Epithelial membrane protein 2 regulates transepithelial migration of neutrophils into the inflamed airspace

Abstract

Abstract Neutrophil (PMN) migration from the circulation to the airway lumen is critical for pulmonary host defense but also causes bystander tissue injury that underlies a wide array of acute and chronic lung diseases. Whereas good evidence supports a role for intestinal epithelial cells in control of transmigration of extravasated PMNs into the intestinal lumen, little is known about whether and how respiratory epithelial cells regulate PMN influx into the airspace. Here, we identify epithelial membrane protein 2 (EMP2), a tetraspan membrane protein highly expressed in alveolar epithelial type 1 (AT1) cells but of unknown function in lung biology, as a master regulator of the terminal entry of PMNs into the airspace. EMP2−/− mice had reduced PMN influx into the airspace after multiple inhaled exposures and as a result exhibited attenuated lung injury and improved survival during bacterial pneumonia. Bone marrow chimeras, intravital PMN labelling, and in vitro assays suggest epithelial dysfunction in EMP2−/− lungs was responsible for deficient transepithelial PMN transit into airspace. We provide evidence that EMP2 supports epithelial surface display of multiple adhesion molecules that are required for cognate interactions with migrating PMNs and that it does so through suppression of epithelial caveolins. Moreover, EMP2 supports epithelial lipid raft mass in a manner dependent on putative cholesterol-binding motifs in its sequence. Taken together, we propose that EMP2-dependent membrane organization ensures proper display on AT1 cells of a suite of proteins required to instruct paracellular PMN traffic into the alveolus. Our findings identify EMP2 as a potential target for treatment of neutrophilic lung diseases.