title: Junctional adhesion molecule A promotes epithelial tight junction assembly to augment lung barrier function.
abstract: Epithelial barrier function is maintained by tight junction proteins that control paracellular fluid flux. Among these proteins is junctional adhesion molecule A (JAM-A), an Ig fold transmembrane protein. To assess JAM-A function in the lung, we depleted JAM-A in primary alveolar epithelial cells using shRNA. In cultured cells, loss of JAM-A caused an approximately 30% decrease in transepithelial resistance, decreased expression of the tight junction scaffold protein zonula occludens 1, and disrupted junctional localization of the structural transmembrane protein claudin-18. Consistent with findings in other organs, loss of JAM-A decreased β1 integrin expression and impaired filamentous actin formation. Using a model of mild systemic endoxotemia induced by i.p. injection of lipopolysaccharide, we report that JAM-A(-/-) mice showed increased susceptibility to pulmonary edema. On injury, the enhanced susceptibility of JAM-A(-/-) mice to edema correlated with increased, transient disruption of claudin-18, zonula occludens 1, and zonula occludens 2 localization to lung tight junctions in situ along with a delay in up-regulation of claudin-4. In contrast, wild-type mice showed no change in lung tight junction morphologic features in response to mild systemic endotoxemia. These findings support a key role of JAM-A in promoting tight junction homeostasis and lung barrier function by coordinating interactions among claudins, the tight junction scaffold, and the cytoskeleton.
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia; Emory Alcohol and Lung Biology Center, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Mitchell
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia; Emory Alcohol and Lung Biology Center, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Christina
authors.initials: C
authors.lastname: Ward
authors.affiliation: Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Mike
authors.initials: M
authors.lastname: Kwon
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Patrick O
authors.initials: PO
authors.lastname: Mitchell
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: David A
authors.initials: DA
authors.lastname: Quintero
authors.affiliation: Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Asma
authors.initials: A
authors.lastname: Nusrat
authors.affiliation: Department of Pathology, University of Michigan School of Medicine, Ann Arbor, Michigan.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Parkos
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia; Emory Alcohol and Lung Biology Center, Emory University School of Medicine, Atlanta, Georgia; Department of Cell Biology, Emory University School of Medicine, Atlanta, Georgia. Electronic address: mhkoval@emory.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Koval
mesh_terms: D000818:Animals; D015824:Blood-Air Barrier / Q000166:cytology / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D057167:Claudins / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D051381:Rats; D020545:Respiratory Mucosa / Q000166:cytology / Q000378:metabolism*; D019108:Tight Junctions / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: C486683:CLDN18 protein, human; D015815:Cell Adhesion Molecules; D057167:Claudins; C520495:F11r protein, rat; D019012:Integrin beta1