Alpha-tocopherylquinone differentially modulates claudins to enhance intestinal epithelial tight junction barrier via AhR and Nrf2 pathways

• Published in: Cell reports (Cambridge) 2023-07, Vol.42 (7), p.112705-112705, Article 112705
• Main Authors: Ganapathy, Ashwinkumar Subramenium, Saha, Kushal, Wang, Alexandra, Arumugam, Priya, Dharmaprakash, Viszwapriya, Yochum, Gregory, Koltun, Walter, Nighot, Meghali, Perdew, Gary, Thompson, Todd A., Ma, Thomas, Nighot, Prashant
• Format: Article
• Language: English
• Subjects: alpha-tocopherylquinone; Animals; aryl hydrocarbon receptor; Caco-2 Cells; claudin-2; claudin-3; Claudins - metabolism; Colitis - metabolism; CP: Cell biology; Humans; inflammatory bowel disease; Intestinal Mucosa - metabolism; intestinal permeability; Mice; NF-E2-Related Factor 2 - metabolism; Permeability; Receptors, Aryl Hydrocarbon - genetics; tight junction; Tight Junctions - metabolism; Vitamin E - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.112705

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. [Display omitted] •Alpha-tocopherylquinone (TQ) enhances intestinal tight junction (TJ) barrier•TQ increases barrier-forming CLDN3 expression via AhR•TQ reduces channel-forming CLDN2 via Nrf-mediated STAT3 inactivation•TQ ameliorates experimental colitis Ganapathy et al. show that alpha-tocopherylquinone reduces intestinal paracellular permeability via an AhR-mediated increase in tight junction barrier-forming CLDN3 and an Nrf2-mediated reduction in channel-forming CLDN2 expression. α-tocopherylquinone-mediated enhancement of the tight junction barrier is associated with amelioration of experimental colitis.