| First Author | Yuk JM | Year | 2015 |
| Journal | Immunity | Volume | 43 |
| Issue | 1 | Pages | 80-91 |
| PubMed ID | 26200012 | Mgi Jnum | J:229104 |
| Mgi Id | MGI:5750812 | Doi | 10.1016/j.immuni.2015.07.003 |
| Citation | Yuk JM, et al. (2015) Orphan Nuclear Receptor ERRalpha Controls Macrophage Metabolic Signaling and A20 Expression to Negatively Regulate TLR-Induced Inflammation. Immunity 43(1):80-91 |
| abstractText | The orphan nuclear receptor estrogen-related receptor alpha (ERRalpha; NR3B1) is a key metabolic regulator, but its function in regulating inflammation remains largely unknown. Here, we demonstrate that ERRalpha negatively regulates Toll-like receptor (TLR)-induced inflammation by promoting Tnfaip3 transcription and fine-tuning of metabolic reprogramming in macrophages. ERRalpha-deficient (Esrra(-/-)) mice showed increased susceptibility to endotoxin-induced septic shock, leading to more severe pro-inflammatory responses than control mice. ERRalpha 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, ERRalpha was required for the regulation of NF-kappaB signaling by controlling p65 acetylation via maintenance of NAD(+) levels and sirtuin 1 activation. These findings unravel a previously unappreciated role for ERRalpha as a negative regulator of TLR-induced inflammatory responses through inducing Tnfaip3 transcription and controlling the metabolic reprogramming. |
