Georgia Cancer Center, Augusta University, Augusta, GA 30912.
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912; and.
J Immunol. 2018 May 1;200(9):3259-3268. doi: 10.4049/jimmunol.1701086. Epub 2018 Mar 30.
Aberrant Wnt/β-catenin signaling occurs in several inflammatory diseases, including inflammatory bowel disease and inflammatory bowel disease-associated colon carcinogenesis. However, its role in shaping mucosal immune responses to commensals in the gut remains unknown. In this study, we investigated the importance of canonical Wnt signaling in CD11c APCs in controlling intestinal inflammation. Using a mouse model of ulcerative colitis, we demonstrated that canonical Wnt signaling in intestinal CD11c APCs controls intestinal inflammation by imparting an anti-inflammatory phenotype. Genetic deletion of Wnt coreceptors, low-density lipoprotein receptor-related proteins 5 and 6 (LRP5/6) in CD11c APCs in LRP5/6 mice, resulted in enhanced intestinal inflammation with increased histopathological severity of colonic tissue. This was due to microbiota-dependent increased production of proinflammatory cytokines and decreased expression of immune-regulatory factors such as IL-10, retinoic acid, and IDO. Mechanistically, loss of LRP5/6-mediated signaling in CD11c APCs resulted in altered microflora and T cell homeostasis. Furthermore, our study demonstrates that conditional activation of β-catenin in CD11c APCs in LRP5/6 mice resulted in reduced intestinal inflammation with decreased histopathological severity of colonic tissue. These results reveal a mechanism by which intestinal APCs control intestinal inflammation and immune homeostasis via the canonical Wnt-signaling pathway.
异常的 Wnt/β-catenin 信号通路存在于几种炎症性疾病中，包括炎症性肠病和炎症性肠病相关的结肠癌发生。然而，其在塑造肠道共生体黏膜免疫反应中的作用尚不清楚。在这项研究中，我们研究了经典 Wnt 信号通路在肠道 CD11c APCs 中对控制肠道炎症的重要性。我们使用溃疡性结肠炎的小鼠模型表明，肠道 CD11c APCs 中的经典 Wnt 信号通路通过赋予抗炎表型来控制肠道炎症。在 LRP5/6 小鼠中，CD11c APCs 中 Wnt 核心受体低密度脂蛋白受体相关蛋白 5 和 6（LRP5/6）的基因缺失导致肠道炎症增强，结肠组织的组织病理学严重程度增加。这是由于依赖于微生物群的促炎细胞因子产生增加和免疫调节因子如 IL-10、视黄酸和 IDO 的表达减少所致。在机制上，CD11c APCs 中 LRP5/6 介导的信号缺失导致微生物群和 T 细胞稳态发生改变。此外，我们的研究表明，在 LRP5/6 小鼠中 CD11c APCs 中β-catenin 的条件激活导致肠道炎症减少，结肠组织的组织病理学严重程度降低。这些结果揭示了肠道 APCs 通过经典 Wnt 信号通路控制肠道炎症和免疫稳态的机制。
