The AhR and NF-κB/Rel Proteins Mediate the Inhibitory Effect of 2,3,7,8-Tetrachlorodibenzo-<i>p</i>-Dioxin on the 3′ Immunoglobulin Heavy Chain Regulatory Region

Salisbury, Richard L.; Sulentic, Courtney E. W.

doi:10.1093/toxsci/kfv193

Cited by 26 publications

(16 citation statements)

References 64 publications

(104 reference statements)

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“…This is a common feature of nuclear receptors, and contributes to modifications to cellular events downstream of their engagement 73 , 74 . For example, the AHR has been shown to interact with subunits of the nuclear factor kappa b (NF-κB) complex in myeloid cells, B cells, and fibroblasts 75 – 77 , although the precise NF-κB family members with which AHR interacts varied among cell types. Thus, interactions with cofactors are likely cell-type specific, which may help to explain some of the cell-type specific effects observed among the AHR ligands.…”

Section: Discussionmentioning

confidence: 99%

Aryl hydrocarbon receptor signaling modulates antiviral immune responses: ligand metabolism rather than chemical source is the stronger predictor of outcome

Boule

Burke

Jin

et al. 2018

Sci Rep

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The aryl hydrocarbon receptor (AHR) offers a compelling target to modulate the immune system. AHR agonists alter adaptive immune responses, but the consequences differ across studies. We report here the comparison of four agents representing different sources of AHR ligands in mice infected with influenza A virus (IAV): TCDD, prototype exogenous AHR agonist; PCB126, pollutant with documented human exposure; ITE, novel pharmaceutical; and FICZ, degradation product of tryptophan. All four compounds diminished virus-specific IgM levels and increased the proportion of regulatory T cells. TCDD, PCB126 and ITE, but not FICZ, reduced virus-specific IgG levels and CD8 + T cell responses. Similarly, ITE, PCB126, and TCDD reduced Th1 and Tfh cells, whereas FICZ increased their frequency. In Cyp1a1-deficient mice, all compounds, including FICZ, reduced the response to IAV. Conditional Ahr knockout mice revealed that all four compounds require AHR within hematopoietic cells. Thus, differences in the immune response to IAV likely reflect variances in quality, magnitude, and duration of AHR signaling. This indicates that binding affinity and metabolism may be stronger predictors of immune effects than a compound's source of origin, and that harnessing AHR will require finding a balance between dampening immune-mediated pathologies and maintaining sufficient host defenses against infection.There is considerable evidence that signaling through the aryl hydrocarbon receptor (AHR) alters the course of adaptive immune responses in a manner that can be protective or detrimental. Adaptive immune responses underlie host protection from pathogens, but when improperly controlled they contribute to numerous diseases. The AHR's remarkable capacity to modulate T cell responses has been demonstrated in autoimmune diseases 1-5 , allergic inflammation 6,7 , and inflammatory bowel diseases [8][9][10] . Yet, these reports also suggest that different AHR ligands may bias adaptive immune responses in opposite directions, and that exposure to the same ligand can worsen or improve pathology in different disease models 1,2,11 . While these issues remain to be resolved, the ability of the AHR to modulate T cell differentiation and T cell-dependent immune responses has generated enthusiasm about targeting therapeutic agents at the AHR in order to modulate the progression of a large spectrum of immune-mediated diseases 12,13 .Yet, there is another aspect of AHR immunobiology that has direct bearing on the potential success of new strategies to use AHR ligands as treatment modalities: the impact on host responses to infection. Several reports demonstrate the importance of AHR in sensing microbes, including pathogenic and commensal bacteria, mycobacteria, and fungi [14][15][16][17] . Epidemiological studies show strong correlations between exposure to anthropogenically-derived AHR ligands from the environment and increased incidence and severity of respiratory infections, most notably viral infections 18,19 . These observations have been extended with a...

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Section: Discussionmentioning

confidence: 99%

Aryl hydrocarbon receptor signaling modulates antiviral immune responses: ligand metabolism rather than chemical source is the stronger predictor of outcome

Boule

Burke

Jin

et al. 2018

Sci Rep

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“…These changes were not due to alterations in viral replication, as the viral load was unchanged by AhR activation or inhibition. The mechanism driving cytokine changes during MHV infection is likely complex but probably involves interaction of activated AhR with NF-B (30,(33)(34)(35)55) (Fig. 1).…”

Section: Mhv-a59 Infection Induces Tiparp Expression Through Ifn-i-dementioning

confidence: 99%

“…AhR activation by chemical agonists has been shown to influence the differentiation (24)(25)(26)(27)(28) and cytokine/chemokine production (25,26,(29)(30)(31)(32) of T cells, dendritic cells, and macrophages. AhR has also been shown to bind to and modulate the transcription specificity of NF-B in multiple experimental settings, which could contribute to cytokine modulation (30,(33)(34)(35). Other studies have shown that AhR activation in immune cells is driven by IDO1, and the resulting IDO1-AhR-IDO1 positivefeedback loop helps to establish immunotolerance (18,36,37).…”

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confidence: 99%

Murine Coronavirus Infection Activates the Aryl Hydrocarbon Receptor in an Indoleamine 2,3-Dioxygenase-Independent Manner, Contributing to Cytokine Modulation and Proviral TCDD-Inducible-PARP Expression

Grunewald

Shaban

Mackin

et al. 2020

J Virol

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The aryl hydrocarbon receptor (AhR) is a cytoplasmic receptor/transcription factor that modulates several cellular and immunological processes following activation by pathogen-associated stimuli, though its role during virus infection is largely unknown. Here, we show that AhR is activated in cells infected with mouse hepatitis virus (MHV), a coronavirus (CoV), and contributes to the upregulation of downstream effector TCDD-inducible poly(ADP-ribose) polymerase (TiPARP) during infection. Knockdown of TiPARP reduced viral replication and increased interferon expression, suggesting that TiPARP functions in a proviral manner during MHV infection. We also show that MHV replication induced the expression of other genes known to be downstream of AhR in macrophages and dendritic cells and in livers of infected mice. Further, we found that chemically inhibiting or activating AhR reciprocally modulated the expression levels of cytokines induced by infection, specifically, interleukin 1␤ (IL-1␤), IL-10, and tumor necrosis factor alpha (TNF-␣), consistent with a role for AhR activation in the host response to MHV infection. Furthermore, while indoleamine 2,3-dioxygenase (IDO1) drives AhR activation in other settings, MHV infection induced equal expression of downstream genes in wild-type (WT) and IDO1 Ϫ/Ϫ macrophages, suggesting an alternative pathway of AhR activation. In summary, we show that coronaviruses elicit AhR activation by an IDO1-independent pathway, contributing to upregulation of downstream effectors, including the proviral factor TiPARP, and to modulation of cytokine gene expression, and we identify a previously unappreciated role for AhR signaling in CoV pathogenesis. IMPORTANCE Coronaviruses are a family of positive-sense RNA viruses with human and agricultural significance. Characterizing the mechanisms by which coronavirus infection dictates pathogenesis or counters the host immune response would provide targets for the development of therapeutics. Here, we show that the aryl hydrocarbon receptor (AhR) is activated in cells infected with a prototypic coronavirus, mouse hepatitis virus (MHV), resulting in the expression of several effector genes. AhR is important for modulation of the host immune response to MHV and plays a role in the expression of TiPARP, which we show is required for maximal viral replication. Taken together, our findings highlight a previously unidentified role for AhR in regulating coronavirus replication and the immune response to the virus.

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“…[48][49][50] Furthermore, a recent paper has shown that upon TCDD treatment altered expression of NFKB/REL members may, along with AHR activation, mediate a decrease in Ig expression. 51 As such, increased PAI2 expression may provide protection to less-sensitive strains via regulation of NFKB/REL signaling. Human PAI2 has also been reported to bind and protect retinoblastoma protein (RB1) from calpain cleavage ultimately leading to increase RB1 levels within the cell leading to increased cell survival.…”

Section: Discussionmentioning

confidence: 99%

Characterizing Serpinb2 as a Modulator of TCDD-Induced Suppression of the B Cell

Dornbos

Warren

Crawford

et al. 2018

Chem. Res. Toxicol.

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2,3,7,8-Tetrachlordibenzo-p-dioxin (TCDD) is an environmental pollutant that can cause various toxic effects, including chloracne, metabolic syndrome, and immune suppression. Most of the toxicity associated with TCDD is mediated through activation of the aryl hydrocarbon receptor (AHR). Recent research has suggested the presence of a wide-range of interindividual variability in TCDD-mediated suppression of the Immunoglobulin-M (IgM) response across the human population. In an attempt to identify putative modifiers of AHR-mediated immunosuppression beyond the AHR, B cells were isolated from a panel of genetically diverse mouse strain to scan for modulators that drive interstrain differences in TCDD-mediated suppression of the IgM response. Results implicated a region of mouse Chromosome 1 near a gene encoding serine peptidase inhibitor, clade B, member 2 (Serpinb2) whose human ortholog is plasminogen activator inhibitor 2 (PAI2). Further downstream analyses indicated that Serpinb2 is dysregulated by TCDD and, furthermore, that B cells from Serpinb2 −/− mice are significantly more sensitive to TCDDmediated suppression as compared to littermate controls. This study suggests a protective role of Serpinb2 within TCDD-mediated immunosuppression and, furthermore, a novel function of Serpinb2-related activity in the IgM response.

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The AhR and NF-κB/Rel Proteins Mediate the Inhibitory Effect of 2,3,7,8-Tetrachlorodibenzo-p-Dioxin on the 3′ Immunoglobulin Heavy Chain Regulatory Region

Cited by 26 publications

References 64 publications

Aryl hydrocarbon receptor signaling modulates antiviral immune responses: ligand metabolism rather than chemical source is the stronger predictor of outcome

Aryl hydrocarbon receptor signaling modulates antiviral immune responses: ligand metabolism rather than chemical source is the stronger predictor of outcome

Murine Coronavirus Infection Activates the Aryl Hydrocarbon Receptor in an Indoleamine 2,3-Dioxygenase-Independent Manner, Contributing to Cytokine Modulation and Proviral TCDD-Inducible-PARP Expression

Characterizing Serpinb2 as a Modulator of TCDD-Induced Suppression of the B Cell

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