Targeted Prostaglandin E2 Inhibition Enhances Antiviral Immunity through Induction of Type I Interferon and Apoptosis in Macrophages

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.

Influenza Virus Infection Induces Platelet-Endothelial Adhesion Which Contributes to Lung Injury

“…7C). Contrary to pre- vious reports, the benefit was not due to a direct or indirect effect on viral replication (40,41), as viral titers from lung homogenates were unchanged by treatment with ASA (Fig. 7D).…”

Alveolar macrophages and type I IFN in airway homeostasis and immunity

“…Similarly, it was found that PGE2 production by pulmonary AMw significantly suppressed type I IFN during IAV infection. However, in contrast to Mtb infection, this reduction of type I IFN was directly linked to an increased susceptibility to IAV infection [32]. However, the connection between eicosanoids, type I IFN, and the cell death program is still not well understood.…”

“…Although respiratory epithelial cells are the primary site of IAV replication, many studies suggest that IAV also infects Mw and replicates productively in these cells [26][27][28][29][30][31]. It has recently been demonstrated that IAV infects and replicates in human bone marrow-derived Mw [32] as well as primary murine alveolar Mw both in vitro and in vivo [33]. While the biological relevance of productive viral replication within residential or bone marrow-derived Mw is not clear, a recent study showed that vesicular stomatitis virus (VSV)-infected CD169 + splenic Mw selectively reduced type I IFN responses to enforce pathogen replication and make viral antigens available for the generation and maintenance of antigen-specific T and B cell responses [34].…”

Evaluation of urinary prostaglandin E2 metabolite as a biomarker in infants with fever due to viral infection

“…PGE 2 elicits inflammatory pain via several mechanisms [1][2][3][4] and is furthermore critical for the induction of fever [5,6]. MPGES1 has been suggested as a therapeutic target for PGE 2 driven inflammation [7] and recently also for treatment of influenza and potentially other viral infections [8]. The immunomodulatory role of PGE 2 correlates to viral load and infection severity in influenza and the possible critical role of PGE 2 in other respiratory viral infections is currently under investigation [9].…”