Targeted prostaglandin E₂ inhibition enhances antiviral immunity through induction of type I interferon and apoptosis in macrophages

Aspirin gained tremendous popularity during the 1918 Spanish Influenza virus pandemic, 50 years prior to the demonstration of their inhibitory action on prostaglandins. Here, we show that during influenza A virus (IAV) infection, prostaglandin E₂ (PGE₂) was upregulated, which led to the inhibition of type I interferon (IFN) production and apoptosis in macrophages, thereby causing an increase in virus replication. This inhibitory role of PGE₂ was not limited to innate immunity, because both antigen presentation and Tcell mediated immunity were also suppressed. Targeted PGE₂ suppression via genetic ablation of microsomal prostaglandin E-synthase 1 (mPGES-1) or by the pharmacological inhibition of PGE₂ receptors EP2 and EP4 substantially improved survival against lethal IAV infection whereas PGE₂ administration reversed this phenotype. These data demonstrate that the mPGES-1-PGE₂ pathway is targeted by IAV to evade host type I IFN-dependent antiviral immunity. We propose that specific inhibition of PGE₂ signaling might serve as a treatment for IAV.