The wnt–b-Catenin–IL-10 signaling axis in intestinal APCs protects mice from colitis-Associated colon cancer in response to gut microbiota

Daniel Swafford, Arulkumaran Shanmugam, Punithavathi Ranganathan, Indumathi Manoharan, Mohamed S. Hussein, Nikhil Patel, Humberto Sifuentes, Pandelakis A. Koni, Puttur D. Prasad, Muthusamy Thangaraju, Santhakumar Manicassamy

Research output: Contribution to journalArticlepeer-review

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–b-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 (LRP5/6DCD11c) 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 LRP5/6DCD11c 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 b-catenin–IL-10 axis. Accordingly, conditional activation of b-catenin specifically in CD11c+ APCs or in vivo administration of IL-10 protected LRP5/6DCD11c mice from CAC by suppressing the expression of inflammatory factors. In summary, in this study, we identify a key role for the LRP5/6–b-catenin–IL-10 signaling pathway in intestinal APCs in resolving chronic intestinal inflammation and protecting against CAC in response to the commensal flora. The Journal of Immunology, 2020, 205: 2265–2275.

Original languageEnglish (US)
Pages (from-to)2265-2275
Number of pages11
JournalJournal of Immunology
Volume205
Issue number8
DOIs
StatePublished - Oct 15 2020

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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