The Wnt-β-catenin-IL-10 signaling axis in intestinal antigen-presenting cells protects mice from colitis-associated colon cancer in response to gut microbiota

Abstract

Abstract Loss of immune tolerance to gut microflora is inextricably linked to inflammatory bowel disease (IBD) and colitis-associated colon cancer (CAC). Intestinal antigen presenting cells (APCs) play a pivotal role in regulating intestinal inflammation and CAC, but underlying signaling pathways and molecular mechanisms remain largely unknown. In the present study, using a mouse model of CAC, we show that the low-density lipoprotein receptor-related proteins 5 and 6 (LRP5/6)-β-catenin-IL-10 signaling axis in CD11c+ APCs suppresses CAC by regulating the expression of tumor-promoting inflammatory factors in response to commensal flora. Genetic deletion of Wnt co-receptors LRP5/6 in CD11c+ APCs in mice (LRP5/6ΔCD11c) resulted in enhanced susceptibility to CAC. This is due to a microbiota-dependent increased expression of tumor-promoting pro-inflammatory factors and decreased expression of the immunosuppressive cytokine, IL-10. This condition could be improved in LRP5/6ΔCD11c mice by depleting the gut flora, indicating the importance of LRP5/6 in mediating immune tolerance to the gut flora. Moreover, mechanistic studies show that LRP5/6 suppresses the expression of tumor promoting inflammatory factors in CD11c+ APCs via the β-catenin-IL-10 axis. Accordingly, conditional activation of β-catenin in CD11c+ APCs or in vivo administration of IL-10 in LRP5/6ΔCD11c mice markedly reduced intestinal inflammation and CAC by suppressing the expression of inflammatory factors. In summary, here we identify a key role for the LRP5/6-β-catenin-IL-10 signaling pathway in intestinal APCs in regulating CAC in response to the commensal flora and suggest potential means for therapeutic intervention in inflammatory intestinal diseases.