TY - JOUR
T1 - Alpha-tocopherylquinone differentially modulates claudins to enhance intestinal epithelial tight junction barrier via AhR and Nrf2 pathways
AU - Ganapathy, Ashwinkumar Subramenium
AU - Saha, Kushal
AU - Wang, Alexandra
AU - Arumugam, Priya
AU - Dharmaprakash, Viszwapriya
AU - Yochum, Gregory
AU - Koltun, Walter
AU - Nighot, Meghali
AU - Perdew, Gary
AU - Thompson, Todd A.
AU - Ma, Thomas
AU - Nighot, Prashant
N1 - Funding Information:
The authors thank the IBD and Colorectal Diseases Biobank, Confocal Microscopy, Animal Facility, and Flow Cytometry core (RRID: SCR_021134 ) at Penn State College of Medicine for their excellent technical assistance. This research was supported in part by the National Institute of Diabetes and Digestive and Kidney Diseases grants DK100562 (P.N.) and DK114024 (P.N.), the National Institute of Environmental Health Sciences R35ES028244 (G.P.), and a Crohn's & Colitis Foundation Award 694583 (M.N.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies. The authors also acknowledge support from the Peter and Marshia Carlino Fund for IBD Research.
Publisher Copyright:
© 2023 The Author(s)
PY - 2023/7/25
Y1 - 2023/7/25
N2 - Defects in intestinal epithelial tight junctions (TJs) allow paracellular permeation of noxious luminal antigens and are important pathogenic factors in inflammatory bowel disease (IBD). We show that alpha-tocopherylquinone (TQ), a quinone-structured oxidation product of vitamin E, consistently enhances the intestinal TJ barrier by increasing barrier-forming claudin-3 (CLDN3) and reducing channel-forming CLDN2 in Caco-2 cell monolayers (in vitro), mouse models (in vivo), and surgically resected human colons (ex vivo). TQ reduces colonic permeability and ameliorates colitis symptoms in multiple colitis models. TQ, bifunctionally, activates both aryl hydrocarbon receptor (AhR) and nuclear factor erythroid 2-related factor 2 (Nrf2) pathways. Genetic deletion studies reveal that TQ-induced AhR activation transcriptionally increases CLDN3 via xenobiotic response element (XRE) in the CLDN3 promoter. Conversely, TQ suppresses CLDN2 expression via Nrf2-mediated STAT3 inhibition. TQ offers a naturally occurring, non-toxic intervention for enhancement of the intestinal TJ barrier and adjunct therapeutics to treat intestinal inflammation.
AB - Defects in intestinal epithelial tight junctions (TJs) allow paracellular permeation of noxious luminal antigens and are important pathogenic factors in inflammatory bowel disease (IBD). We show that alpha-tocopherylquinone (TQ), a quinone-structured oxidation product of vitamin E, consistently enhances the intestinal TJ barrier by increasing barrier-forming claudin-3 (CLDN3) and reducing channel-forming CLDN2 in Caco-2 cell monolayers (in vitro), mouse models (in vivo), and surgically resected human colons (ex vivo). TQ reduces colonic permeability and ameliorates colitis symptoms in multiple colitis models. TQ, bifunctionally, activates both aryl hydrocarbon receptor (AhR) and nuclear factor erythroid 2-related factor 2 (Nrf2) pathways. Genetic deletion studies reveal that TQ-induced AhR activation transcriptionally increases CLDN3 via xenobiotic response element (XRE) in the CLDN3 promoter. Conversely, TQ suppresses CLDN2 expression via Nrf2-mediated STAT3 inhibition. TQ offers a naturally occurring, non-toxic intervention for enhancement of the intestinal TJ barrier and adjunct therapeutics to treat intestinal inflammation.
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U2 - 10.1016/j.celrep.2023.112705
DO - 10.1016/j.celrep.2023.112705
M3 - Article
C2 - 37393618
AN - SCOPUS:85163991617
SN - 2211-1247
VL - 42
JO - Cell Reports
JF - Cell Reports
IS - 7
M1 - 112705
ER -