Heazlewood, Chad; Cook, Matthew; Rajaraman, Eri; Price, Gareth; Tauro, Sharyn; Taupin, Doug; Thornton, David; Png, Chin Wen; Crockford, Tanya; Cornall, Richard J.; Adams, Rachel; Kato, Masato; Nelms, Keats; Hong, Nancy A.; Florin, Timothy H. J.; Goodnow, Christopher; McGuckin, Michael A.
Description
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...[Show more] 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-1b, TNF-a, and IFN-c 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-c, TNF-a, 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.
The Editors’ Summary of this article follows the references.
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