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Aberrant mucin assembly in mice causes endoplasmic reticulum stress and spontaneous inflammation resembling ulcerative colitis
Heazlewood, Chad K., Cook, Matthew C., Eri, Rajaraman, Price, Gareth R., Tauro, Sharyn B., Taupin, Douglas, Thornton, David J., Png, Chin Wen, Crockford, Tanya L., Cornall, Richard J., Adams, Rachel, Kato, Masato, Nelms, Keats A., Hong, Nancy A., Florin, Timothy H. J., Goodnow, Christopher C. and McGuckin, Michael A. (2008-03) Aberrant mucin assembly in mice causes endoplasmic reticulum stress and spontaneous inflammation resembling ulcerative colitis. PLoS Medicine, 5 3: 440-460.
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| Author(s) |
Heazlewood, Chad K.
Cook, Matthew C.
Eri, Rajaraman
Price, Gareth R.
Tauro, Sharyn B.
Taupin, Douglas
Thornton, David J.
Png, Chin Wen
Crockford, Tanya L.
Cornall, Richard J.
Adams, Rachel
Kato, Masato
Nelms, Keats A.
Hong, Nancy A.
Florin, Timothy H. J.
Goodnow, Christopher C.
McGuckin, Michael A.
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| Title |
Aberrant mucin assembly in mice causes endoplasmic reticulum stress and spontaneous inflammation resembling ulcerative colitis
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| Journal name |
PLoS Medicine
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| Publication date |
2008-03
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| Volume number |
5
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| Issue number |
3
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| ISSN |
1549-1277
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| Start page |
440
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| End page |
460
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| Total pages |
21
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| Editor(s) |
Stefan Schreiber
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| Place of publication |
San Francisco, CA, USA
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| Publisher |
Public Library Science
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| Collection year |
2009
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| Language |
eng
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| Subject |
C1
970111 Expanding Knowledge in the Medical and Health Sciences
970106 Expanding Knowledge in the Biological Sciences
060403 Developmental Genetics (incl. Sex Determination)
110706 Immunogenetics (incl. Genetic Immunology)
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| Formatted abstract |
Background
MUC2 mucin produced by intestinal goblet cells is the major component of the intestinal mucus barrier. The inflammatory bowel disease ulcerative colitis is characterized by depleted goblet cells and a reduced mucus layer, but the aetiology remains obscure. In this study we used random mutagenesis to produce two murine models of inflammatory bowel disease, characterised the basis and nature of the inflammation in these mice, and compared the pathology with human ulcerative colitis.
Methods and Findings
By murine N-ethyl-N-nitrosourea mutagenesis we identified two distinct noncomplementing missense mutations in Muc2 causing an ulcerative colitis-like phenotype. 100% of mice of both strains developed mild spontaneous distal intestinal inflammation by 6 wk (histological colitis scores versus wild-type mice, p < 0.01) and chronic diarrhoea. Monitoring over 300 mice of each strain demonstrated that 25% and 40% of each strain, respectively, developed severe clinical signs of colitis by age 1 y. Mutant mice showed aberrant Muc2 biosynthesis, less stored mucin in goblet cells, a diminished mucus barrier, and increased susceptibility to colitis induced by a luminal toxin. Enhanced local production of IL-1β, TNF-α, and IFN-γ was seen in the distal colon, and intestinal permeability increased 2-fold. The number of leukocytes within mesenteric lymph nodes increased 5-fold and leukocytes cultured in vitro produced more Th1 and Th2 cytokines (IFN-γ, TNF-α, and IL-13). This pathology was accompanied by accumulation of the Muc2 precursor and ultrastructural and biochemical evidence of endoplasmic reticulum (ER) stress in goblet cells, activation of the unfolded protein response, and altered intestinal expression of genes involved in ER stress, inflammation, apoptosis, and wound repair. Expression of mutated Muc2 oligomerisation domains in vitro demonstrated that aberrant Muc2 oligomerisation underlies the ER stress. In human ulcerative colitis we demonstrate similar accumulation of nonglycosylated MUC2 precursor in goblet cells together with ultrastructural and biochemical evidence of ER stress even in noninflamed intestinal tissue. Although our study demonstrates that mucin misfolding and ER stress initiate colitis in mice, it does not ascertain the genetic or environmental drivers of ER stress in human colitis.
Conclusions
Characterisation of the mouse models we created and comparison with human disease suggest that ER stress-related mucin depletion could be a fundamental component of the pathogenesis of human colitis and that clinical studies combining genetics, ER stress-related pathology and relevant environmental epidemiology are warranted.
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| Keyword(s) |
Tumor-necrosis-factor
Factor-kappa-b
Unfolded Protein Response
Bowel-disease patients
Human Colonic Mucin
NK-T-Cells
Crohns-disease
Epithelial-cells
Monozygotic Twins
Core Protein
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