Aberrant Mucin Assembly in Mice Causes Endoplasmic Reticulum Stress and Spontaneous Inflammation Resembling Ulcerative Colitis
By Chad K. Heazlewood, M. Cook, R. Eri, G. Price, S. Tauro, D. Taupin, D. Thornton, C. Png, T. Crockford, R. Cornall and 7 more. PLoS Medicine, 2008
732 citations recorded by the source corpus.
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.
Subfields: Genetics, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/6f53f3334fcb65c62fe61c1504a32fb9a6b9fdd4
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- Bifidobacteria or fiber protect against diet-induced microbiota-mediated colonic mucus deterioration (2017, background): “Accordingly, structural defects or complete absence of the mucus layer can cause severe colitis in mice (Fu et al., 2011; Heazlewood et al., 2008; Johansson et al., 2008).”
- New developments in goblet cell mucus secretion and function (2015, unknown): “Single mutations in mouse Muc2 can cause endoplasmic reticulum accumulation that triggers a UPR response and increased levels of inflammatory cytokines.(65,66) Higher quantitative demands for MUC2 synthesis, such as an increased bacterial load in contact with the epithelium, will further challenge t”
- Negative Effects of a High-Fat Diet on Intestinal Permeability: A Review. (2019, background): “In this setting, the destruction of the mucus layer correlated directly to gut barrier dysfunction, assessed by enhanced endotoxemia, either as a result of diminished TJ protein expression, increased TJ protein misfolding, or inflammation (64, 125).”
- The two mucus layers of colon are organized by the MUC2 mucin, whereas the outer layer is a legislator of host–microbial interactions (2010, background): “Finally, it has also been observed that several mouse strains with mutations causing a dysfunctional Muc2 mucin show a strong unfolded response (31).”
- Muc2 Protects against Lethal Infectious Colitis by Disassociating Pathogenic and Commensal Bacteria from the Colonic Mucosa (2010, background): “Although the exact mechanisms that lead to these intestinal disorders are still elusive, deficiency in mucus production appears to alter the normal localization of commensal microbiota within the colon [27] as well as disrupt the mechanisms that govern epithelial [28,30,31] and immune homeostasis [2”
- Mucins in cancer: function, prognosis and therapy (2009, background): “In support of a crucial role for MUC2, mice deficient in MUC2 spontaneously develop inflammation of the colon and superficial erosions consistent with ulcerative coliti”
- Intestinal mucosal barrier function in health and disease (2009, background): “Defective mucus production has also been reported in various immune-mediated diseases, and spontaneous colitis develops in mice that lack specific mucin gene”
- Endoplasmic Reticulum Stress and Oxidative Stress in Cell Fate Decision and Human Disease (2014, background): “Mice that express a misfolding-prone mutant of MUC2 mucin, the major mucin in the large intestine, displayed ER stress, goblet cell dysfunction, and spontaneous colitis (73).”
- The mucus and mucins of the goblet cells and enterocytes provide the first defense line of the gastrointestinal tract and interact with the immune system (2014, unknown): “This stress placed on the ER is probably also the reason for the relationship between ER stress, the unfolded protein response and colonic inflammation, something that has been discussed in detail elsewhere (20, 70, 71).”