Huang, SuJiang, LiCheon, In SuSu, Jie2020-07-292020-07-292019-05-15Huang, S., Jiang, L., Cheon, I. S., & Sun, J. (2019). Targeting Peroxisome Proliferator-Activated Receptor-Gamma Decreases Host Mortality After Influenza Infection in Obese Mice. Viral immunology, 32(4), 161–169. https://doi.org/10.1089/vim.2019.0016https://hdl.handle.net/1805/23422Obesity 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.en-USPublisher PolicyPPAR-γObesityMacrophageArticle