Peroxisome Proliferator-activated Receptor gamma (PPARγ) suppresses inflammation and bacterial control during influenza bacterial super-infection

Abstract

Abstract Influenza is one of the most common causes of respiratory illness worldwide and can be complicated by secondary bacterial pneumonia, which is a common cause of mortality. Influenza-induced “cytokine storm” is thought to play a role in lung pathogenesis during influenza infection. PPARγ is a member of nuclear hormone receptor superfamily that is known to enhance lipid and glucose metabolism, cellular differentiation and suppress the inflammatory immune response. Synthetic PPARγ agonists (thiazolidinedione, rosiglitazone) have been used clinically in the treatment of type II diabetes. In this study, we determined the effect of rosiglitazone in mice infected with influenza or influenza, methicillin-resistant Staphylococcus aureus (MRSA) super-infection. We found decreased influenza viral burden, decreased numbers of neutrophils and macrophages in bronchoalveolar lavage (BAL), and decreased production of IL-6, IL-12, CCL2, and CXCL10 in influenza-infected, rosiglitazone-treated mice when compared to influenza-infected control mice. However, rosiglitazone treatment compromised bacterial control during influenza-bacterial super-infection. Further, we found decreased numbers of neutrophils and decreased gene expression of neutrophil elastase and cathepsin G during super-infection in rosiglitazone-treated mice. Similarly, using data from the National Health and Nutrition Examination Survey (NHANES), we found increased influenza/pneumonia mortality in rosiglitazone-treated patients compared to other diabetic patients (adjusted hazard ratio=3.4, 95% confidence interval=1.1–10.7). Both human and mouse data suggest that rosiglitazone treatment worsens the outcome of influenza-associated pneumonia.