Canonical Wnt Signaling in Cd11c(+) Antigen Presenting Cells Controls Inflammation-Associated Colon Carcinogenesis and Commensal Homeostasis
JOURNAL OF IMMUNOLOGY(2017)
Abstract
Abstract The intestine contains high levels of the Wnt family of ligands, and the Wnt-signaling pathway is essential for intestinal homeostasis. Thus, aberrant Wnt/β-catenin-signaling may result in inflammatory bowel disease (IBD) and IBD-associated colon carcinogenesis. Although past studies have focused on this signaling pathway’s role in intestinal stem cell proliferation and epithelial cell maintenance, its role in shaping mucosal immune responses and commensal homeostasis in the gut remains unknown. In the present study, using a mouse model of colitis-associated colorectal cancer, we demonstrated that canonical Wnt-signaling in intestinal CD11c+ antigen presenting cells (APCs) controls intestinal inflammation and suppresses inflammation-driven colon carcinogenesis by imparting an anti-inflammatory phenotype. Genetic deletion of Wnt co-receptors, low-density lipoprotein receptor-related protein 5 and 6 (LRP5/6), in CD11c+ APCs in mice (LRP5/6ΔAPC mice) caused enhanced intestinal inflammation with increased tumor numbers in the colon due to increased production of pro-inflammatory cytokines and decreased expression of immune regulatory factors resulting from commensal dysbiosis. Mechanistically, loss of LRP5/6-mediated signaling in intestinal APCs resulted in enhanced effector T cell differentiation and decreased regulatory T cell differentiation. Furthermore, our study demonstrates that in LRP5/6ΔAPC mice conditional activation of β-catenin in intestinal APCs or in vivo blockade of IL-6 results in reduced intestinal inflammation with decreased colon tumor burden. These results reveal a mechanism by which intestinal APCs control gut inflammation and commensal homeostasis via canonical Wnt signaling.
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