Role of Epithelial Cell Death for Re-Establishment of the Gut Barrier During Resolution of Intestinal Inflammation

• Applicant: Professor Dr. Christoph Becker
• Subject Area: Gastroenterology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 536563567

Chronic intestinal inflammation is driven by a vicious cycle of epithelial cell death leading to barrier dysfunction, microbial translocation and excessive immune cell activation triggering more epithelial cell death. Conversely, resolution of intestinal inflammation is associated with epithelial restitution and restoration of robust barrier function in an attempt to break this vicious cycle. The mechanisms by which the epithelial barrier is restored in the presence of a cytotoxic inflammatory environment during an inflammatory flare of IBD are currently unknown. We have previously shown that dysregulated necroptosis is a driver of chronic intestinal inflammation. More recently, we have shown that the lipid mediator prostaglandin E2 (PGE2), via binding to the EP4 receptor on IEC, is able to induce resolution of intestinal inflammation by suppressing RIPK3-MLKL-induced IEC necroptosis in an inflammatory environment. Strikingly, we have introduced a novel EP4 agonist with therapeutic efficacy in preclinical models and demonstrated a beneficial outcome of high EP4 expression in inflammatory bowel disease patients. In the proposed project, we will continue in this vein, with a focus on unravelling the molecular mechanisms of EP4-mediated resolution of inflammation and the development and evaluation of novel EP4 agonism-based therapeutic approaches. Accordingly, we aim to delineate EP4-dependent barrier protection at the molecular level by deciphering the link between the prostanoid signalling pathway in IECs and necrosome formation and the influence of pro- and anti-inflammatory pathways on this signalling hub, taking advantage of inducible EP4-IEC-specific conditional knockout mice. Since EP4 receptor signalling induces resolution of intestinal inflammation, we aim to develop a gut-tropic EP4 receptor agonist. To achieve this, we will evaluate candidate molecules for efficacy and gut specificity in vivo. In addition, our unpublished data show that PGJ2 blocks necroptosis induction in IECs in addition to PGE2. We will therefore investigate whether PGJ2 is similarly efficient or even complementary to PGE2 in promoting resolution of inflammation, and we will elucidate the cellular source, receptor usage and downstream signalling of these molecules in mediating the protective effects against pathological cell death in an inflammatory context. In summary, our project aims to establish specific prostanoids as key molecules in breaking the vicious cycle of chronic inflammation, epithelial cell death and barrier dysfunction in the gut. We are confident that the proposed project will lead to new insights into the resolution of IBD and new strategies for effective therapies for affected patients.

• DFG Programme: Research Grants