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¹ Epithelial Pathobiology Research Unit, Department of Pathology and ² Division of Pulmonary and Critical Care, Department of Medicine, Emory University, Atlanta, GA 30322
³ Deparment of General Surgery, University of Muenster, 48149 Muenster, Germany
⁴ Department of Microbiology and Immunology and Pediatrics and ⁵ Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University, Nashville, TN 37232

CORRESPONDENCE Charles A. Parkos: cparkos{at}emory.edu OR Asma Nusrat: anusrat{at}emory.edu

Recent evidence has linked intestinal permeability to mucosal inflammation, but molecular studies are lacking. Candidate regulatory molecules localized within the tight junction (TJ) include Junctional Adhesion Molecule (JAM-A), which has been implicated in the regulation of barrier function and leukocyte migration. Thus, we analyzed the intestinal mucosa of JAM-A–deficient (JAM-A^–/–) mice for evidence of enhanced permeability and inflammation. Colonic mucosa from JAM-A^–/– mice had normal epithelial architecture but increased polymorphonuclear leukocyte infiltration and large lymphoid aggregates not seen in wild-type controls. Barrier function experiments revealed increased mucosal permeability, as indicated by enhanced dextran flux, and decreased transepithelial electrical resistance in JAM-A^–/– mice. The in vivo observations were epithelial specific, because monolayers of JAM-A^–/– epithelial cells also demonstrated increased permeability. Analyses of other TJ components revealed increased expression of claudin-10 and -15 in the colonic mucosa of JAM-A^–/– mice and in JAM-A small interfering RNA–treated epithelial cells. Given the observed increase in colonic inflammation and permeability, we assessed the susceptibility of JAM-A^–/– mice to the induction of colitis with dextran sulfate sodium (DSS). Although DSS-treated JAM-A^–/– animals had increased clinical disease compared with controls, colonic mucosa showed less injury and increased epithelial proliferation. These findings demonstrate a complex role of JAM-A in intestinal homeostasis by regulating epithelial permeability, inflammation, and proliferation.

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