Orphan Nuclear Receptor ERR alpha Controls Macrophage Metabolic Signaling and A20 Expression to Negatively Regulate TLR-Induced Inflammation
- Authors
- Yuk, Jae-Min; Kim, Tae Sung; Kim, Soo Yeon; Lee, Hye-Mi; Han, Jeongsu; Dufour, Catherine Rosa; Kim, Jin Kyung; Jin, Hyo Sun; Yang, Chul-Su; Park, Ki-Sun; Lee, Chul-Ho; Kim, Jin-Man; Kweon, Gi Ryang; Choi, Hueng-Sik; Vanacker, Jean-Marc; Moore, David D.; Giguere, Vincent; Jo, Eun-Kyeong
- Issue Date
- Jul-2015
- Publisher
- Cell Press
- Citation
- Immunity, v.43, no.1, pp 80 - 91
- Pages
- 12
- Indexed
- SCI
SCIE
SCOPUS
- Journal Title
- Immunity
- Volume
- 43
- Number
- 1
- Start Page
- 80
- End Page
- 91
- URI
- https://scholarworks.bwise.kr/erica/handle/2021.sw.erica/17490
- DOI
- 10.1016/j.immuni.2015.07.003
- ISSN
- 1074-7613
1097-4180
- Abstract
- The orphan nuclear receptor estrogen-related receptor alpha (ERR alpha; NR3B1) is a key metabolic regulator, but its function in regulating inflammation remains largely unknown. Here, we demonstrate that ERRa negatively regulates Toll-like receptor (TLR)-induced inflammation by promoting Tnfaip3 transcription and fine-tuning of metabolic reprogramming in macrophages. ERR alpha-deficient (Esrra(-/-)) mice showed increased susceptibility to endo-toxin-induced septic shock, leading to more severe pro-inflammatory responses than control mice. ERR alpha 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, ERR alpha was required for the regulation of NF-kappa B signaling by controlling p65 acetylation via maintenance of NAD(+) levels and sirtuin 1 activation. These findings unravel a previously unappreciated role for ERR alpha as a negative regulator of TLR-induced inflammatory responses through inducing Tnfaip3 transcription and controlling the metabolic reprogramming.
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