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

Abstract

Prostaglandin D2 (PGD), an eicosanoid with both pro- and anti-inflammatory properties, is the most abundantly expressed prostaglandin in the brain. Here we show that PGD 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/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/DP1 signaling, type 1 IFN (IFN-I) signaling is required for PYDC3 expression. In the absence of up-regulation, IL-1β expression and, subsequently, mortality were increased in infected 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, 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 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.

Microglia influence host defense, disease, and repair following murine coronavirus infection of the central nervous system

“…We undertook the present study to better understand how microglia contribute to host defense as well as demyelination and repair following JHMV infection of the CNS using sophisticated molecular, cellular, and histologic approaches. Expression of IFN-I is critical in host defense in response to JHMV infection of the CNS (Athmer et al, 2018;Ireland et al, 2008;Vijay et al, 2017). PLX5622-mediated targeting of microglia did not affect IFN-I signaling as GSEA analysis revealed IFN-α response genes were significantly enriched in both macrophages and dendritic cells within the brains of PLX5622-treated mice at days 7 compared with controls (Figure 3d,e).…”

“…Importantly, we were able to show that PLX5622 treatment resulted in decreased expression of microgliaassociated transcripts Tmem119, P2ry12, and Sparc compared with control mice (Figure 3c). Expression of IFN-α is critical in effective control of JHMV replication within the CNS (Athmer et al, 2018;Ireland et al, 2008;Vijay et al, 2017). We examined IFN-α responses by both macrophages and DCs in order to gain better insight into potential mechanisms by which PLX5622 treatment led to impaired control of viral replication.…”

mTORC1 in Pulmonary Arterial Hypertension. At the Crossroads between Vasoconstriction and Vascular Remodeling?

“…Prostaglandin D2/DP1 signaling plays an important role in inflammatory response (15), a key player in PAH pathogenesis, and the link between DP1 and mTORC1 in the inflammation and immunity in PAH remains to be established. Furthermore, the mTORC1 is upregulated in right ventricle (RV) myocardium from rats with severe experimental PH and contributes to cardiomyocyte hypertrophy (16).…”

The novel immunomodulatory biologic LMWF5A for pharmacological attenuation of the “cytokine storm” in COVID-19 patients: a hypothesis

“…To illustrate, in mouse studies, age-related differences in PGD2 release result in defective migration of dendritic cells and cytotoxic CD8+ T-cell activity into the lung [53]. Furthermore, it has also been found that anti-inflammatory PGD2 signaling, through D-prostanoid receptor 1, reduces inflammasome-induced IL-1β release and mortality in coronavirus-infected mice [54]. Finally, influenza studies have established that 15d-PGJ2 treatment protects mice against lethal influenza infection through a PPARγdependent mechanism with a marked reduction in viral load and lung inflammation observed [55].…”