The orphan nuclear receptor estrogen-related receptor α negatively regulates Toll-like receptor-induced inflammation through A20 induction (IRM11P.759)

Abstract

Abstract Estrogen-related receptor (ERR) α, an orphan nuclear receptor member, is a key metabolic regulator in various organs and tissues. However, its function in regulating innate immune responses has remained largely unknown. Herein we show that ERRα negatively regulates toll-like receptor (TLR)-induced inflammatory responses through induction of A20. ERRα-deficient (ERRα-/-) mice showed a higher susceptibility to endotoxin-induced septic shock, with a concurrent increase of proinflammatory responses in vivo and in vitro. Global gene expression analysis showed that ERRα regulated TLR-induced inflammation through induction of A20, a deubiquitinating enzyme in TLR signaling. Lack of ERRα in macrophages increased NF-κB signaling and IKK activation. In addition, treatment of macrophages with inverse agonist XCT-790 led to an increase of inflammatory responses induced by TLR4 stimulation. These findings identify a novel function of ERRα as an intrinsic negative regulator of inflammation through induction of A20.