Inflammation-induced epithelial injury results in compromised mucosal barrier function. In response to injury, epithelial cells migrate as a sheet to cover denuded surfaces. We have recently reported that a calcium dependent phospholipid binding protein Annexin A1 (AnxA1) is a pro-resolving mediator that signals via epithelial formyl peptide receptors (FPRs) to promote intestinal mucosal wound repair. Analysis of signaling pathways downstream of epithelial FPRs identified intestinal epithelial NADPH oxidase-1 (Nox1) and Rac1 as key elements responsible for generation of reactive oxygen species (ROS). We determined that ROS-induced oxidative modification of phosphatases, in turn, activate proteins involved in controlling focal cell matrix adhesions and epithelial cell migration. Exogenous AnxA1 administration was observed to promote intestinal mucosal wound closure in WT mice but not in mice lacking intestinal epithelial Nox1 (Nox1-/-IEC). Analysis of AnxA1 released from the epithelial cells revealed that it is shed in membranes that have properties of microparticles (<1 µm) as an N-terminal cleaved product. Incubation of wounded epithelial monolayers with AnxA1containing microparticles promoted wound closure. These findings define a mechanism by which intracellular AnxA1 is cleaved and released in epithelial-derived microparticles during inflammation which can then signal in a paracrine fashion via FPR and Nox1 to promote intestinal mucosal wound repair.
- Copyright © 2013 by The American Association of Immunologists, Inc.