Virus-induced inflammasome activation is suppressed by prostaglandin D2/DP1 signaling.

Abstract

Prostaglandin D2 (PGD2), an eicosanoid with both pro- and anti-inflammatory properties, is the most abundantly expressed prostaglandin in the brain. Here we show that PGD2 signaling through the D-prostanoid receptor 1 (DP1) receptor is necessary for optimal microglia/macrophage activation and IFN expression after infection with a neurotropic coronavirus. Genome-wide expression analyses indicated that PGD2/DP1 signaling is required for up-regulation of a putative inflammasome inhibitor, PYDC3, in CD11b+ cells in the CNS of infected mice. Our results also demonstrated that, in addition to PGD2/DP1 signaling, type 1 IFN (IFN-I) signaling is required for PYDC3 expression. In the absence of Pydc3 up-regulation, IL-1β expression and, subsequently, mortality were increased in infected DP1-/- mice. Notably, survival was enhanced by IL1 receptor blockade, indicating that the effects of the absence of DP1 signaling on clinical outcomes were mediated, at least in part, by inflammasomes. Using bone marrow-derived macrophages in vitro, we confirmed that PYDC3 expression is dependent upon DP1 signaling and that IFN priming is critical for PYDC3 up-regulation. In addition, Pydc3 silencing or overexpression augmented or diminished IL-1β secretion, respectively. Furthermore, DP1 signaling in human macrophages also resulted in the up-regulation of a putative functional analog, POP3, suggesting that PGD2 similarly modulates inflammasomes in human cells. These findings demonstrate a previously undescribed role for prostaglandin signaling in preventing excessive inflammasome activation and, together with previously published results, suggest that eicosanoids and inflammasomes are reciprocally regulated.

• Authors: Rahul Vijay, Anthony R Fehr, Ann M Janowski, Jeremiah Athmer, Dorthea L Wheeler, Matthew Grunewald, Ramakrishna Sompallae, Samarchith P Kurup, David K Meyerholz, Fayyaz S Sutterwala, Shuh Narumiya, Stanley Perlman
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 114 Issue 27 Pg. E5444-E5453 (07 03 2017) ISSN: 1091-6490 [Electronic] United States
• PMID: 28630327 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• IL1B protein, human
• IL1B protein, mouse
• Inflammasomes
• Interferon Type I
• Interleukin-1beta
• Receptors, Prostaglandin
• prostanoid D receptor 1, human
• prostanoid D receptor 1, mouse
• Cyclic AMP
• Prostaglandin D2

Topics

• Animals
• Coronavirus
• Cyclic AMP (metabolism)
• Cytokines (metabolism)
• Humans
• Inflammasomes (metabolism)
• Inflammation (metabolism)
• Interferon Type I (metabolism)
• Interleukin-1beta (metabolism)
• Macrophages (metabolism)
• Mice
• Mice, Inbred C57BL
• Oligonucleotide Array Sequence Analysis
• Prostaglandin D2 (metabolism)
• Protein Domains
• Receptors, Prostaglandin (antagonists & inhibitors, metabolism)
• Signal Transduction
• Up-Regulation