The role of indoleamine 2,3-dioxygenase-aryl hydrocarbon receptor pathway in the TLR4-induced tolerogenic phenotype in human DCs

Salazar, Fabián; Awuah, Dennis; Negm, Ola H.; Shakib, F; Ghaemmaghami, Amir M.

doi:10.1038/srep43337

Cited by 52 publications

(52 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…RV infection inhibited the IFNmediated induction of Ido-1 (indoleamine 2,3-dioxygenase) in the intestine (Fig. 7D), which is a critical determinant of LPS-induced lethality in mice (38)(39)(40). Previously, we found that RV infection also leads to a significant inhibition of the IFN response and NF-B signaling in uninfected bystander cells (4, 7).…”

Section: Resultsmentioning

confidence: 69%

“…7D), has been shown to be a critical determinant of LPS-induced lethality in mice (30,(38)(39)(40)48). Expression of Ido-1 occurs primarily in activated macrophages and dendritic cells and has profound effects on T cell and T regulatory (Treg) cell responses to inflammatory signals including LPS (38)(39)(40). Based on these prior findings, we chose to examine the effect of RV infection on LPS-induced lethality in suckling mice.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Rotavirus Degrades Multiple Interferon (IFN) Type Receptors To Inhibit IFN Signaling and Protects against Mortality from Endotoxin in Suckling Mice

Sharma

Greenberg

2018

J Virol

View full text Add to dashboard Cite

STAT1 phosphorylation in response to exogenous IFN administration can be inhibited by rotaviral replication both and In addition many rotavirus strains are resistant to the actions of different IFN types . The regulation of multiple IFN type-mediated antiviral pathways by RVs is not well understood. In this study, we find that during infection and RV significantly depletes IFN-type I, II, and III receptors (IFNRs). Regulation of IFNRs occurred exclusively within RV-infected cells and could be abrogated by inhibiting the lysosomal-endosomal degradation pathway. , IFNR degradation was conserved across multiple RV strains that differ in their modes of regulating IFN induction. In suckling mice, exogenously administered types I, II, or III IFN each induced phosphorylation of STAT1-Y701 within intestinal epithelial cells (IECs) of suckling mice. Murine EW strain RV infection transiently activated intestinal STAT1 at 1dpi, but not subsequently at 2-3dpi. In response to injection of purified IFN-α/β or -λ, IECs in EW-infected mice exhibited impaired STAT1-Y701 phosphorylation, correlating with depletion of different intestinal IFNRs and impaired IFN-mediated transcription. The ability of EW murine RV to inhibit multiple IFN types led us to test protection of suckling mice from endotoxin-mediated shock, an outcome that is dependent on the host IFN response. Compared to controls, mice infected with EW murine RV were substantially protected against mortality following parenteral endotoxin administration. These studies identify a novel mechanism of IFN subversion by RV and reveal an unexpected protective effect of RV infection on endotoxin-mediated shock in suckling mice. Antiviral functions of types 1, 2, and 3 IFN are mediated by receptor-dependent activation of STAT1. Here we find that RV degrades the types 1, 2, and 3 IFN receptors (IFNR) In a suckling mouse model, RV effectively blocked STAT1 activation and transcription following injection of different purified IFNs. This correlated with significantly decreased protein expression of intestinal types 1 and 2 IFNRs. Recent studies demonstrate that in mice, LPS-induced lethality is prevented by genetic ablation of IFN signaling genes such as IFNAR1 and STAT1. When suckling mice were infected with RV they were substantially protected from lethal exposure to endotoxin. These findings provide novel insights into the mechanisms underlying rotavirus regulation of different interferons and are likely to stimulate new research into both rotavirus pathogenesis and endotoxemia.

show abstract

Section: Resultsmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Rotavirus Degrades Multiple Interferon (IFN) Type Receptors To Inhibit IFN Signaling and Protects against Mortality from Endotoxin in Suckling Mice

Sharma

Greenberg

2018

J Virol

View full text Add to dashboard Cite

show abstract

“…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). In contrast, less is known about the role of AhR during virus infection.…”

mentioning

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

View full text Add to dashboard Cite

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.

show abstract

“…Modeling immune organs in vitro also facilitates tunable immune system parameters enabling investigation into the fundamental development of the immune system, including immune cell development, recruitment, selection, and activation . In vitro models can also enable the development of immunotherapies like vaccines, antibodies, or antigen‐specific T cells …”

Section: Immune Organs Modelingmentioning

confidence: 99%

Organ‐on‐a‐Chip for Cancer and Immune Organs Modeling

Sun

Luo

Lee

et al. 2019

Adv Healthcare Materials

119

View full text Add to dashboard Cite

Bridging the gap between findings in preclinical 2D cell culture models and in vivo tissue cultures has been challenging; the simple microenvironment of 2D monolayer culture systems may not capture the cellular response to drugs accurately. Three‐dimensional organotypic models have gained increasing interest due to their ability to recreate precise cellular organizations. These models facilitate investigation of the interactions between different sub‐tissue level components through providing physiologically relevant microenvironments for cells in vitro. The incorporation of human‐sourced tissues into these models further enables personalized prediction of drug responses. Integration of microfluidic units into the 3D models can be used to control their local environment, dynamic simulation of cell behaviors, and real‐time readout of drug testing data. Cancer and immune system related diseases are severe burdens to our health care system and have created an urgent need for high‐throughput, and effective drug development plans. This review focuses on recent progress in the development of “cancer‐on‐a‐chip” and “immune organs‐on‐a‐chip” systems designed to study disease progression and predict drug‐induced responses. Future challenges and opportunities are also discussed.

show abstract

The role of indoleamine 2,3-dioxygenase-aryl hydrocarbon receptor pathway in the TLR4-induced tolerogenic phenotype in human DCs

Cited by 52 publications

References 57 publications

Rotavirus Degrades Multiple Interferon (IFN) Type Receptors To Inhibit IFN Signaling and Protects against Mortality from Endotoxin in Suckling Mice

Rotavirus Degrades Multiple Interferon (IFN) Type Receptors To Inhibit IFN Signaling and Protects against Mortality from Endotoxin in Suckling Mice

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

Organ‐on‐a‐Chip for Cancer and Immune Organs Modeling

Contact Info

Product

Resources

About