Alpha-tocopherylquinone-mediated activation of the Aryl Hydrocarbon Receptor regulates the production of inflammation-inducing cytokines and ameliorates intestinal inflammation

Saha, Kushal; Subramenium Ganapathy, Ashwinkumar; Wang, Alexandra; Arumugam, Priya; Michael Morris, Nathan; Harris, Leonard; Yochum, Gregory; Koltun, Walter; Perdew, Gary H.; Nighot, Meghali; Ma, Thomas; Nighot, Prashant

doi:10.1016/j.mucimm.2023.09.003

Mucosal Immunology

2023

DOI: 10.1016/j.mucimm.2023.09.003

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Alpha-tocopherylquinone-mediated activation of the Aryl Hydrocarbon Receptor regulates the production of inflammation-inducing cytokines and ameliorates intestinal inflammation

Kushal Saha,

Ashwinkumar Subramenium Ganapathy,

Alexandra Wang

et al.

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2024

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Cited by 2 publications

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Intestinal Epithelial Tight Junction Barrier Regulation by Novel Pathways

Arumugam,

Saha,

Nighot

2024

Inflammatory Bowel Diseases

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Intestinal epithelial tight junctions (TJs), a dynamically regulated barrier structure composed of occludin and claudin family of proteins, mediate the interaction between the host and the external environment by allowing selective paracellular permeability between the luminal and serosal compartments of the intestine. TJs are highly dynamic structures and can undergo constant architectural remodeling in response to various external stimuli. This is mediated by an array of intracellular signaling pathways that alters TJ protein expression and localization. Dysfunctional regulation of TJ components compromising the barrier homeostasis is an important pathogenic factor for pathological conditions including inflammatory bowel disease (IBD). Previous studies have elucidated the significance of TJ barrier integrity and key regulatory mechanisms through various in vitro and in vivo models. In recent years, considerable efforts have been made to understand the crosstalk between various signaling pathways that regulate formation and disassembly of TJs. This review provides a comprehensive view on the novel mechanisms that regulate the TJ barrier and permeability. We discuss the latest evidence on how ion transport, cytoskeleton and extracellular matrix proteins, signaling pathways, and cell survival mechanism of autophagy regulate intestinal TJ barrier function. We also provide a perspective on the context-specific outcomes of the TJ barrier modulation. The knowledge on the diverse TJ barrier regulatory mechanisms will provide further insights on the relevance of the TJ barrier defects and potential target molecules/pathways for IBD.

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Intestinal Epithelial Tight Junction Barrier Regulation by Novel Pathways

Arumugam,

Saha,

Nighot

2024

Inflammatory Bowel Diseases

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Regulation of Bacteroides acidifaciens by the aryl hydrocarbon receptor in IL-22-producing immune cells has sex-dependent consequential impact on colitis

Mitchell,

Staley,

Williams

et al. 2024

Front. Immunol.

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IntroductionColitis is an inflammatory bowel disease (IBD) characterized by immune cell dysregulation and alterations in the gut microbiome. In our previous report, we showed a natural product in cruciferous vegetables and ligand of the aryl hydrocarbon receptor (AhR), indole-3-carbinol (I3C), was able to reduce colitis-induced disease severity and microbial dysbiosis in an interleukin-22 (IL-22) dependent manner.MethodsIn the current study, we performed single-cell RNA sequencing (scRNAseq) from colonocytes during colitis induction and supplementation with I3C and show how this treatment alters expression of genes involved in IL-22 signaling. To further define the role of IL-22 signaling in I3C-mediated protection during colitis and disease-associated microbial dysbiosis, we generated mice with AhR deficiency in RAR-related orphan receptor c (Rorc)-expressing cells (AhRΔRorc) which depletes this receptor in immune cells involved in production of IL-22. Colitis was induced in wildtype (WT), AhRΔRorc, and littermate (LM) mice with or without I3C treatment. ResultsResults showed AhRΔRorc mice lost the efficacy effects of I3C treatment which correlated with a loss of ability to increase IL-22 by innate lymphoid type 3 (ILC3s), not T helper 22 (Th22) cells. 16S rRNA microbiome profiling studies showed AhRΔRorc mice were unable to regulate disease-associated increases in Bacteroides, which differed between males and females. Lastly, inoculation with a specific disease-associated Bacteroides species, Bacteroides acidifaciens (B. acidifaciens), was shown to exacerbate colitis in females, but not males. DiscussionCollectively, this report highlights the cell and sex-specific role of AhR in regulating microbes that can impact colitis disease.

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Alpha-tocopherylquinone-mediated activation of the Aryl Hydrocarbon Receptor regulates the production of inflammation-inducing cytokines and ameliorates intestinal inflammation

Cited by 2 publications

References 63 publications

Intestinal Epithelial Tight Junction Barrier Regulation by Novel Pathways

Intestinal Epithelial Tight Junction Barrier Regulation by Novel Pathways

Regulation of Bacteroides acidifaciens by the aryl hydrocarbon receptor in IL-22-producing immune cells has sex-dependent consequential impact on colitis

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