Epithelial membrane protein 2 governs transepithelial migration of neutrophils into the airspace

J Clin Invest. 2020 Jan 2;130(1):157-170. doi: 10.1172/JCI127144.

Abstract

Whether respiratory epithelial cells regulate the final transit of extravasated neutrophils into the inflamed airspace or are a passive barrier is poorly understood. Alveolar epithelial type 1 (AT1) cells, best known for solute transport and gas exchange, have few established immune roles. Epithelial membrane protein 2 (EMP2), a tetraspan protein that promotes recruitment of integrins to lipid rafts, is highly expressed in AT1 cells but has no known function in lung biology. Here, we show that Emp2-/- mice exhibit reduced neutrophil influx into the airspace after a wide range of inhaled exposures. During bacterial pneumonia, Emp2-/- mice had attenuated neutrophilic lung injury and improved survival. Bone marrow chimeras, intravital neutrophil labeling, and in vitro assays suggested that defective transepithelial migration of neutrophils into the alveolar lumen occurs in Emp2-/- lungs. Emp2-/- AT1 cells had dysregulated surface display of multiple adhesion molecules, associated with reduced raft abundance. Epithelial raft abundance was dependent upon putative cholesterol-binding motifs in EMP2, whereas EMP2 supported adhesion molecule display and neutrophil transmigration through suppression of caveolins. Taken together, we propose that EMP2-dependent membrane organization ensures proper display on AT1 cells of a suite of proteins required to instruct paracellular neutrophil traffic into the alveolus.

Keywords: Inflammation; Innate immunity; Lipid rafts; Neutrophils; Pulmonology.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Alveolar Epithelial Cells / physiology*
  • Animals
  • Cell Line
  • Cell Movement
  • Chemokine CXCL1 / physiology
  • Membrane Glycoproteins / physiology*
  • Membrane Microdomains / physiology
  • Mice
  • Mice, Inbred C57BL
  • Neutrophils / physiology*
  • Pneumonia, Bacterial / mortality

Substances

  • Chemokine CXCL1
  • Cxcl1 protein, mouse
  • EMP2 protein, human
  • Membrane Glycoproteins