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
High IFN-γ and low SLPI mark severe asthma in mice and humans
Mahesh Raundhal, … , Prabir Ray, Anuradha Ray
Mahesh Raundhal, … , Prabir Ray, Anuradha Ray
Published June 29, 2015
Citation Information: J Clin Invest. 2015;125(8):3037-3050. https://doi.org/10.1172/JCI80911.
View: Text | PDF
Research Article Pulmonology

High IFN-γ and low SLPI mark severe asthma in mice and humans

  • Text
  • PDF
Abstract

Severe asthma (SA) is a challenge to control, as patients are not responsive to high doses of systemic corticosteroids (CS). In contrast, mild-moderate asthma (MMA) is responsive to low doses of inhaled CS, indicating that Th2 cells, which are dominant in MMA, do not solely orchestrate SA development. Here, we analyzed broncholalveolar lavage cells isolated from MMA and SA patients and determined that IFN-γ (Th1) immune responses are exacerbated in the airways of individuals with SA, with reduced Th2 and IL-17 responses. We developed a protocol that recapitulates the complex immune response of human SA, including the poor response to CS, in a murine model. Compared with WT animals, Ifng–/– mice subjected to this SA model failed to mount airway hyperresponsiveness (AHR) without appreciable effect on airway inflammation. Conversely, AHR was not reduced in Il17ra–/– mice, although airway inflammation was lower. Computer-assisted pathway analysis tools linked IFN-γ to secretory leukocyte protease inhibitor (SLPI), which is expressed by airway epithelial cells, and IFN-γ inversely correlated with SLPI expression in SA patients and the mouse model. In mice subjected to our SA model, forced SLPI expression decreased AHR in the absence of CS, and it was further reduced when SLPI was combined with CS. Our study identifies a distinct immune response in SA characterized by a dysregulated IFN-γ/SLPI axis that affects lung function.

Authors

Mahesh Raundhal, Christina Morse, Anupriya Khare, Timothy B. Oriss, Jadranka Milosevic, John Trudeau, Rachael Huff, Joseph Pilewski, Fernando Holguin, Jay Kolls, Sally Wenzel, Prabir Ray, Anuradha Ray

×

Figure 8

Inverse correlation between IFN-γ and SLPI expression in human SA.

Options: View larger image (or click on image) Download as PowerPoint
Inverse correlation between IFN-γ and SLPI expression in human SA.
(A) S...
(A) SLPI mRNA expression analyzed by qRT-PCR in epithelial brushings of MMA and SA subjects. n = 17 and n = 20 for MMA and SA, respectively. **P ≤ 0.01, Student’s unpaired t test. (B) Correlation analysis between BAL cell IFNG and airway epithelial cell–expressed SLPI mRNA in MMA (top) and SA (bottom) subjects. Spearman’s rank correlation test was used to calculate the correlation coefficient (rs) using GraphPad Prism software. Regression line for the SA cohorts is shown in the right panel. n = 9 and n = 13 for MMA and SA, respectively. (C) Primary airway (bronchial) epithelial cells from nonasthmatic human subjects were stimulated with rhIFN-γ ± anti–IFN-γ or left untreated for 8 hours. SLPI mRNA expression was analyzed by qRT-PCR, and fold change over untreated was calculated using HPRT as internal reference control. n = 5. ***P ≤ 0.001, 1-way ANOVA with Tukey’s post-hoc test. (D) Detection of hSLPI protein in sera of mice that received hSLPI expression plasmid by tail vein injection. *P ≤ 0.05, 1-way ANOVA with Tukey’s post-hoc test. (E) AHR measurement in mice subjected to the SA model with or without hSLPI introduced in an expression plasmid via hydrodynamic tail vein injection. *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001, 1-way ANOVA with Tukey’s post-hoc test. (F) Cytokine concentrations in whole lungs of mice treated as in E. **P ≤ 0.01, 1-way ANOVA with Tukey’s post-hoc test. For D–F, data shown represent mean ± SEM and representative of 2 independent experiments.

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

Sign up for email alerts