Estrogen-related receptor γ increases poly(I:C)-mediated type I IFN expression in mouse macrophages

Abstract

Although type I IFNs (IFN-I) are important for the innate and adaptive immune responses to suppress viral replication, prolonged IFN-I signaling in macrophages suppresses the immune response. Nuclear receptor estrogen-related receptor γ (ERRγ) regulates the transcription of genes involved in endocrine and metabolic functions. However, the role of ERRγ in macrophage immune responses to viruses remains largely unknown. ERRγ expression was significantly induced in mouse bone marrow-derived macrophages (BMDMs) treated with polyinosinic-polycytidylic acid (poly(I:C)). Our results indicated that the induction of ERRγ expression by poly(I:C) is mediated through activation of the cytoplasmic dsRNA receptors, retinoic acid-inducible gene I and melanoma differentiation-associated protein 5. In BMDMs, overexpression of ERRγ significantly increased gene expression and secretion of the IFN-I genes, IFN-α and IFN-β, whereas abolition of ERRγ significantly attenuated poly(I:C)-mediated IFN-I secretion. Chromatin immunoprecipitation assays and mutation analyses of the IFN-I promoters revealed that ERRγ regulates the transcription of IFN-α and IFN-β by binding to a conserved ERR response element in each promoter region. Finally, GSK5182 significantly suppressed poly(I:C)-mediated induction of IFN-I gene expression and secretion in BMDMs. Taken together, these findings reveal a previously unrecognized role for ERRγ in the transcriptional control of innate and adaptive immune response to dsRNA virus replication.