Influenza virus causes lung immunopathology through down-regulating PPAR gamma activity in macrophages

Fatal influenza (flu) virus infection often activates excessive inflammatory signals, leading to multi-organ failure and death, also referred to as cytokine storm. PPAR gamma (Peroxisome proliferator-activated receptor gamma) agonists are well-known candidates for cytokine storm modulation. The present study identified that influenza infection reduced PPAR gamma expression and decreased PPAR gamma transcription activity in human alveolar macrophages (AMs) from different donors. Treatment with PPAR gamma agonist Troglitazone ameliorated virus-induced proinflammatory cytokine secretion but did not interfere with the IFN-induced antiviral pathway in human AMs. In contrast, PPAR gamma antagonist and knockdown of PPAR gamma in human AMs further enhanced virus-stimulated proinflammatory response. In a mouse model of influenza infection, flu virus dose-dependently reduced PPAR gamma transcriptional activity and decreased expression of PPAR gamma. Moreover, PPAR gamma agonist troglitazone significantly reduced high doses of influenza infection-induced lung pathology. In addition, flu infection reduced PPAR gamma expression in all mouse macrophages, including AMs, interstitial macrophages, and bone-marrow-derived macrophages but not in alveolar epithelial cells. Our results indicate that the influenza virus specifically targets the PPAR gamma pathway in macrophages to cause acute injury to the lung.