The DOI matches its Crossref record; 45 of the 45 references it cites were found in a registry or an index.
The Environmental Sensor AHR Protects from Inflammatory Damage by Maintaining Intestinal Stem Cell Homeostasis and Barrier Integrity
Open accessAbstract
The epithelium and immune compartment in the intestine are constantly exposed to a fluctuating external environment. Defective communication between these compartments at this barrier surface underlies susceptibility to infections and chronic inflammation. Environmental factors play a significant, but mechanistically poorly understood, role in intestinal homeostasis. We found that regeneration of intestinal epithelial cells (IECs) upon injury through infection or chemical insults was profoundly influenced by the environmental sensor aryl hydrocarbon receptor (AHR). IEC-specific deletion of Ahr resulted in failure to control C. rodentium infection due to unrestricted intestinal stem cell (ISC) proliferation and impaired differentiation, culminating in malignant transformation. AHR activation by dietary ligands restored barrier homeostasis, protected the stem cell niche, and prevented tumorigenesis via transcriptional regulation of of Rnf43 and Znrf3, E3 ubiquitin ligases that inhibit Wnt-β-catenin signaling and restrict ISC proliferation. Thus, activation of the AHR pathway in IECs guards the stem cell niche to maintain intestinal barrier integrity.
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“Dietary supplementation with indole-3-carbinol activates the AHR in intestinal epithelial cells to restore intestinal barrier integrity in mice infected with Citrobacter rodentium.”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [653]
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Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche
Sato, T., Vries, R. G., Snippert, H. J., van de Wetering, M., Barker, N., Stange, D. E., van Es, J. H., Abo, A., Kujala, P., Peters, P. J., et al. (2009) · Nature · doi:10.1038/nature07935 · Cited by 7,204 · cited 1×
“Wnt-b-Catenin Signaling The intestinal epithelium continuously renews itself from crypt stem cells that differentiate into short-lived specialized epithelial subtypes (Sato et al., 2009).”
BackgroundIdentification of stem cells in small intestine and colon by marker gene Lgr5
Barker, N., van Es, J. H., Kuipers, J., Kujala, P., van den Born, M., Cozijnsen, M., Haegebarth, A., Korving, J., Begthel, H., Peters, P. J., et al. (2007) · Nature · doi:10.1038/nature06196 · Cited by 5,687 · cited 6×
“Since we were not able to maintain Ahr-deficient Lgr5Egfp-Ires-creErt2 reporter mice viable for long enough, we used mice heterozygous for Ahr deletion, which were partially affected.”
BackgroundMethodInfluentialZelante, T., Iannitti, R. G., Cunha, C., De Luca, A., Giovannini, G., Pieraccini, G., Zecchi, R., D’Angelo, C., Massi-Benedetti, C., Fallarino, F., et al. (2013) · Immunity · doi:10.1016/j.immuni.2013.08.003 · Cited by 2,614 · cited 2×
“Although the AHR was originally described as a receptor for dioxin and other xenobiotics, it is now clear that physiological AHR ligands such as dietary components and tryptophan metabolites (Denison and Nagy, 2003; Hubbard et al., 2015; Lamas et al., 2016;McMillan and Bradfield, 2007; Moura-Alves et al., 2014; Zelant…”
BackgroundLiu, J. Z., van Sommeren, S., Huang, H., Ng, S. C., Alberts, R., Takahashi, A., Ripke, S., Lee, J. C., Jostins, L., Shah, T., et al. (2015) · Nature Genetics · doi:10.1038/ng.3359 · Cited by 2,603
Denison, M. S., & Nagy, S. R. (2003) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.43.100901.135828 · Cited by 1,895 · cited 2×
“Although the AHR was originally described as a receptor for dioxin and other xenobiotics, it is now clear that physiological AHR ligands such as dietary components and tryptophan metabolites (Denison and Nagy, 2003; Hubbard et al., 2015; Lamas et al., 2016;McMillan and Bradfield, 2007; Moura-Alves et al., 2014; Zelant…”
BackgroundLamas, B., Richard, M. L., Leducq, V., Pham, H.-P., Michel, M.-L., Da Costa, G., Bridonneau, C., Jegou, S., Hoffmann, T. W., Natividad, J. M., et al. (2016) · Nature Medicine · doi:10.1038/nm.4102 · Cited by 1,482 · cited 2×
“Although the AHR was originally described as a receptor for dioxin and other xenobiotics, it is now clear that physiological AHR ligands such as dietary components and tryptophan metabolites (Denison and Nagy, 2003; Hubbard et al., 2015; Lamas et al., 2016;McMillan and Bradfield, 2007; Moura-Alves et al., 2014; Zelant…”
BackgroundGrowing Self-Organizing Mini-Guts from a Single Intestinal Stem Cell: Mechanism and Applications
Sato, T., & Clevers, H. (2013) · Science · doi:10.1126/science.1234852 · Cited by 1,170 · cited 1×
“In order to directly investigate the role of AHR in the process of crypt stem cell proliferation and differentiation, we generated colon organoids (Sato and Clevers, 2013).”
BackgroundTumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors
Koo, B.-K., Spit, M., Jordens, I., Low, T. Y., Stange, D. E., van de Wetering, M., van Es, J. H., Mohammed, S., Heck, A. J. R., Maurice, M. M., et al. (2012) · Nature · doi:10.1038/nature11308 · Cited by 980 · cited 3×
“Our results provide evidence that Wnt-b-catenin pathway dysregulation in Ahrdeficient IECs occurred upstream of b-catenin degradation, affecting the response to WNT signals themselves through the expression of the two related E3 ubiquitin ligases (ZNRF3 and RNF43) that degrade the Wnt frizzled receptors (Koo et al., 2…”
BackgroundCancer as an overhealing wound: an old hypothesis revisited
Schäfer, M., & Werner, S. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2455 · Cited by 974
ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner
Hao, H.-X., Xie, Y., Zhang, Y., Charlat, O., Oster, E., Avello, M., Lei, H., Mickanin, C., Liu, D., Ruffner, H., et al. (2012) · Nature · doi:10.1038/nature11019 · Cited by 962 · cited 2×
“We focused on the tumor suppressors RNF43 and ZNRF3, which are transmembrane E3 ubiquitin ligases expressed in LGR5 stem cells that regulate WNT signals by targeting WNT receptors for degradation in an R-spondin-sensitive manner (Hao et al., 2012; Koo et al., 2012; Tsukiyama et al., 2015).”
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Rothhammer, V., & Quintana, F. J. (2019) · Nature Reviews Immunology · doi:10.1038/s41577-019-0125-8 · Cited by 1,197
Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases
Loh, J. S., Mak, W. Q., Tan, L. K. S., Ng, C. X., Chan, H. H., Yeow, S. H., Foo, J. B., Ong, Y. S., How, C. W., & Khaw, K. Y. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01743-1 · Cited by 1,193
Regulation of Intestinal Barrier Function by Microbial Metabolites
Ghosh, S., Whitley, C. S., Haribabu, B., & Jala, V. R. (2021) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2021.02.007 · Cited by 835
Pathway paradigms revealed from the genetics of inflammatory bowel disease
Graham, D. B., & Xavier, R. J. (2020) · Nature · doi:10.1038/s41586-020-2025-2 · Cited by 801
Interaction Between the Microbiota, Epithelia, and Immune Cells in the Intestine
Kayama, H., Okumura, R., & Takeda, K. (2020) · Annual Review of Immunology · doi:10.1146/annurev-immunol-070119-115104 · Cited by 784
Metadata
- Authors
- Metidji, A., Omenetti, S., Crotta, S., Li, Y., Nye, E., Ross, E., Li, V., Maradana, M. R., Schiering, C., & Stockinger, B.
- Affiliations
- The Francis Crick Institute (GB)
- University of London (GB)
- Corresponding author
- Schiering, Chris
- Stockinger, Brigitta
- ORCID
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2018-08
- Volume
- 49
- Issue
- 2
- Pages
- 353-362.e5
- ISSN
- 1074-7613 (ISSN-L)
- PMC
- PMC6104739
- OpenAlex
- W2887221348
- Cited by
- 402
- References
- 45
- Citations by year
- 2026: 37 · 2025: 50 · 2024: 56 · 2023: 63 · 2022: 55 · 2021: 60 · 2020: 50 · 2019: 30
- FWCI
- 12.45
- Type
- journal article
- Language
- en
- Update notices
- erratum (2019-06-18)
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Immunity (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- Cancer Research UK (FC001105, FC001159, 103156/B/13/Z, 19691)
- Fondation Acteria
- Medical Research Council
- Wellcome Trust (100910/Z/13/Z)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Health Sciences › Medicine › Gastroenterology › Inflammatory Bowel Disease
- Life Sciences › Immunology and Microbiology › Immunology › IL-33, ST2, and ILC Pathways
- Keywords
- aryl hydrocarbon receptor, intestinal stem cells, intestinal barrier integrity, intestinal homeostasis, intestinal inflammation, RNF43, ZNRF3, Wnt/β-catenin signaling, E3 ubiquitin ligase, stem cell niche, intestinal tumorigenesis
- MeSH terms
- Animals, Cell Differentiation, Cell Line, Enterobacteriaceae Infections, Epithelial Cells, Humans, Intestinal Mucosa, Mice, Inbred C57BL, Stem Cells, Receptors, Aryl Hydrocarbon, Mice, Knockout, Tight Junctions, Citrobacter rodentium, Ubiquitin-Protein Ligases, Cell Proliferation, Mice, Basic Helix-Loop-Helix Proteins, Basic Helix-Loop-Helix Transcription Factors, HEK293 Cells, Wnt Signaling Pathway, Carcinogenesis
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