Adhesive Interactions between Mononuclear Phagocytes and Intestinal Epithelium Perturb Normal Epithelial Differentiation and Serve as a Therapeutic Target in Inflammatory Bowel Disease.
J Crohns Colitis
; 12(10): 1219-1231, 2018 Nov 09.
Article
en En
| MEDLINE
| ID: mdl-29917067
ABSTRACT
BACKGROUND AND AIMS:
Disturbance of intestinal homeostasis is associated with the development of inflammatory bowel disease [IBD], and TGF-ß 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.
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Sistema Mononuclear Fagocítico
/
Enfermedades Inflamatorias del Intestino
/
Cadherinas
/
Adhesión Celular
Idioma:
En
Revista:
J Crohns Colitis
Asunto de la revista:
GASTROENTEROLOGIA
Año:
2018
Tipo del documento:
Article