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

TL;DR

Disabling PTEN in mouse intestinal cells reduces colitis severity and speeds up recovery by boosting cell growth and strengthening the gut barrier.

Contribution

This study reveals that PTEN inactivation in intestinal epithelial cells protects against colitis and promotes healing.

Findings

PTEN invalidation in intestinal cells reduces DSS-induced colitis symptoms and weight loss.

PTEN knockout enhances intestinal barrier function by strengthening tight junctions and reducing permeability.

Sustained epithelial cell proliferation due to PTEN inactivation aids in mucosal repair after injury.

Abstract

The PTEN tumor suppressor controls a broad range of cellular functions, including cell proliferation, differentiation, migration and apoptosis. The purpose of our study was to delineate the physiopathological role of PTEN in intestinal homeostasis and in susceptibility to colitis. Using a transgenic mouse model, we showed that PTEN invalidation in intestinal epithelium promotes cell proliferation and triggers colonic mucosa hyperplasia. We also evidenced that this invalidation alleviates chemically induced colitis. The underlying mechanisms involved a sustained colonic epithelial cell proliferation in the vicinity of mucosal lesions, favoring re-epithelization, and the enhancement of intestinal barrier function through the strengthening of tight junctions and the reduction of paracellular permeability. Thus, PTEN inactivation exerts a protective effect on the onset of colitis, and the transient and local restraint of PTEN activity might hasten healing following acute inflammation.

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 PTENflox/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 PTENflox/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.

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