TY - JOUR
T1 - The wnt–b-Catenin–IL-10 signaling axis in intestinal APCs protects mice from colitis-Associated colon cancer in response to gut microbiota
AU - Swafford, Daniel
AU - Shanmugam, Arul Kumaran
AU - Ranganathan, Punithavathi
AU - Manoharan, Indumathi
AU - Hussein, Mohamed S.
AU - Patel, Nikhil
AU - Sifuentes, Humberto
AU - Koni, Pandelakis
AU - Prasad, Puttur D.
AU - Thangaraju, Muthusamy
AU - Manicassamy, Santhakumar
N1 - Funding Information:
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.
Publisher Copyright:
Copyright © 2020 by The American Association of Immunologists, Inc.
PY - 2020/10/15
Y1 - 2020/10/15
N2 - 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.
AB - 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.
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U2 - 10.4049/jimmunol.1901376
DO - 10.4049/jimmunol.1901376
M3 - Article
C2 - 32917787
AN - SCOPUS:85092294849
VL - 205
SP - 2265
EP - 2275
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 8
ER -