Constitutive aryl hydrocarbon receptor signaling constrains type I interferon–mediated antiviral innate defense

Abstract

Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates the toxic activity of many environmental xenobiotics. However, its role in innate immune responses during viral infection is not fully understood. Here we demonstrate that constitutive AHR signaling negatively regulates the type I interferon (IFN-I) response during infection with various types of virus. Virus-induced IFN-β production was enhanced in AHR- IFN-I-mediated innate response and, further, suggests that the AHR-TIPARP axis is a potential therapeutic target for enhancing antiviral responses.AHR was originally discovered as a xenobiotic sensor that mediates the toxicity of the persistent environmental contaminant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), more commonly known as dioxin [1][2][3][4] . Activation of AHR induces its target genes, including those encoding cytochrome P4501A1, cytochrome P4501B1, AHR repressor, TCDD-inducible poly(ADP-ribose)polymerase (TIPARP) and aldehyde dehydrogenase 1A3 (refs. 1,2,5-9), which are involved in the adaptive metabolism of xenobiotic compounds. This property of AHR has been implicated in host defense against bacterial infection, as certain bacterial pigmented virulence factors are AHR agonists that are subsequently metabolized by AHR-regulated drug-metabolizing enzymes 10 . Studies of AHR-deficient mice have identified important physiological roles for AHR in response to endogenous ligands in cell cycle regulation, cell differentiation and immune responses 8,[11][12][13][14] . In relation to this, several putative endogenous ligands for the AHR have also been reported, including heme metabolites, arachidonic acids or leukotrienes and tryptophan metabolites, such as 6-formylindolo(3,2-b)carbazole (FICZ) and kynurenine (Kyn) 2,8,15 .There has been increased interest in understanding the role of AHR in immunity.Several reports, most of which are based mainly on experiments with dioxin treatment, have shown that the AHR is involved in the differentiation and/or function of T cells, macrophages and dendritic cells 7,9,11,[16][17][18][19][20][21] . AHR has been implicated in the control of acute graft-versus-host disease and autoimmunity 11,12,21 . Dioxin-activated AHR also reduces the survival rate of mice infected with influenza A virus 22,23 and indirectly suppresses the proliferation and differentiation of virus-specific CD8 + T cells via its regulatory role in dendritic cells 24 . FICZ and dioxin diminish CD8 + T cell responsiveness, whereas dioxin, but not FICZ, affects neutrophil recruitment or pulmonary inducible nitric oxide synthase (iNOS) induction in response to influenza virus infection 25 .Tryptophan metabolites such as Kyn are upregulated during inflammation and/or tumor progression in several types of immune and tumor cells through the catalytic activity of tryptophan dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO), which catalyze the first step in the formation of Kyn from tryptophan 2,9 . This increase in Kyn leads to an increase in regulatory T c...

The aryl hydrocarbon receptor and interferon gamma generate antiviral states via transcriptional repression

“…For example, TCCD enhanced morbidity and mortality in mice and/or rats infected with influenza A viruses (Lawrence and Vorderstrasse, 2013), Coxsackievirus (Funseth et al, 2002) or following ocular HSV infection (Veiga-Parga et al, 2011). Exacerbation of viral infection may be related to the fact that AhR activation constrains the type-I interferon response (Yamada et al, 2016). Other studies have reported that TCDD triggers AhR-dependent HIV-1 gene expression in cell lines, but there has been conflicting data on which HIV-1 promoter elements are responsible (reviewed by Rao and Kumar, 2015).…”

“…Additionally, AhR was recently identified as a pattern-recognition receptor for bacterial pigments (Moura-Alves et al, 2014). AhR signaling can reduce type-I IFN antiviral immune responses (Yamada et al, 2016) and AhR expression is induced in astrocytes by type-I IFN, leading to the suppression of inflammation in the central nervous system (Rothhammer et al, 2016). …”

Fish IRF6 is a positive regulator of IFN expression and involved in both of the MyD88 and TBK1 pathways

“…In our results, the expression of irf3 and irf7 are increasing at 6 and 24 h after stimulation, while decreasing at 12 h is observed. For host cells, although IFN is the pivotal cytokine in defensing against viruses, unrestricted production of IFN can lead to some diseases [30]. Herein, as the key regulators of IFN production, the expression of irf3 and irf7 should be restricted according to the specific situation but not unlimited.…”

The impact of PARPs and ADP-ribosylation on inflammation and host–pathogen interactions

“…TiPARP negatively regulates the type I IFN response by ADP-ribosylating TBK1 (Fig. 1A; Yamada et al 2016). The ADP-ribosylation of the kinase domain of TBK1 suppresses IFN production.…”