Key Points
The canonical Wnt pathway in intestinal APCs protects against CAC.
LRP5/6–β-catenin–IL-10 signaling in APCs suppresses chronic intestinal inflammation.
This pathway plays an important role in regulating intestinal commensal homeostasis.
Abstract
Loss of immune tolerance to gut microflora is inextricably linked to chronic intestinal inflammation and colitis-associated colorectal cancer (CAC). The LRP5/6 signaling cascade in APCs contributes to immune homeostasis in the gut, but whether this pathway in APCs protects against CAC is not known. In the current study, using a mouse model of CAC, we show that the LRP5/6–β-catenin–IL-10 signaling axis in intestinal CD11c+ APCs protects mice from CAC by regulating the expression of tumor-promoting inflammatory factors in response to commensal flora. Genetic deletion of 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 proinflammatory 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 specifically in CD11c+ APCs or in vivo administration of IL-10 protected LRP5/6ΔCD11c mice from CAC by suppressing the expression of inflammatory factors. In summary, in this study, we identify a key role for the LRP5/6–β-catenin–IL-10 signaling pathway in intestinal APCs in resolving chronic intestinal inflammation and protecting against CAC in response to the commensal flora.
Footnotes
This work was supported by National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases Awards DK097271 and DK123360 and Augusta University Awards IGPB0003 and ESA00041 to S.M.
The online version of this article contains supplemental material.
Abbreviations used in this article:
- AOM
- azoxymethane
- AU
- Augusta University
- CAC
- colitis-associated CRC
- CA-βcat
- constitutively active β-catenin
- CD
- Crohn's disease
- CRC
- colorectal cancer
- DC
- dendritic cell
- DN-βcat
- dominant-negative β-catenin
- DSS
- dextran sodium sulfate
- FMT
- fecal microbiota transplantation
- IBD
- inflammatory bowel disease
- LP
- lamina propria
- qPCR
- quantitative PCR
- SFB
- segmented filamentous bacteria
- SOCS
- suppressor of cytokine signaling
- Tr1
- type 1 Treg
- Treg
- regulatory T cell
- UC
- ulcerative colitis
- WT
- wild type.
- Received November 18, 2019.
- Accepted August 17, 2020.
- Copyright © 2020 by The American Association of Immunologists, Inc.
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