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Viral Immunol. 2019 May;32(4):161-169. doi: 10.1089/vim.2019.0016. Epub 2019 Apr 19.

Targeting Peroxisome Proliferator-Activated Receptor-Gamma Decreases Host Mortality After Influenza Infection in Obese Mice.

Huang S1,2,3, Jiang L1,2,3, Cheon IS1,2,3, Sun J1,2,3.

Author information

1
1 Thoracic Diseases Research Unit, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota.
2
2 Department of Immunology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota.
3
3 Department of Pediatrics, HB Wells Pediatric Research Center, Indiana University School of Medicine, Indianapolis, Indiana.

Abstract

Obesity is an independent risk factor for severe influenza infection. However, the underlying cellular and molecular mechanisms are still incompletely understood. In this study, we have utilized a murine influenza infection model in genetic-induced obese (db/db) mice to explore the mechanisms by which obesity increases host susceptibility to influenza infection. We find that db/db mice have enhanced viral replication, exaggerated inflammatory responses, and dysregulated lung repair process after influenza infection, and consequently increased host mortality. Furthermore, we demonstrate that the transcription factor peroxisome proliferator-activated receptor-gamma (PPAR-γ), an important inflammation regulator, was downregulated in the lung macrophages of db/db mice after influenza infection. Strikingly, the treatment of 15-deoxy-Δ12, 14-prostaglandin J2 (15d-PGJ2), a PPAR-γ agonist, largely rescued the survival of db/db mice after influenza infection. Interestingly, macrophage PPAR-γ-deficient mice exhibited enhanced mortality after influenza infection and 15d-PGJ2 fails to rescue host mortality in macrophage PPAR-γ-deficient mice, suggesting that PPAR-γ expression in macrophages is critical for the action of 15d-PGJ2. These data indicate that obesity attenuates lung antiviral immunity and hampers host recovery through the modulation of macrophage PPAR-γ expression. Furthermore, modalities targeting macrophage PPAR-γ expression and/or function may serve as promising therapeutics to treat severe influenza infection in obese patients.

KEYWORDS:

; macrophage; obesity

PMID:
31009317
PMCID:
PMC6534095
[Available on 2020-05-01]
DOI:
10.1089/vim.2019.0016

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