Abstract
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.
Copyright © 2015 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylation
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Animals
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Calcium / metabolism
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Calcium-Calmodulin-Dependent Protein Kinase Kinase / metabolism
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Cells, Cultured
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Cysteine Endopeptidases / biosynthesis*
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Cysteine Endopeptidases / genetics
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ERRalpha Estrogen-Related Receptor
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Enzyme Activation / genetics
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Glycolysis / genetics
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
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Inflammation / immunology*
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Intracellular Signaling Peptides and Proteins / biosynthesis*
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Intracellular Signaling Peptides and Proteins / genetics
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Lipopolysaccharides
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Macrophages / immunology
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Macrophages / metabolism*
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Mice
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Mice, Knockout
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Myeloid Differentiation Factor 88 / metabolism
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NAD / metabolism
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Oxidative Phosphorylation
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Promoter Regions, Genetic / genetics
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Promoter Regions, Genetic / immunology
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Receptors, Estrogen / genetics*
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Shock, Septic / immunology
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Signal Transduction
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Sirtuin 1 / metabolism
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TNF Receptor-Associated Factor 6 / metabolism
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Toll-Like Receptor 4 / immunology*
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Transcription Factor RelA / metabolism
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Transcription, Genetic / genetics
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Tumor Necrosis Factor alpha-Induced Protein 3
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Ubiquitination
Substances
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Hif1a protein, mouse
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Hypoxia-Inducible Factor 1, alpha Subunit
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Intracellular Signaling Peptides and Proteins
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Lipopolysaccharides
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Myd88 protein, mouse
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Myeloid Differentiation Factor 88
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Receptors, Estrogen
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Rela protein, mouse
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TNF Receptor-Associated Factor 6
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Tlr4 protein, mouse
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Toll-Like Receptor 4
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Transcription Factor RelA
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NAD
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Calcium-Calmodulin-Dependent Protein Kinase Kinase
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Tumor Necrosis Factor alpha-Induced Protein 3
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Cysteine Endopeptidases
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Tnfaip3 protein, mouse
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Sirt1 protein, mouse
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Sirtuin 1
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Calcium