Jae-Min Yuk1, 4, 5, Tae Sung Kim1, 5, Soo Yeon Kim1, 5, Hye-Mi Lee1, 5, Jeongsu Han2, 5, Catherine Rosa Dufour6, Jin Kyung Kim1, 5, Hyo Sun Jin1, 5, Chul-Su Yang7, Ki-Sun Park8, Chul-Ho Lee9, Jin-Man Kim3, 5, Gi Ryang Kweon2, 5, Hueng-Sik Choi10, Jean-Marc Vanacker11, David D. Moore12, Vincent Giguere6, Eun-Kyeong Jo1, 5, *
1 Department of Microbiology, Chungnam National University School of Medicine, Daejeon 301-747, South Korea
2 Department of Biochemistry, Chungnam National University School of Medicine, Daejeon 301-747, South Korea
3 Department of Pathology, Chungnam National University School of Medicine, Daejeon 301-747, South Korea
4 Department of Infection Biology, Chungnam National University School of Medicine, Daejeon 301-747, South Korea
5 Infection Signaling Network Research Center, Chungnam National University School of Medicine, Daejeon 301-747, South Korea
6 Goodman Cancer Research Centre, McGill University, 1160 Pine Avenue West, Montreal, QC H3A 1A3, Canada
7 Department of Molecular and Life Sciences, College of Science and Technology, Hanyang University, Ansan 426-791, South Korea
8 Program in Genomics of Differentiation, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA
9 Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, South Korea
10 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
11 Institut de Genomique Fonctionnelle de Lyon, Universite de Lyon, Universite Lyon 1, CNRS, INRA, Ecole Normale Superieure de Lyon, 46 allee d’Italie, 69364 Lyon cedex 07, France
12 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
*Corresponding author : Eun-Kyeong Jo
Summary
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.