatively regulates TLR4 signaling in macrophages through transcriptional activation of A20 and control of cellular metabolic reprogramming.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1074-7613eISSN: 1097-4180DOI: 10.1016/j.immuni.2015.07.003Titel-ID: cdi_hal_primary_oai_HAL_hal_02632561v1
- Format
- –
- Schlagworte
- Acetylation, Animals, Calcium - metabolism, Calcium-Calmodulin-Dependent Protein Kinase Kinase - metabolism, Cells, Cultured, Computer Science, Cysteine Endopeptidases - biosynthesis, Cysteine Endopeptidases - genetics, Enzyme Activation - genetics, ERRalpha Estrogen-Related Receptor, Glycolysis - genetics, Hypoxia-Inducible Factor 1, alpha Subunit - metabolism, Inflammation - immunology, Intracellular Signaling Peptides and Proteins - biosynthesis, Intracellular Signaling Peptides and Proteins - genetics, Life Sciences, Lipopolysaccharides, Macrophages - immunology, Macrophages - metabolism, Mice, Mice, Knockout, Myeloid Differentiation Factor 88 - metabolism, NAD - metabolism, Oxidative Phosphorylation, Promoter Regions, Genetic - genetics, Promoter Regions, Genetic - immunology, Receptors, Estrogen - genetics, Shock, Septic - immunology, Signal Transduction, Sirtuin 1 - metabolism, TNF Receptor-Associated Factor 6 - metabolism, Toll-Like Receptor 4 - immunology, Transcription Factor RelA - metabolism, Transcription, Genetic - genetics, Tumor Necrosis Factor alpha-Induced Protein 3, Ubiquitination