Binding Mode and Structure–Activity Relationships of ITE as an Aryl Hydrocarbon Receptor (AhR) Agonist

Dolciami, Daniela; Gargaro, Marco; Cerra, Bruno; Scalisi, Giulia; Bagnoli, Luana; Servillo, Giuseppe; Fazia, Maria Agnese Della; Puccetti, Paolo; Quintana, Francisco J.; Fallarino, Francesca; Macchiarulo, Antonio

doi:10.1002/cmdc.201700669

Cited by 24 publications

(19 citation statements)

References 36 publications

(126 reference statements)

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“…This point is particularly important given the growing interest in AhR research on identifying novel classes of potent, non-toxic AhR ligands for use in various therapeutic settings (Stockinger 2009). Moreover, these observations raise concerns about potential off target immune toxicities associated with the use of ITE based immune therapies (Abron et al 2018;Dolciami et al 2018;Hao and Whitelaw 2013;Nugent et al 2013;Quintana et al 2010b).…”

Section: Discussionmentioning

confidence: 99%

Targeted deletion of the aryl hydrocarbon receptor in dendritic cells prevents thymic atrophy in response to dioxin

et al. 2018

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In nearly every species examined, administration of the persistent environmental pollutant, 2,3,7,8tetrachlorodibenzo-p-dioxin (dioxin, TCDD) causes profound immune suppression and thymic atrophy in an aryl hydrocarbon receptor (AhR) dependent manner. Moreover, TCDD alters the development and differentiation of thymocytes, resulting in decreases in the relative proportion and absolute number of double positive (DP, CD4 + CD8 +) thymocytes, as well as a relative enrichment in the relative proportion and absolute number of double negative (DN, CD4-CD8-) and single-positive (SP) CD4 + CD8and CD4-CD8 + thymocytes. Previous studies suggested that the target for TCDD-induced thymic atrophy resides within the hemopoietic compartment and implicated apoptosis, proliferation arrest of thymic progenitors, and emigration of DN thymocytes to the periphery as potential contributors to TCDD-induced thymic atrophy. However, the precise cellular and molecular mechanisms involved remain largely unknown. Our results show that administration of 10 μg/kg TCDD and 8 mg/kg 2-(1H-indol-3-ylcarbonyl)-4-thiazolecarboxylic acid methyl ester (ITE) induced AhR-dependent thymic atrophy in mice on day 7, whereas 100 mg/kg indole 3-carbinol (I3C) did not. Though our studies demonstrate that TCDD triggers a twofold increase in the frequency of apoptotic thymocytes, TCDD-induced thymic atrophy is not dependent on Fas-FasL interactions, and thus, enhanced apoptosis is unlikely to be a major mechanistic contributor. Finally, our results show that activation of the AhR in CD11c + dendritic cells is directly responsible for TCDD-induced alterations in the development and differentiation of thymocytes, which results in thymic atrophy. Collectively, these results suggest that CD11c + dendritic cells play a critical role in mediating TCDD-induced thymic atrophy and disruption of T lymphocyte development and differentiation in the thymus. Author contributions CAB, JMK, and DMS designed the studies, coordinated the experiments, prepared the figures, and composed the manuscript. SLC performed the qRT-PCR analysis and assisted with experimental harvests. All authors have read and approved the final version of the manuscript.

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Section: Discussionmentioning

confidence: 99%

Targeted deletion of the aryl hydrocarbon receptor in dendritic cells prevents thymic atrophy in response to dioxin

et al. 2018

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“…Mouse embryonic fibroblasts (MEFs) were obtained according to the guidelines of the University of Perugia Ethical Committee and the European Communities Council Directive 2010/63/EU. MEFs and Ahr −/− MEFs were prepared as described (14). Briefly, pregnant mice were sacrificed at 13.5 days post-coitum (dpc) by cervical dislocation.…”

Section: Cell Lines and Cell Culturementioning

confidence: 99%

Pharmacologic Induction of Endotoxin Tolerance in Dendritic Cells by L-Kynurenine

et al. 2020

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Endotoxin tolerance aims at opposing hyperinflammatory responses to lipopolysaccharide (LPS) exposure. The aryl hydrocarbon receptor (AhR) participates in protection against LPS-mediated tissue damage, as it plays a necessary role in restraining the proinflammatory action of IL-1β and TNF-α while fostering the expression of protective TGF-β. TGF-β, in turn, promotes durable expression of the immune regulatory enzyme indoleamine 2,3-dioxygenase 1 (IDO1). IDO1 degrades L-tryptophan to L-kynurenine-an activating ligand for AhR-thus establishing a feed-forward loop. In this study, we further demonstrate that L-kynurenine also promotes the dissociation of the Src kinase-AhR cytosolic complex, leading to the activation of both genomic and non-genomic events in conventional dendritic cells (cDCs) primed with LPS. Specifically, the Src kinase, by phosphorylating the downstream target IDO1, triggers IDO1's signaling ability, which results in enhanced production of TGF-β, an event key to establishing full endotoxin tolerance. We demonstrated that exogenous L-kynurenine can substitute for the effects of continued or repeated LPS exposure and that the AhR-Src-IDO1 axis represents a critical step for the transition from endotoxin susceptibility to tolerance. Moreover, much like fully endotoxin-tolerant dendritic cells (DCs) (i.e., treated twice with LPS in vitro), DCs-treated once with LPS in vitro and then with kynurenine-confer resistance on naïve recipients to an otherwise lethal LPS challenge. This may have clinical implications under conditions in which pharmacologically induced onset of endotoxin tolerance is a therapeutically desirable event.

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“…XRs are also extremely involved in regulating general physiology since they can also transcribe for genes involved in immune regulation, cell metabolism, energy homeostasis (Figure 1). Families of XRs may bind a very large family of unrelated ligands by direct or indirect binding (27,28). XRs may include the pregnane X receptor (PXR), the AhR, the constitutive androstane receptor (CAR), and the peroxisome proliferator-activated receptors (PPARs) (Figure 1).…”

Section: The Indole Pyruvate (Ipya) Route: a Direct Effect On Immunitymentioning

confidence: 99%

Tryptophan Co-Metabolism at the Host-Pathogen Interface

et al. 2020

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Binding Mode and Structure–Activity Relationships of ITE as an Aryl Hydrocarbon Receptor (AhR) Agonist

Cited by 24 publications

References 36 publications

Targeted deletion of the aryl hydrocarbon receptor in dendritic cells prevents thymic atrophy in response to dioxin

Targeted deletion of the aryl hydrocarbon receptor in dendritic cells prevents thymic atrophy in response to dioxin

Pharmacologic Induction of Endotoxin Tolerance in Dendritic Cells by L-Kynurenine

Tryptophan Co-Metabolism at the Host-Pathogen Interface

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