Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 27, Pages E5444-E5453Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1704099114
Keywords
coronavirus; inflammasomes; pyrin domain-only protein; encephalitis; prostaglandin D2
Categories
Funding
- NIH [R01 NS36592, R01 AI118719, T32 AI007485, P30CA086862]
- National MS Society [RG5340-A-7]
- Grants-in-Aid for Scientific Research [17H01531] Funding Source: KAKEN
Ask authors/readers for more resources
Prostaglandin D2 (PGD(2)), an eicosanoid with both pro-and anti-inflammatory properties, is the most abundantly expressed prostaglandin in the brain. Here we show that PGD(2) 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 PGD(2)/DP1 signaling is required for upregulation of a putative inflammasome inhibitor, PYDC3, in CD11b(+) cells in the CNS of infected mice. Our results also demonstrated that, in addition to PGD(2)/DP1 signaling, type 1 IFN (IFN-I) signaling is required for PYDC3 expression. In the absence of Pydc3 up-regulation, IL-1 beta 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-1 beta secretion, respectively. Furthermore, DP1 signaling in human macrophages also resulted in the up-regulation of a putative functional analog, POP3, suggesting that PGD(2) 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
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available