title: Orphan Nuclear Receptor ERRα Controls Macrophage Metabolic Signaling and A20 Expression to Negatively Regulate TLR-Induced Inflammation.
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.
authors.affiliation: Department of Microbiology, Chungnam National University School of Medicine, Daejeon 301-747, South Korea; Department of Infection Biology, Chungnam National University School of Medicine, Daejeon 301-747, South Korea; Infection Signaling Network Research Center, Chungnam National University School of Medicine, Daejeon 301-747, South Korea.
authors.forename: Jae-Min
authors.initials: JM
authors.lastname: Yuk
authors.affiliation: Department of Microbiology, Chungnam National University School of Medicine, Daejeon 301-747, South Korea; Infection Signaling Network Research Center, Chungnam National University School of Medicine, Daejeon 301-747, South Korea.
authors.forename: Tae Sung
authors.initials: TS
authors.lastname: Kim
authors.affiliation: Department of Microbiology, Chungnam National University School of Medicine, Daejeon 301-747, South Korea; Infection Signaling Network Research Center, Chungnam National University School of Medicine, Daejeon 301-747, South Korea.
authors.forename: Soo Yeon
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Department of Microbiology, Chungnam National University School of Medicine, Daejeon 301-747, South Korea; Infection Signaling Network Research Center, Chungnam National University School of Medicine, Daejeon 301-747, South Korea.
authors.forename: Hye-Mi
authors.initials: HM
authors.lastname: Lee
authors.affiliation: Department of Biochemistry, Chungnam National University School of Medicine, Daejeon 301-747, South Korea; Infection Signaling Network Research Center, Chungnam National University School of Medicine, Daejeon 301-747, South Korea.
authors.forename: Jeongsu
authors.initials: J
authors.lastname: Han
authors.affiliation: Goodman Cancer Research Centre, McGill University, 1160 Pine Avenue West, Montréal, QC H3A 1A3, Canada.
authors.forename: Catherine Rosa
authors.initials: CR
authors.lastname: Dufour
authors.affiliation: Department of Microbiology, Chungnam National University School of Medicine, Daejeon 301-747, South Korea; Infection Signaling Network Research Center, Chungnam National University School of Medicine, Daejeon 301-747, South Korea.
authors.forename: Jin Kyung
authors.initials: JK
authors.lastname: Kim
authors.affiliation: Department of Microbiology, Chungnam National University School of Medicine, Daejeon 301-747, South Korea; Infection Signaling Network Research Center, Chungnam National University School of Medicine, Daejeon 301-747, South Korea.
authors.forename: Hyo Sun
authors.initials: HS
authors.lastname: Jin
authors.affiliation: Department of Molecular and Life Sciences, College of Science and Technology, Hanyang University, Ansan 426-791, South Korea.
authors.forename: Chul-Su
authors.initials: CS
authors.lastname: Yang
authors.affiliation: Program in Genomics of Differentiation, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Ki-Sun
authors.initials: KS
authors.lastname: Park
authors.affiliation: Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, South Korea.
authors.forename: Chul-Ho
authors.initials: CH
authors.lastname: Lee
authors.affiliation: Department of Pathology, Chungnam National University School of Medicine, Daejeon 301-747, South Korea; Infection Signaling Network Research Center, Chungnam National University School of Medicine, Daejeon 301-747, South Korea.
authors.forename: Jin-Man
authors.initials: JM
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, Chungnam National University School of Medicine, Daejeon 301-747, South Korea; Infection Signaling Network Research Center, Chungnam National University School of Medicine, Daejeon 301-747, South Korea.
authors.forename: Gi Ryang
authors.initials: GR
authors.lastname: Kweon
authors.affiliation: National Creative Research Initiatives Center for Nuclear Receptor Signals and Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 500-757, South Korea.
authors.forename: Hueng-Sik
authors.initials: HS
authors.lastname: Choi
authors.affiliation: Institut de Génomique Fonctionnelle de Lyon, Université de Lyon, Université Lyon 1, CNRS, INRA, Ecole Normale Supérieure de Lyon, 46 allée d'Italie, 69364 Lyon cedex 07, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Vanacker
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: David D
authors.initials: DD
authors.lastname: Moore
authors.affiliation: Goodman Cancer Research Centre, McGill University, 1160 Pine Avenue West, Montréal, QC H3A 1A3, Canada.
authors.forename: Vincent
authors.initials: V
authors.lastname: Giguère
authors.affiliation: Department of Microbiology, Chungnam National University School of Medicine, Daejeon 301-747, South Korea; Infection Signaling Network Research Center, Chungnam National University School of Medicine, Daejeon 301-747, South Korea. Electronic address: hayoungj@cnu.ac.kr.
authors.forename: Eun-Kyeong
authors.initials: EK
authors.lastname: Jo
mesh_terms: D000107:Acetylation; D000818:Animals; D002118:Calcium / Q000378:metabolism; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000378:metabolism; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000096:biosynthesis* / Q000235:genetics; D004789:Enzyme Activation / Q000235:genetics; D006019:Glycolysis / Q000235:genetics; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007249:Inflammation / Q000276:immunology*; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000235:genetics; D008070:Lipopolysaccharides; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D010085:Oxidative Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000276:immunology; D011960:Receptors, Estrogen / Q000235:genetics*; D012772:Shock, Septic / Q000276:immunology; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000276:immunology*; D051996:Transcription Factor RelA / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D054875:Ubiquitination; D000097983:ERRalpha Estrogen-Related Receptor
chemical_list: D002118:Calcium; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D003546:Cysteine Endopeptidases; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; D009243:NAD; D011960:Receptors, Estrogen; D056564:Sirtuin 1; D048029:TNF Receptor-Associated Factor 6; D051197:Toll-Like Receptor 4; D051996:Transcription Factor RelA; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D000097983:ERRalpha Estrogen-Related Receptor; C497443:Hif1a protein, mouse; C507780:Myd88 protein, mouse; C498144:Rela protein, mouse; C493487:Tlr4 protein, mouse; C513261:Tnfaip3 protein, mouse; C470545:Sirt1 protein, mouse