Canonical Wnt Signaling in CD11c+ APCs Regulates Microbiota-Induced Inflammation and Immune Cell Homeostasis in the Colon

Abstract

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.

Downregulation of Dickkopf-1 Augments the Therapeutic Effects of Endometrial Regenerative Cells on Experimental Colitis

“…Wnt/β-catenin signaling was recorded with anti-in ammatory effects in the development of ulcer colitis [35]. As previous studies described, with the activating of canonical Wnt signaling, β-catenin would accumulate in cytoplasm and regulates the expressions of Wnt-related genes [65].…”

“…Proved by previous reports, Wnt/β-catenin pathway is involved in regulating cell differentiation, embryonic development, tissue regeneration and other important physiological processes [32,33]. However in recent years, accumulating researches have revealed its another important role which was associated with the immunoregulatory porperties in various immune-related in ammations and auto-immune diseases, comprising cancer, rheumatoid arthritis, enteritis and so on [34][35][36]. Wnt/β-catenin pathway is partcipating in regulating the development and differentiation of immunocytes [30] and exhibiting encouraging and promising anti-in ammatory effects in chronic disease, such as in ammatory bowel disease [37][38][39].…”

Molecular Aspects of Colorectal Adenomas: The Interplay among Microenvironment, Oxidative Stress, and Predisposition

“…In animal models of colon carcinogenesis, the use of nonsteroidal anti-inflammatory drugs (NSAIDs) can inhibit antigen-presenting cells and control intestinal inflammation and intestinal immune homeostasis via the canonical signal Wnt [100]. In fact, commensal-polarized macrophages induce gene mutation, chromosomal instability, and endogenous transformation through microbiome-induced bystander effects (MIBE) that activate Wnt/β-catenin signaling [101].…”

Glucocorticoid receptor modulators CpdX and CpdX-D3 exhibit the same in vivo antiinflammatory activities as synthetic glucocorticoids

“…4C). It has been shown that the expression of Wnt ligands was increased in several colitis mouse models (18,19), and also that the Wnt−β-catenin signaling is pivotal for homeostasis of the intestinal epithelium by promoting stem cell renewal (20). In keeping with these data, the expression of WNT ligands, WNT2, WNT2B, and WNT4, was drastically increased in colon samples treated with DSS, whereas it was significantly decreased upon a treatment with either Dex, CpdX, CpdX(eA), CpdX(eB), CpdX-D3, CpdX-D3(eA), or CpdX-D3(eB) (Fig.…”