Virus-induced inflammasome activation is suppressed by prostaglandin D ₂/DP1 signaling

Significance

Inflammatory responses to viral infections must be optimized to clear the pathogen without tissue damage. Inflammasomes comprise an important component of the innate immune response. Inflammasome activity must be carefully controlled to prevent a hyperinflammatory response, especially in brain infections. Here we identify a host factor, PYDC3, that is dependent upon prostaglandin D2 (PGD ₂) and IFN-I signaling and is required to modulate inflammasome activation. After infection, inflammasome activation and expression of a downstream proinflammatory cytokine, IL-1β, were increased in mice deficient in PGD ₂ signaling, decreasing survival. Excess mortality was reversed by IL-1β receptor blockade. These results define a consequence of prostaglandin signaling and shed light on prostaglandin–inflammasome interactions, which modulate excessive inflammation and tissue damage in the virus-infected brain.

Abstract

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 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 PGD ₂/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 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.