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

Immunity. 2014 Apr 17;40(4):554-68. doi: 10.1016/j.immuni.2014.02.013. Epub 2014 Apr 10.

Abstract

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 T cell 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen Presentation / drug effects
  • Apoptosis / drug effects
  • Cells, Cultured
  • Dinoprostone / immunology
  • Dinoprostone / metabolism*
  • Gene Expression Regulation / drug effects
  • Immunity / drug effects
  • Immunity / genetics
  • Influenza A virus / physiology*
  • Interferon Type I / genetics
  • Interferon Type I / metabolism*
  • Intramolecular Oxidoreductases / antagonists & inhibitors*
  • Intramolecular Oxidoreductases / genetics
  • Macrophages / drug effects*
  • Macrophages / immunology
  • Macrophages / virology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Molecular Targeted Therapy
  • Orthomyxoviridae Infections / drug therapy*
  • Orthomyxoviridae Infections / immunology
  • Prostaglandin-E Synthases
  • Receptors, Prostaglandin E, EP2 Subtype / antagonists & inhibitors
  • Receptors, Prostaglandin E, EP4 Subtype / antagonists & inhibitors
  • T-Lymphocytes / immunology
  • T-Lymphocytes / virology
  • Virus Replication / genetics

Substances

  • Interferon Type I
  • Receptors, Prostaglandin E, EP2 Subtype
  • Receptors, Prostaglandin E, EP4 Subtype
  • Intramolecular Oxidoreductases
  • Prostaglandin-E Synthases
  • Ptges protein, mouse
  • Dinoprostone