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Epithelial restitution is an essential process that is required to repair barrier function at mucosal surfaces following injury. Prolonged breaches in epithelial barrier function result in inflammation and further damage; therefore, a better understanding of the epithelial restitution process has potential for improving the development of therapeutics. In this work, we demonstrate that endogenous annexin A1 (ANXA1) is released as a component of extracellular vesicles (EVs) derived from intestinal epithelial cells, and these ANXA1-containing EVs activate wound repair circuits. Compared with healthy controls, patients with active inflammatory bowel disease had elevated levels of secreted ANXA1-containing EVs in sera, indicating that ANXA1-containing EVs are systemically distributed in response to the inflammatory process and could potentially serve as a biomarker of intestinal mucosal inflammation. Local intestinal delivery of an exogenous ANXA1 mimetic peptide (Ac2-26) encapsulated within targeted polymeric nanoparticles (Ac2-26 Col IV NPs) accelerated healing of murine colonic wounds after biopsy-induced injury. Moreover, one-time systemic administration of Ac2-26 Col IV NPs accelerated recovery following experimentally induced colitis. Together, our results suggest that local delivery of proresolving peptides encapsulated within nanoparticles may represent a potential therapeutic strategy for clinical situations characterized by chronic mucosal injury, such as is seen in patients with IBD.
Introduction
The gastrointestinal epithelium functions as a dynamic and selective barrier, which plays an important role in limiting the access of luminal contents to the mucosal and systemic immune system. Epithelial injury results in compromised barrier function, as seen in pathologic states that are associated with mucosal inflammation. A major consequence of the breeched epithelial barrier is exposure of immunocompetent subepithelial lamina propria cells to luminal antigens and bacteria. This results in local recruitment of leukocytes and generation of proresolving mediators that orchestrate resolution of inflammation and ultimately epithelial repair. Thus, healing of epithelial wounds represents active coordination of proresolving mediators and repair events, wherein platelets, fibroblasts, and epithelial, endothelial, and inflammatory cells act together to restore the epithelial barrier and reestablish mucosal homeostasis (1). Recent studies have highlighted a critical role of secreted lipids and proteins in facilitating epithelial wound repair. Such proresolving mediators include lipoxins, resolvins, protectins, maresins, prostaglandins, cytokines, and annexin A1 (ANXA1) (2, 3).
ANXA1 facilitates resolution of inflammation by binding to formyl peptide receptors (FPRs) expressed on responsive cells,...