Cellular prion protein suppresses colitis and colorectal carcinogenesis via modulating inflammatory responses.

Reducing prion protein (PrP) levels is a leading therapeutic strategy against prion disease. However, the normal function of PrP remains incompletely understood, creating uncertainty about the potential consequences of this approach. We investigated the role of PrP on intestinal tumorigenesis using the ApcMin/+ familial adenomatous polyposis model and the Azoxymethane/Dextran Sodium Sulfate (AOM/DSS) induced colitis-associated colorectal cancer model. In Prnp-/- background, both tumor burden and survival rates of ApcMin/+ mice were significantly improved; in contrast, the absence of PrP significantly intensified AOM/DSS-induced carcinogenesis. PrP's capability to promote cell proliferation accounts for the findings in ApcMin/+ mice, but it cannot explain the substantial increase in carcinogenesis in AOM/DSS model. We found that AOM/DSS-treated Prnp-/- mice had elevated numbers of pro-inflammatory M1 macrophages, which transitioned to an antigen-presenting state, thereby prolonging the inflammatory response. In bone marrow-derived macrophages (BMDMs), the absence of PrP resulted in delayed but sustained NFκB nuclear localization, leading to an extended inflammatory response to lipopolysaccharide (LPS). The exacerbated chronic inflammatory response in Prnp-/- mice was further corroborated by LPS-induced colitis, which resulted in more severe diarrhea, higher levels of pro-inflammatory cytokine expression, and increased infiltration of CD4+ cell during the later phases of inflammation. Our results indicate that PrP deletion delays and extends the inflammatory response, resulting in severer colitis and associated colorectal carcinogenesis. These findings raise the potential implication that monitoring for chronic inflammation may be warranted in patients undergoing PrP-reduction therapy.