Estrogen-related receptor gamma 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 gamma (ERR gamma) regulates the transcription of genes involved in endocrine and metabolic functions. However, the role of ERR gamma in macrophage immune responses to viruses remains largely unknown. ERR gamma 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 ERR gamma 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 ERR gamma significantly increased gene expression and secretion of the IFN-I genes, IFN-alpha and IFN-beta, whereas abolition of ERR gamma significantly attenuated poly(I:C)-mediated IFN-I secretion. Chromatin immunoprecipitation assays and mutation analyses of the IFN-I promoters revealed that ERR gamma regulates the transcription of IFN-alpha and IFN-beta 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 ERR gamma in the transcriptional control of innate and adaptive immune response to dsRNA virus replication.