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

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

Author information

1
Department of Medicine, Department of Microbiology & Immunology, Department of Pathology, McGill International TB Centre, McGill University Health Centre and Research Institute, Meakins-Christie Laboratories, 3626 St. Urbain Street, Montreal, Quebec H2X 2P2, Canada.
2
Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, 1015 Arlington Street, Winnipeg, MB R3E 3R2, Canada.
3
McMaster Immunology Research Centre and Department of Pathology and Molecular Medicine, McMaster University, 1200 Main Street West, Hamilton, Ontario L8N 3Z5, Canada.
4
Department of Pathology, Centre Hospitalier Universitaire de Québec, Hôtel-Dieu de Québec, 11 côte du Palais, Quebec, Quebec G1R 2J6, Canada.
5
Department of Microbiology & Immunology, McGill Life Sciences Complex, Complex Traits Group, Bellini Pavilion, 3649 Promenade Sir William Osler, Montreal, Quebec H3G 0B1, Canada.
6
Department of Medicine, Department of Microbiology & Immunology, Department of Pathology, McGill International TB Centre, McGill University Health Centre and Research Institute, Meakins-Christie Laboratories, 3626 St. Urbain Street, Montreal, Quebec H2X 2P2, Canada. Electronic address: maziar.divangahi@mcgill.ca.

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.

PMID:
24726877
DOI:
10.1016/j.immuni.2014.02.013
[Indexed for MEDLINE]
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