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Targeted Epithelial Tight Junction Dysfunction Causes Immune Activation and Contributes to Development of Experimental Colitis
Open accessAbstract
Background & aims Inflammatory bowel disease (IBD) is a multifactorial disease thought to be caused by alterations in epithelial function, innate and adaptive immunity, and luminal microbiota. The specific role of epithelial barrier function remains undefined, although increased activity of intestinal epithelial myosin light chain kinase (MLCK), which is the primary mechanism of tumor necrosis factor-induced barrier dysfunction, occurs in human IBD. Our aim was to determine whether, in an intact epithelium, primary dysregulation of the intestinal epithelial barrier by pathophysiologically relevant mechanisms can contribute to development of colitis.Methods We developed transgenic (Tg) mice that express constitutively active MLCK (CA-MLCK) specifically within intestinal epithelia. Their physiology, immune status, and susceptibility to disease were assessed and compared with non-Tg littermate controls.Results CA-MLCK Tg mice demonstrated significant barrier loss but grew and gained weight normally and did not develop spontaneous disease. CA-MLCK Tg mice did, however, develop mucosal immune activation demonstrated by increased numbers of lamina propria CD4(+)lymphocytes, redistribution of CD11c+cells, increased production of interferon-gamma and tumor necrosis factor, as well as increased expression of epithelial major histocompatibility complex class I. When challenged with CD4+CD45+Rb(hi) lymphocytes, Tg mice developed an accelerated and more severe form of colitis and had shorter survival times than non-Tg littermates.Conclusions Primary pathophysiologically relevant intestinal epithelial barrier dysfunction is insufficient to cause experimental intestinal disease but can broadly activate mucosal immune responses and accelerate the onset and severity of immune-mediated colitis.
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“The leak pathway is believed to be regulated by myosin light-chain kinase (MLCK), where constitutively active MLCK is sufficient to increase the leak pathway–dependent permeability both in vitro and in vivo.52,53”
From Regulation of Intestinal Barrier Function by Microbial Metabolites (2021) · cites this paper as [53]
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Metadata
- Authors
- Su, L., Shen, L., Clayburgh, D. R., Nalle, S. C., Sullivan, E. A., Meddings, J. B., Abraham, C., & Turner, J. R.
- Affiliations
- University of Chicago (US)
- University of Alberta (CA)
- Yale University (US)
- Corresponding author
- Abraham, Clara
- Turner, Jerrold R.
- ORCID
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2009-02
- Volume
- 136
- Issue
- 2
- Pages
- 551-563
- ISSN
- 0016-5085 (ISSN-L)
- PMC
- PMC2712351
- OpenAlex
- W2131810438
- Cited by
- 455
- References
- 41
- Citations by year
- 2026: 17 · 2025: 17 · 2024: 21 · 2023: 20 · 2022: 29 · 2021: 32 · 2020: 30 · 2019: 19 · 2018: 18 · 2017: 34 · 2016: 29 · 2015: 35 · 2014: 23 · 2013: 23 · 2012: 38
- FWCI
- 12.94
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (T32HL007237)
- National Cancer Institute (P30CA014599)
- National Institute of General Medical Sciences (T32GM007281)
- National Institute of Diabetes and Digestive and Kidney Diseases (P01DK067887, R56DK094954, R01DK077905, R01DK058964, R01DK068271, R01DK061931)
- Topics
- Health Sciences › Medicine › Gastroenterology › Inflammatory Bowel Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Keywords
- intestinal epithelial barrier dysfunction, tight junctions, myosin light chain kinase, transgenic mice, experimental colitis, inflammatory bowel disease, mucosal immune activation, interferon-gamma, TNF-α, MHC class I expression, disease susceptibility
- MeSH terms
- Animals, Cell Membrane Permeability, Colitis, Disease Models, Animal, Epithelial Cells, Immunity, Innate, Interferon-gamma, Major Histocompatibility Complex, Mice, Transgenic, Mucous Membrane, Myosin-Light-Chain Kinase, Severity of Illness Index, Tumor Necrosis Factor-alpha, CD4-Positive T-Lymphocytes, Tight Junctions, Mice
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