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.

MYC-dependent oxidative metabolism regulates osteoclastogenesis via nuclear receptor ERRα

“…ERRα transcriptionally regulates the expression of genes encoding energy metabolism regulators (28,30,31). To test whether ERRα could functionally phenocopy the role of MYC in mitochondrial respiration in osteoclasts, we measured mitochondrial respiration following RANKL stimulation using ERRα-deficient OCPs isolated from ERRα-null mice.…”

PPAR-α Activation Mediates Innate Host Defense through Induction of TFEB and Lipid Catabolism

“…Immunoblotting was performed as described previously (22). For immunoblotting, cells were lysed in RIPA (10 mM Tris-HCl at pH 8, 1 mM EDTA, 140 mM NaCl, 0.1% SDS, 0.1% sodium deoxycholate, and 1% Triton X-100) and a protease inhibitor mixture (Roche).…”

“…Briefly, total RNA from cells was isolated using TRIzol reagent (15596-026; Thermo Fisher Scientific) and used for synthesis of cDNA with Superscript II reverse transcriptase (Invitrogen). For semiquantitative RT-PCR reactions involved 30 cycles of annealing, extension, and denaturation as described previously (22). Reactions were run on a Veriti 96-Well Thermal Cycler (Thermo Fisher).…”

Immunometabolism governs dendritic cell and macrophage function

“…A recent interesting finding concerns a connection between the orphan nuclear receptor ERRα and a critical negative regulator of inflammation, the deubiquitinating enzyme A20 (Yuk et al, 2015). ERRα is a well-known regulator of energy metabolism and mitochondrial biogenesis (Villena and Kralli, 2008).…”

“…A20 has been shown to be a key inhibitor of inflammation in multiple human diseases, recent notable examples being to prevent rheumatoid arthritis and also asthma (Vande Walle et al, 2014;Schuijs et al, 2015). Yuk et al (2015) have shown that ERRα directly binds to the A20 gene promoter and increases its expression. ERRα-deficient mice are highly susceptible to LPS-induced septic shock and also have elevated glycolysis and decreased oxidative phosphorylation.…”