Endogenous Prion Protein Attenuates Experimentally Induced Colitis

Although the cellular prion protein (PrPC) is expressed in the enteric nervous system and lamina propria, its function(s) in the gut is unknown. Because PrPC may exert a cytoprotective effect in response to various physiologic stressors, we hypothesized that PrPC expression levels might modulate the severity of experimental colitis. We evaluated the course of dextran sodium sulfate (DSS)-induced colitis in hemizygous Tga20 transgenic mice (approximately sevenfold overexpression of PrPC), Prnp(-/-) mice, and wild-type mice. On day 7, colon length, disease severity, and histologic activity indices were determined. Unlike DSS-treated wild-type and Prnp(-/-) animals, PrPC overexpressing mice were resistant to colitis induction, exhibited much milder histopathologic features, and did not exhibit weight loss or colonic shortening. In keeping with these results, pro-survival molecule expression and/or phosphorylation levels were elevated in DSS-treated Tga20 mice, whereas pro-inflammatory cytokine production and pSTAT3 levels were reduced. In contrast, DSS-treated Prnp(-/-) mice exhibited increased BAD protein expression and a cytokine expression profile predicted to favor inflammation and differentiation. PrPC expression from both the endogenous Prnp locus or the Tga20 transgene was increased in the colons of DSS-treated mice. Considered together, these findings demonstrate that PrPC has a previously unrecognized cytoprotective and/or anti-inflammatory function within the murine colon. (Am J Pathol 2011, 170:2290-2301; DOI: 10.1016/j.ajpath.2011.07.025)