PTEN Inactivation in Mouse Colonic Epithelial Cells Curtails DSS-Induced Colitis and Accelerates Recovery

Background: PTEN is a tumor suppressor that controls many pathophysiological pathways, including cell proliferation, differentiation, apoptosis and invasiveness. Although PTEN down-modulation is a critical event in neoplastic progression, it becomes apparent that transient and local inhibition of PTEN activity might be beneficial for the healing process. Methods: In the present study, we investigated the impact of PTEN invalidation in mouse intestinal epithelium under a physiological condition and after dextran sulfate sodium (DSS) treatment to induce experimental colitis. PTEN conditional knockout was induced in intestinal epithelial cells after crossing villin-Cre and PTEN^flox/flox mice. Results: PTEN invalidation alleviates experimental colitis induced by DSS, as evidenced by decreased weight loss during the acute phase, the lower expression of inflammation markers, including the proinflammatory cytokines IFN-γ, CXCL1 and CXCL2, reduced mucosal lesions, and faster recovery after resolution of inflammation. This protective effect might result in part from the sustained proliferation of colonic epithelium, leading to hyperplasia and increased colonic crypt depth under physiological conditions, which was further exacerbated in the vicinity of mucosal injury induced by DSS treatment. Furthermore, PTEN knockout decreased paracellular permeability, thereby enhancing the intestinal barrier function. This process was associated with the reinforcement of claudin-3 immunostaining, especially on the surface epithelium of villin-Cre PTEN^flox/flox mice. Conclusions: PTEN inactivation exerts a protective effect on the onset of colitis, and the transient and local down-modulation of PTEN might constitute an approach to drive recovery following acute intestinal inflammation.