Crohn's disease and ulcerative colitis comprise intestinal inflammatory conditions that when active lead to intestinal epithelia ulceration. The restoration of the damaged mucosa and the re-establishment of the intestinal homeostatic milieu require an active resolution response that will induce intestinal epithelial cell migration and proliferation. Resolution of inflammation and epithelial repair are active processes mediated by protein/peptides and lipids known as specialized pro-resolving mediators. Resolvin E1 (RvE1), a pro-resolving bioactive lipid mediator derived from omega-3 fatty acid has been described to decreased the inflammatory response and promote the establishment of a restitution phase in different tissues. RvE1 associates with the G protein coupled receptor Chemokine Like Receptor 1 (CMKLR1).Methods:
We used intestinal epithelial cell cultures in-vitro to perform scratch wound healing and evaluate the activation of different signaling pathways upon RvE1 stimulation. Using a mouse colonoscopy based biopsy wound model we studied the role of RvE1 in intestinal epithelial wound healing in-vivo.Results:
In the absence of the CMKLR1 receptor mice present delay wound healing when a biopsy induced wound healing experiment is performed. Complimentary in vitro experiments showed how RvE1 treatment of model intestinal epithelial cell (IEC) lines promote wound repair by increasing epithelial cell proliferation and migration. Analysis of the signaling pathways revealed activation of Notch and the mTOR pathways, which promote epithelial cell proliferation and ultimately wound repair. To harness this mechanism of repair, we performed intramucosal injection of synthetic nanoparticles containing RvE1 in injured murine colon. RvE1 nanoparticles increase wound closure compared to naked RvE1 and empty nanoparticlesConclusions:
Our findings provide important insight on mechanisms of intestinal mucosal wound repair driven by RvE1 and determine its potential as a therapeutic agent aimed at facilitating epithelial wound closure and barrier recovery in people suffering intestinal inflammatory diseases such as IBD.