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 ...
    • Pancreatic Cancer (Jul 2025)
    • 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)
    • 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
Agonistic induction of PPARγ reverses cigarette smoke–induced emphysema
Ming Shan, … , David B. Corry, Farrah Kheradmand
Ming Shan, … , David B. Corry, Farrah Kheradmand
Published February 24, 2014
Citation Information: J Clin Invest. 2014;124(3):1371-1381. https://doi.org/10.1172/JCI70587.
View: Text | PDF
Research Article Article has an altmetric score of 15

Agonistic induction of PPARγ reverses cigarette smoke–induced emphysema

  • Text
  • PDF
Abstract

The development of emphysema in humans and mice exposed to cigarette smoke is promoted by activation of an adaptive immune response. Lung myeloid dendritic cells (mDCs) derived from cigarette smokers activate autoreactive Th1 and Th17 cells. mDC-dependent activation of T cell subsets requires expression of the SPP1 gene, which encodes osteopontin (OPN), a pleiotropic cytokine implicated in autoimmune responses. The upstream molecular events that promote SPP1 expression and activate mDCs in response to smoke remain unknown. Here, we show that peroxisome proliferator–activated receptor γ (PPARG/Pparg) expression was downregulated in mDCs of smokers with emphysema and mice exposed to chronic smoke. Conditional knockout of PPARγ in APCs using Cd11c-Cre Ppargflox/flox mice led to spontaneous lung inflammation and emphysema that resembled the phenotype of smoke-exposed mice. The inflammatory phenotype of Cd11c-Cre Ppargflox/flox mice required OPN, suggesting an antiinflammatory mechanism in which PPARγ negatively regulates Spp1 expression in the lung. A 2-month treatment with a PPARγ agonist reversed emphysema in WT mice despite continual smoke exposure. Furthermore, endogenous PPARγ agonists were reduced in the plasma of smokers with emphysema. These findings reveal a proinflammatory pathway, in which reduced PPARγ activity promotes emphysema, and suggest that targeting this pathway in smokers could prevent and reverse emphysema.

Authors

Ming Shan, Ran You, Xiaoyi Yuan, Michael V. Frazier, Paul Porter, Alexander Seryshev, Jeong-Soo Hong, Li-zhen Song, Yiqun Zhang, Susan Hilsenbeck, Lawrence Whitehead, Nazanin Zarinkamar, Sarah Perusich, David B. Corry, Farrah Kheradmand

×

Figure 1

Decreased PPARγ expression in emphysematous lung mDCs.

Options: View larger image (or click on image) Download as PowerPoint
Decreased PPARγ expression in emphysematous lung mDCs.
(A and B) Microar...
(A and B) Microarray comparison of genes upregulated in emphysema and following PPARγ agonism. (A) Heatmaps depicting gene expression in lung mDCs obtained from former smokers without (control; n = 3) and with emphysema (GSE26296) (n = 3). Right panel: Expression of the same genes in human MDDCs with and without PPARγ agonist treatment (GSE8658). n = 3 per group. (B) Left: Heatmap of the top 51 genes upregulated in PPARγ agonist–treated human MDDCs (GSE8658). Right: Heatmap depicting expression of the same genes in control and emphysematous lung DCs (GSE26296). n = 3 per group. Heatmaps scales: Bright blue to bright yellow: <–2.0, –1.59, –1.26, 1.0, 1.26, 1.59, >2.0. (C) Heatmap showing PPARG gene expression by microarray analysis (GSE26296). P < 0.003. (D) PPARG mRNA expression in control lung DCs (n = 8) and emphysematous lung DCs (n = 10) as determined by qPCR (normalized to 18S expression). *P < 0.05 as determined by a Mann-Whitney U test. Lower panel: Correlation between PPARG expression and emphysema severity (FEV1%) as assessed by linear regression. (E) qPCR analysis of Pparg mRNA expression (normalized to 18S expression) in total lung cells, lung DCs, and alveolar macrophages (AMΦ) from air- (n = 3) and cigarette smoke–exposed mice (n = 3). *P < 0.05, **P < 0.01, by 2-tailed Student’s t test. Emphys, emphysema.

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

Sign up for email alerts

Picked up by 1 news outlets
Blogged by 1
Posted by 2 X users
55 readers on Mendeley
See more details