Loss of intestinal core 1–derived O-glycans causes spontaneous colitis in mice
| Autor: | Maomeng Tong, Malin E. V. Johansson, Thomas J. Sferra, Jerrold R. Turner, Hong Chen, Xiaowei Liu, Kristina A. Thomsson, Samuel McGee, Bo Wei, Jonathan Braun, Lijun Xia, Tao Wen, Lilah Mansour, Gunnar C. Hansson, Emily M. Bradford, Jianxin Fu, J. Michael McDaniel |
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| Rok vydání: | 2011 |
| Předmět: |
Mice
129 Strain Myeloid Colon Mice Transgenic Biology Mice Intestinal mucosa Polysaccharides medicine Animals Humans Antigens Tumor-Associated Carbohydrate Intestinal Mucosa Colitis DNA Primers Inner mucus layer Mice Knockout Base Sequence Mucin General Medicine Galactosyltransferases medicine.disease Ulcerative colitis Molecular biology Gut Epithelium Mice Inbred C57BL Disease Models Animal medicine.anatomical_structure Mutation Immunology Crypt Abscess Research Article Molecular Chaperones |
| Zdroj: | Journal of Clinical Investigation. 121:1657-1666 |
| ISSN: | 0021-9738 |
| Popis: | Mucin-type O-linked oligosaccharides (O-glycans) are primary components of the intestinal mucins that form the mucus gel layer overlying the gut epithelium. Impaired expression of intestinal O-glycans has been observed in patients with ulcerative colitis (UC), but its role in the etiology of this disease is unknown. Here, we report that mice with intestinal epithelial cell-specific deficiency of core 1-derived O-glycans, the predominant form of O-glycans, developed spontaneous colitis that resembled human UC, including massive myeloid infiltrates and crypt abscesses. The colitis manifested in these mice was also characterized by TNF-producing myeloid infiltrates in colon mucosa in the absence of lymphocytes, supporting an essential role for myeloid cells in colitis initiation. Furthermore, induced deletion of intestinal core 1-derived O-glycans caused spontaneous colitis in adult mice. These data indicate a causal role for the loss of core 1-derived O-glycans in colitis. Finally, we detected a biosynthetic intermediate typically exposed in the absence of core 1 O-glycan, Tn antigen, in the colon epithelium of a subset of UC patients. Somatic mutations in the X-linked gene that encodes core 1 β1,3-galactosyltransferase-specific chaperone 1 (C1GALT1C1, also known as Cosmc), which is essential for core 1 O-glycosylation, were found in Tn-positive epithelia. These data suggest what we believe to be a new molecular mechanism for the pathogenesis of UC. |
| Databáze: | OpenAIRE |
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