Junctional adhesion molecule-like protein (JAML) expressed on neutrophils (PMN) has been shown to bind to the epithelial tight junction protein cocksackie-adenovirus receptor (CAR) and partially mediate neutrophil transepithelial migration. Since CAR has also been implicated in regulating epithelial barrier function, we investigated the contribution of JAML-CAR interactions to CAR-mediated mucosal epithelial homeostasis during inflammation. Here we report that JAML is shed from activated/migrating PMN and monocytes in a stimulus and dose-dependent manner that is mediated by zinc-metalloproteases. Using complementary in-vitro and in-vivo approaches, we demonstrate that CAR ligation by shed JAML as well as by adenoviral fiber knob protein-5, an analogous CAR ligand that binds to the same site as JAML, inhibits intestinal epithelial barrier function and impairs epithelial wound healing. Inhibitory effects of soluble JAML on CAR-mediated regulation of wound repair were secondary to downregulation of ERK-dependent epithelial cell proliferation. Lastly, an anti-JAML mAb that blocks JAML-CAR binding, reversed the inhibitory effects of JAML released by migrating PMN on epithelial wound repair. These findings represent a new mechanism by which transmigrating myelomonocytic cells actively shed TJ-binding ligands that alter epithelial homeostasis and contribute to disease pathophysiology.
- Copyright © 2013 by The American Association of Immunologists, Inc.