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Vol. 16, Issue 6, 2694-2703, June 2005
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* Epithelial Pathobiology Research Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322;
Department of Biology, Georgia State University, Atlanta, GA 30034
Submitted January 18, 2005;
Revised March 15, 2005;
Accepted March 22, 2005
Monitoring Editor: Keith Mostov
Neutrophil (polymorphonuclear leukocytes [PMN]) transepithelial migration during inflammatory episodes involves a complex series of adhesive interactions and signaling events. Previous studies have shown that key adhesive interactions between leukocyte CD11b/CD18 and basally expressed fucosylated glycoproteins followed by binding to desmosomal-associated JAM-C are key elements of the transmigration response. Here we provide the first evidence that PMN-expressed junctional adhesion molecule-like protein (JAML) regulates transmigration via binding interactions with epithelial coxsackie and adenovirus receptor (CAR). Experiments with a JAML fusion protein revealed specific binding of JAML to epithelial CAR expressed at tight junctions in T84 cell monolayers and normal human colonic mucosa. Furthermore, JAML-CAR binding is mediated via the membrane distal immunoglobulin (Ig) loop of CAR and the membrane proximal Ig loop of JAML. PMN bound to immobilized CAR but not JAML in a divalent cation-independent manner. Lastly, in assays of PMN transepithelial migration, JAML/CAR fusion proteins and their antibodies significantly inhibited transmigration in a specific manner. Taken together, these results indicate that JAML and CAR are a novel pair of adhesion molecules that play an important role in modulating PMN migration cross epithelial tight junctions. These findings add a new element to a multistep model of PMN transepithelial migration and may provide new targets for anti-inflammatory therapies.
Abbreviations used: PMN, polymorphonuclear neutrophil; JAM, junctional adhesion molecule; JAML, junctional adhesion molecule-like protein; CTX, cortical thymocyte marker in Xenopus; IgSF, Ig superfamily; CAR, coxsackie and adenovirus receptor; MPO, myeloperoxidase; PF, paraformaldehyde; HBSS–, Hanks' balanced salt buffer devoid of Ca2+ and Mg2+; fMLP, formylmethionylleucylphenylalanine.
Address correspondence to: Ke Zen (kzen{at}emory.edu) or Charles A. Parkos (cparkos{at}emory.edu).
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