Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • 100th Anniversary of Insulin's Discovery (Jan 2021)
    • Hypoxia-inducible factors in disease pathophysiology and therapeutics (Oct 2020)
    • Latency in Infectious Disease (Jul 2020)
    • Immunotherapy in Hematological Cancers (Apr 2020)
    • Big Data's Future in Medicine (Feb 2020)
    • Mechanisms Underlying the Metabolic Syndrome (Oct 2019)
    • Reparative Immunology (Jul 2019)
    • View all review series ...
  • Viewpoint
  • Collections
    • Recently published
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • Recently published
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
Epithelial membrane protein 2 governs transepithelial migration of neutrophils into the airspace
Wan-Chi Lin, … , Joseph P. Mizgerd, Michael B. Fessler
Wan-Chi Lin, … , Joseph P. Mizgerd, Michael B. Fessler
Published September 24, 2019
Citation Information: J Clin Invest. 2020;130(1):157-170. https://doi.org/10.1172/JCI127144.
View: Text | PDF
Research Article Inflammation Pulmonology

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

  • Text
  • PDF
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.

Authors

Wan-Chi Lin, Kymberly M. Gowdy, Jennifer H. Madenspacher, Rachel L. Zemans, Kazuko Yamamoto, Miranda Lyons-Cohen, Hideki Nakano, Kyathanahalli Janardhan, Carmen J. Williams, Donald N. Cook, Joseph P. Mizgerd, Michael B. Fessler

×

Figure 2

EMP2 regulates transepithelial migration of neutrophils into the alveolar lumen.

Options: View larger image (or click on image) Download as PowerPoint
EMP2 regulates transepithelial migration of neutrophils into the alveola...
(A) Bone marrow chimeric mice were made by transfer of bone marrow cells from Emp2+/+ (WT) or Emp2–/– (KO) donors to Emp2+/+ or Emp2–/– irradiated recipients (donor[arrow]recipient). Chimeras were exposed to inhaled LPS, and BAL PMNs quantified 24 hours later (n = 3–6/chimera). (B) Eight hours after LPS inhalation, Ly6G+ PMNs were quantified by flow cytometry in lavaged and perfused lungs (left) and in the BAL (right) of Emp2+/+ and Emp2–/– mice (n = 4–5/genotype). (C) Pulmonary interstitial (I) and endovascular (EV) Ly6G+ PMNs were quantified under similar conditions to those in panel I (n = 4/genotype). (D) Live lung slices from Emp2+/+ and Emp2–/– mice were stained for E-cadherin (epithelium), CD31 (endothelium), and Ly-6G (PMNs) 6 hours after LPS. Emp2–/– lungs display an excess accumulation of peribronchovascular (interstitial) PMNs. Results are representative of n = 3–4/genotype. (E) Human PMNs that transmigrated across a monolayer of scramble or EMP2 shRNA-transduced Calu-3 cells in response to fMLP during a time course were quantified (n = 3/condition/time point). Data are the mean ± SEM and are representative of at least 3 independent experiments. *P < 0.05; **P < 0.01 analyzed using ANOVA followed by Dunnett’s test in A, or unpaired 2-tailed Student’s t test in B, C, and E.
Follow JCI:
Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts