Profiling of primary murine macrophage responses to PPAR-a activation using RNA-seq

PPAR-? Modulates STING Activity and Herpesvirus Reactivation through the Production of Reactive Oxygen SpeciesPeroxisomes are essential sites of fatty acid metabolism and may play roles in regulating immune signaling. Peroxisomes are expanded by chronic herpesvirus infections and peroxisomal lipid metabolism is required for survival of latently infected cell lines. We investigated the function of increased peroxisomal metabolism in herpesvirus infection in vivo and found that induction of peroxisomal proliferation through the activation of the nuclear receptor, PPAR-a enhanced herpesvirus replication. PPAR-a activation inhibited the induction of type I interferon responses downstream of stimulator of interferon (STING). PPAR-a activation induced reactive oxygen species (ROS) production and ROS inhibited STING activation, blocking interferon induction. Administration of PPAR-a agonist to mice harboring latent herpesvirus infection induced herpesvirus reactivation from latency, indicating an important role for induction of fatty acid oxidation and peroxisomal proliferation in chronic herpesvirus infection. These data implicate PPAR-a activation in modulating ROS and STING activation in virally infected cells. This is the first data to indicate that peroxisomal lipid metabolism and ROS directly modify antiviral immunity downstream of cytoplasmic DNA sensing.