ERRγ, a new player in the type I IFN arena
Year: 2021
Type: editorial
Abstract: Estrogen plays a role in host defense, cancer, and metabolic and autoimmune diseases. Estrogen signaling through estrogen receptor (ER) α and β regulates immune responses including type I IFN production1 (Figure 1). However, the role of estrogen signaling is not always straightforward. For example, levels of estrogen or ERs cannot be easily linked to their contributions to biological functions. In addition to context-dependent pleotropic effects of ER-mediated estrogen signaling, ERs are known to regulate transcription through binding to estrogen response elements (EREs) as well as through non-ERE binding mechanisms involving interactions with other transcription factors.2 Furthermore, we now learn from Choi and colleagues that estrogen-related receptor (ERR)γ, a member of a family of nuclear receptors that are closely related to ERs and bind EREs2 but have unknown ligands, induce type I IFNs. ERRs may influence the estrogenic response in host defense and disease progression (Figure 1). ERRγ-mediated type I IFN production by poly (I:C), and its potential impact on ER-mediated functions and diseases. (A) Estrogen receptors (ERs) are involved in human health and diseases. There is a crosstalk between IFNs and ER signaling in host defense. ERRs may regulate ER-mediated target genes by binding to ER binding sites. (B) MDA5 and RIG-I are involved in poly (I:C)-mediated ERRγ induction through JNK/AP-1 pathway. ERRγ induces expression of IFNα and IFNβ by binding to their promoters. Anti-IFNAR1 antibodies block ERRγ induction, suggesting a potential positive feedback loop between ERRγ and type I IFNs. TF: transcriptional factor ERRs are constitutively expressed and share target genes and coregulatory proteins with ERs.3 ERRs regulate various metabolic pathways including fatty acid oxidation, mitochondrial function, glucogenesis, and ion metabolism.2 Similar to ERs, ERRs are also involved in carcinogenesis,4 autophagy,5 and brain function.6 Their transcriptional activities appear to be positively or negatively regulated by various co-activators.2 Gene expression of ERR α, β, and γ is detected, albeit with differential abundance, in a broad range of tissues and cell types. It is apparent that the functions of ERR α, β, and γ are not redundant: ERRα knockout mice display reduced fat mass, whereas ERRβ knockout is an embryonic lethal, and ERRγ knockout is a neonatal lethal.6 Our understanding of immune regulation by ERRs is limited; most of what we know pertains to ERRα. ERRα is a metabolic regulator for activation and differentiation of T effector and T regulatory cells.7 ERRα suppresses IFNβ production by inhibiting TBK-IRF3 interactions in murine bone marrow-derived macrophages in response to vesicular stomatitis virus, poly(I:C), LPS, or flagellin.8 ERRα is required for AMP-activation of the protein kinase pathway and for SIRT1 activation of autophagy against respiratory syncytial virus or mycobacterial infection.5 It is not clear whether there is a differential role of ERRα in response to different viruses or stimuli for the opposing effects of ERRα in host defense. Now, a new report from Choi and colleagues details the heretofore unknown role of another member of the ERR family, ERRγ, in type I IFN induction, providing important insights and raising new questions.9 Choi et al describe the role of ERRγ in type I IFN induction in macrophages in response to poly(I:C).9 Stimulation with poly (I:C) but not Pam3CSK4, LPS, or R848, known ligands for TLR3, TLR2, TLR4, and TLR7/8, respectively, induces ERRγ in murine macrophages, suggesting that induction is independent of MyD88, which signals through TLR2, 4, 7, and 8. Expression of ERRγ, IFNα, and IFNβ is induced by poly(I:C) within an hour, and expression of all three genes declines after 24 h. Interestingly, macrophages from TLR3- or TRIF-deficient mice did not abolish the induction of ERRγ, IFNα, and IFNβ, which is a surprise, considering that poly(I:C) is a known TLR3 agonist and signals through TRIF to induce type I IFNs. This result indicates that poly(I:C) induces ERRγ and type I IFN expression through the TLR3 independent pathway. Poly (I:C) also signals through RIG-I and MDA-5, which both signal through mitochondrial antiviral-signaling protein. When authors investigated this pathway, RIG-I or MDA5 knockdown abolished the induction of ERRγ and IFNα, and moderately reduced IFNβ induction. The authors used kinase-specific inhibitors to address the pathway involved in poly(I:C)-mediated ERRγ induction, and found that induction of ERRγ was mediated through JNK but not NF-kB. The report provides direct evidence that expression of IFNα and IFNβ is dependent on ERRγ. Similar to earlier data, ERRγ exerted a greater effect on IFNα induction than on IFNβ in both gain-of-function or lost-of-function studies. The authors elegantly demonstrate that regulation of transcription by ERRγ involves the direct binding of ERRγ to the murine IFNα or IFNβ promoter through an ERE site. Additionally, GSK5182, a 4-hydroxytamoxifen analog, and a selective inverse agonist that blocks transcriptional activity of ERRγ, inhibits poly(I:C)-mediated type I IFN induction. One interesting result indicated that anti-IFNAR1 Ab blocked poly(I:C)-mediated ERRγ induction. Although induction of ERRγ by IFNα/β and the underlying mechanism remain to be determined, this result suggests that there is a positive feedback loop between ERRγ and type I IFNs. This study raises multiple questions regarding the biological functions of ERRγ-mediated type I IFN production and the role of ERRs in ER-mediated type I production and disease outcomes (Figure 1). A better characterization of type I IFN induction by ERRγ in specific cell types and stimuli is essential to understand its action. For example, will similar results be found in important players of the innate host defense, including myeloid cells, epithelial cells, or human macrophages of various activation states? Does viral infection lead to induction of ERRγ, which in turn up-regulates type I IFNs, similar to the effect of poly (I:C) in this study? What are the implications of the transient poly (I:C)-mediated induction of ERRγ and type I IFNs, which was diminished within 24 h, and what is the regulatory mechanism? Another exciting area for further investigation will be on the role and mechanism of ERRγ in host defense. Given that ERRα and ERRγ exhibit opposing effects on IFNβ production, would ERRα contribute to a differential effect of ERRγ on regulation of IFNα and β? Which transcriptional factors (IRF3 or IRF7) does ERRγ interact with to regulate type I IFNs? Are there any interactions between ERRγ-mediated MAD5-JNK/AP-1 pathways and autophagy that are important for host defense? The role of ERRγ in type IFN production in response to different types of RNA viruses during acute versus chronic infection and disease outcomes remains to be determined. Although type I IFNs play a role in antiviral immunity, they also contribute to advancing autoimmune diseases such as systemic lupus erythematosus, and are involved in promoting immune activation and disease progression during chronic viral infections, such as LCMV and HIV. Would blockade of ERRγ with GSK5182 ameliorate chronic immune activation and disease symptoms mediated by uncontrolled production of type I IFNs? A most interesting research area will be to determine the role of ERRγ in estrogen signaling-related functions. What is the contribution of ERRγ to sex differences in immune responses and human diseases? How do the interactions between ERs and ERRγ impact their target genes? Bisphenol A (BPA), a common substance in plastics, binds strongly to ERRγ but not ER,10 and is also known to induce type I IFNs through inflammasome activation. The role of ERRγ in type I IFN production by BPA or other estrogen-mimicking chemicals remains to be determined. ERRα- and ERRγ-specific inhibitors are available for conducting in vitro and in vivo experiments addressing their roles in different models, which will almost certainly have translational consequences. The work by Choi and colleagues will surely prompt future studies assessing clinical implications of the role of ERRs in immune regulation and in estrogen signaling. We thank Dr. Eric B. Milner for editing the manuscript. This work was supported by NIH grants NIH R01AI36948 and R01AI110372.
Source: Journal of Leukocyte Biology
Authors: Chuan Xu, Theresa L Chang
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W3128724163