Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • 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
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Exophilin-5 regulates allergic airway inflammation by controlling IL-33–mediated Th2 responses
Katsuhide Okunishi, … , Susumu Nakae, Tetsuro Izumi
Katsuhide Okunishi, … , Susumu Nakae, Tetsuro Izumi
Published April 2, 2020
Citation Information: J Clin Invest. 2020;130(7):3919-3935. https://doi.org/10.1172/JCI127839.
View: Text | PDF
Research Article Immunology Article has an altmetric score of 4

Exophilin-5 regulates allergic airway inflammation by controlling IL-33–mediated Th2 responses

  • Text
  • PDF
Abstract

A common variant in the RAB27A gene in adults was recently found to be associated with the fractional exhaled nitric oxide level, a marker of eosinophilic airway inflammation. The small GTPase Rab27 is known to regulate intracellular vesicle traffic, although its role in allergic responses is unclear. We demonstrated that exophilin-5, a Rab27-binding protein, was predominantly expressed in both of the major IL-33 producers, lung epithelial cells, and the specialized IL-5 and IL-13 producers in the CD44hiCD62LloCXCR3lo pathogenic Th2 cell population in mice. Exophilin-5 deficiency increased stimulant-dependent damage and IL-33 secretion by lung epithelial cells. Moreover, it enhanced IL-5 and IL-13 production in response to TCR and IL-33 stimulation from a specific subset of pathogenic Th2 cells that expresses a high level of IL-33 receptor, which exacerbated allergic airway inflammation in a mouse model of asthma. Mechanistically, exophilin-5 regulates extracellular superoxide release, intracellular ROS production, and phosphoinositide 3-kinase activity by controlling intracellular trafficking of Nox2-containing vesicles, which seems to prevent the overactivation of pathogenic Th2 cells mediated by IL-33. This is the first report to our knowledge to establish the significance of the Rab27-related protein exophilin-5 in the development of allergic airway inflammation, and provides insights into the pathophysiology of asthma.

Authors

Katsuhide Okunishi, Hao Wang, Maho Suzukawa, Ray Ishizaki, Eri Kobayashi, Miho Kihara, Takaya Abe, Jun-ichi Miyazaki, Masafumi Horie, Akira Saito, Hirohisa Saito, Susumu Nakae, Tetsuro Izumi

×

Figure 3

IL-33 secretion is enhanced in the lungs of Exph5-KO mice.

Options: View larger image (or click on image) Download as PowerPoint
IL-33 secretion is enhanced in the lungs of Exph5-KO mice.
(A) Levels of...
(A) Levels of epithelial cell–derived cytokines and LDH in BALF of mice obtained 30 minutes after intratracheal injections of PBS or 10 μg of Alternaria extract (Alt). LDH levels were normalized to the averages of those in PBS-treated WT mice. *P < 0.05; **P < 0.01 by unpaired t test. (B) IL-33 levels in the lungs of mice after the final OVA aerosol challenge. At the indicated time point after the third OVA aerosol challenge, BALF and lung tissues were collected from OVA-sensitized mice, and IL-33 concentrations in BALF and lung homogenates were determined by ELISA. (C) IL-33 levels in the lungs of mice at 1 hour after the final OVA aerosol challenge. *P < 0.05 by paired t test. Data were obtained from n = 3–5 mice gathered from 2 to 3 independent experiments.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Posted by 6 X users
Highlighted by 1 platforms
31 readers on Mendeley
See more details