Adhesive Interactions between Mononuclear Phagocytes and Intestinal Epithelium Perturb Normal Epithelial Differentiation and Serve as a Therapeutic Target in Inflammatory Bowel Disease
Adhesive Interactions between Mononuclear Phagocytes and Intestinal Epithelium Perturb Normal Epithelial Differentiation and Serve as a Therapeutic Target in Inflammatory Bowel Disease
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DOI：
10.1093/ecco-jcc/jjy088
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发表时间：
2018-10-01
影响因子：
8
通讯作者：
Koike, Kazuhiko
中科院分区：
文献类型：
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作者：
Ihara, Sozaburo;Hirata, Yoshihiro;Koike, Kazuhiko
背景和目的：肠道内稳态紊乱与炎症性肠病（IBD）的发生有关，单核吞噬细胞（MPs）中tgf - β信号通路损伤可导致小鼠结肠炎伴杯状细胞耗损。在这里，我们研究了一个类器官- MPs共培养系统，以研究MPs在肠上皮分化和稳态中的作用。方法：将肠道类器官与CD11c-cre Tgfbr2（fl/fl）小鼠固有层白细胞和骨髓来源树突状细胞（bmdc）共培养。通过显微镜、RT-PCR和流式细胞术评估类器官- mp粘附相互作用。采用小鼠结肠炎模型（葡聚糖硫酸钠[DSS]、CD11c-cre、Tgfbr2（fl/fl）、t细胞转移）进行组织学和免疫组织化学分析。通过抗E-cadherin抗体治疗或CD11c（+）细胞特异性CDH1基因缺失来中和或敲除E-cadherin。用流式细胞术分析溃疡性结肠炎患者的结肠活检。结果：与CD11c-cre Tgfbr2（fl/fl）小鼠的CD11c（+）固有层白细胞或BMDCs共培养的肠道类器官出现形态改变和杯状细胞消耗，伴有Notch信号激活，类似于CD11c-cre Tgfbr2（fl/fl）结肠炎。E-cadherin在CD11c-cre Tgfbr2（fl/fl）小鼠的CD11c(+) MPs中表达上调，尤其是CX(3)CR1(+)CCR2（+）单核细胞。e -cadherin介导的BMDC粘附促进Notch激活和类器官囊性改变。抗e -cadherin抗体治疗CD11c-cre Tgfbr2（fl/fl）和t细胞转移小鼠的减毒结肠炎。此外，CD11c（+）细胞中的E-cadherin缺失减轻了CD11c-cre Tgfbr2（fl/fl）和dss处理小鼠的结肠炎。溃疡性结肠炎患者肠道CD11c（+）白细胞表达的E-cadherin较健康对照增强。结论：e -钙粘蛋白介导的mp -上皮粘连与结肠炎的发展有关，阻断这些粘连可能具有治疗IBD的潜力。
Background and Aims: Disturbance of intestinal homeostasis is associated with the development of inflammatory bowel disease [IBD], and TGF-beta 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 Tgfbr2(fl/fl) mice. Organoid-MP adhesive interactions were evaluated by microscopy, RT-PCR, and flow cytometry. Murine colitis models (dextran sodium sulphate [DSS], CD11c-cre Tgfbr2(fl/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 Tgfbr2(fl/fl) mice showed morphological changes and goblet cell depletion with Notch signal activation, analogous to CD11c-cre Tgfbr2(fl/fl) colitis. E-cadherin was upregulated in CD11c(+) MPs, especially CX(3)CR1(+)CCR2(+) monocytes, of CD11c-cre Tgfbr2(fl/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 Tgfbr2(fl/fl) and T-cell-transferred mice. In addition, E-cadherin deletion in CD11c(+) cells attenuated colitis in both CD11c-cre Tgfbr2(fl/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.