Adhesive Interactions between Mononuclear Phagocytes and Intestinal Epithelium Perturb Normal Epithelial Differentiation and Serve as a Therapeutic Target in Inflammatory Bowel Disease
| Autor: | Kosuke Sakitani, Hayato Nakagawa, Nobumi Suzuki, Aya Yamashita, Keisuke Tateishi, Yoku Hayakawa, Masahiro Hata, Hiroto Kinoshita, Yohko Hikiba, Kazuhiko Koike, Mitsuru Konishi, Sozaburo Ihara, Mayo Tsuboi, Hideaki Ijichi, Yoshihiro Hirata |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Colon Biopsy CD11c Inflammatory bowel disease Gene Knockout Techniques Mice 03 medical and health sciences Cell Adhesion medicine Animals Humans Intestinal Mucosa Colitis Mononuclear Phagocyte System Mice Knockout Goblet cell Lamina propria business.industry Gastroenterology Antibodies Monoclonal hemic and immune systems General Medicine Mononuclear phagocyte system Cadherins Inflammatory Bowel Diseases medicine.disease Intestinal epithelium Ulcerative colitis Up-Regulation 030104 developmental biology medicine.anatomical_structure Cancer research business |
| Zdroj: | Journal of Crohn's and Colitis. |
| ISSN: | 1876-4479 1873-9946 |
| DOI: | 10.1093/ecco-jcc/jjy088 |
| Popis: | Background and aims Disturbance of intestinal homeostasis is associated with the development of inflammatory bowel disease [IBD], and TGF-β signalling impairment in mononuclear phagocytes [MPs] causes murine colitis with goblet cell depletion. Here, we examined an organoid-MP co-culture system to study the role of MPs in intestinal epithelial differentiation and homeostasis. Methods Intestinal organoids were co-cultured with lamina propria leukocytes and bone marrow-derived dendritic cells [BMDCs] from CD11c-cre Tgfbr2fl/fl mice. Organoid-MP adhesive interactions were evaluated by microscopy, RT-PCR, and flow cytometry. Murine colitis models (dextran sodium sulphate [DSS], CD11c-cre Tgfbr2fl/fl, T-cell-transfer) were used for histological and immunohistochemical analysis. Anti-E-cadherin antibody treatment or CD11c+-cell-specific CDH1 gene deletion were performed for E-cadherin neutralization or knockout. Colonic biopsies from patients with ulcerative colitis were analysed by flow cytometry. Results Intestinal organoids co-cultured with CD11c+ lamina propria leukocytes or BMDCs from CD11c-cre Tgfbr2fl/fl mice showed morphological changes and goblet cell depletion with Notch signal activation, analogous to CD11c-cre Tgfbr2fl/fl colitis. E-cadherin was upregulated in CD11c+ MPs, especially CX3CR1+CCR2+ monocytes, of CD11c-cre Tgfbr2fl/fl mice. E-cadherin-mediated BMDC adhesion promoted Notch activation and cystic changes in organoids. Anti-E-cadherin antibody treatment attenuated colitis in CD11c-cre Tgfbr2fl/fl and T-cell-transferred mice. In addition, E-cadherin deletion in CD11c+ cells attenuated colitis in both CD11c-cre Tgfbr2fl/fl and DSS-treated mice. In patients with ulcerative colitis, E-cadherin expressed by intestinal CD11c+ leukocytes was enhanced compared with that in healthy controls. Conclusions E-cadherin-mediated MP-epithelium adhesion is associated with the development of colitis, and blocking these adhesions may have therapeutic potential for IBD. |
| Databáze: | OpenAIRE |
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