| First Author | Swafford D | Year | 2020 |
| Journal | J Immunol | Volume | 205 |
| Issue | 8 | Pages | 2265-2275 |
| PubMed ID | 32917787 | Mgi Jnum | J:300376 |
| Mgi Id | MGI:6502454 | Doi | 10.4049/jimmunol.1901376 |
| Citation | Swafford D, et al. (2020) The Wnt-beta-Catenin-IL-10 Signaling Axis in Intestinal APCs Protects Mice from Colitis-Associated Colon Cancer in Response to Gut Microbiota. J Immunol 205(8):2265-2275 |
| abstractText | 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-beta-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 (LRP5/6(DeltaCD11c)) 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 LRP5/6(DeltaCD11c) 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 beta-catenin-IL-10 axis. Accordingly, conditional activation of beta-catenin specifically in CD11c(+) APCs or in vivo administration of IL-10 protected LRP5/6(DeltaCD11c) mice from CAC by suppressing the expression of inflammatory factors. In summary, in this study, we identify a key role for the LRP5/6-beta-catenin-IL-10 signaling pathway in intestinal APCs in resolving chronic intestinal inflammation and protecting against CAC in response to the commensal flora. |
