Virus-induced inflammasome activation is suppressed by prostaglandin D₂/DP1 signaling
Prostaglandin D2 (PGD₂), an eicosanoid with both pro- and antiinflammatory 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 exp...
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Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2017-07, Vol.114 (27), p.E5444-E5453 |
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creator | Vijay, Rahul Fehr, Anthony R. Janowski, Ann M. Athmer, Jeremiah Wheeler, Dorthea L. Grunewald, Matthew Sompallae, Ramakrishna Kurup, Samarchith P. Meyerholz, David K. Sutterwala, Fayyaz S. Narumiya, Shuh Perlman, Stanley |
description | Prostaglandin D2 (PGD₂), an eicosanoid with both pro- and antiinflammatory 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. |
doi_str_mv | 10.1073/pnas.1704099114 |
format | Article |
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−/− 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.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1704099114</identifier><identifier>PMID: 28630327</identifier><language>eng</language><publisher>National Academy of Sciences</publisher><subject>Biological Sciences ; PNAS Plus</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2017-07, Vol.114 (27), p.E5444-E5453</ispartof><rights>Volumes 1–89 and 106–114, copyright as a collective work only; author(s) retains copyright to individual articles</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/26485387$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/26485387$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,315,728,781,785,804,886,27929,27930,53796,53798,58022,58255</link.rule.ids></links><search><creatorcontrib>Vijay, Rahul</creatorcontrib><creatorcontrib>Fehr, Anthony R.</creatorcontrib><creatorcontrib>Janowski, Ann M.</creatorcontrib><creatorcontrib>Athmer, Jeremiah</creatorcontrib><creatorcontrib>Wheeler, Dorthea L.</creatorcontrib><creatorcontrib>Grunewald, Matthew</creatorcontrib><creatorcontrib>Sompallae, Ramakrishna</creatorcontrib><creatorcontrib>Kurup, Samarchith P.</creatorcontrib><creatorcontrib>Meyerholz, David K.</creatorcontrib><creatorcontrib>Sutterwala, Fayyaz S.</creatorcontrib><creatorcontrib>Narumiya, Shuh</creatorcontrib><creatorcontrib>Perlman, Stanley</creatorcontrib><title>Virus-induced inflammasome activation is suppressed by prostaglandin D₂/DP1 signaling</title><title>Proceedings of the National Academy of Sciences - PNAS</title><description>Prostaglandin D2 (PGD₂), an eicosanoid with both pro- and antiinflammatory 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.</description><subject>Biological Sciences</subject><subject>PNAS Plus</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><recordid>eNpVkEtLw0AcxBdRbK2ePQk5ekn733f2IkjrCwp68HEMm2RTtyS7MZsUeu1H9ZMYaRE8zWF-zDCD0CWGKQZJZ43TYYolMFAKY3aExhgUjgVTcIzGAETGCSNshM5CWAOA4gmcohFJBAVK5Bh9vNu2D7F1RZ-bIrKurHRd6-BrE-m8sxvdWe8iG6LQN01rQhiobBs1rQ-dXlXaFdZFi-_dbrZ4wVGwK6cr61bn6KTUVTAXB52gt_u71_ljvHx-eJrfLuM1YaKLCSa84JRKBkYoVgrOC6VlBpiWZaYzMEWOgRGa5QQroqXMGeemoIoQAVjQCbrZ5zZ9Vg-wcV2rq7Rpba3bbeq1Tf87zn6mK79JOQfye8IEXR8CWv_Vm9CltQ25qYZlxvchxcOvQikCdECv9ug6dL796yCCJZwmkv4AsDl5GQ</recordid><startdate>20170703</startdate><enddate>20170703</enddate><creator>Vijay, Rahul</creator><creator>Fehr, Anthony R.</creator><creator>Janowski, Ann M.</creator><creator>Athmer, Jeremiah</creator><creator>Wheeler, Dorthea L.</creator><creator>Grunewald, Matthew</creator><creator>Sompallae, Ramakrishna</creator><creator>Kurup, Samarchith P.</creator><creator>Meyerholz, David K.</creator><creator>Sutterwala, Fayyaz S.</creator><creator>Narumiya, Shuh</creator><creator>Perlman, Stanley</creator><general>National Academy of Sciences</general><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20170703</creationdate><title>Virus-induced inflammasome activation is suppressed by prostaglandin D₂/DP1 signaling</title><author>Vijay, Rahul ; Fehr, Anthony R. ; Janowski, Ann M. ; Athmer, Jeremiah ; Wheeler, Dorthea L. ; Grunewald, Matthew ; Sompallae, Ramakrishna ; Kurup, Samarchith P. ; Meyerholz, David K. ; Sutterwala, Fayyaz S. ; Narumiya, Shuh ; Perlman, Stanley</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-j246t-2125d533740e694f655d9a7b013ffbab0edc10423bc2192a77c455ed392260163</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Biological Sciences</topic><topic>PNAS Plus</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Vijay, Rahul</creatorcontrib><creatorcontrib>Fehr, Anthony R.</creatorcontrib><creatorcontrib>Janowski, Ann M.</creatorcontrib><creatorcontrib>Athmer, Jeremiah</creatorcontrib><creatorcontrib>Wheeler, Dorthea L.</creatorcontrib><creatorcontrib>Grunewald, Matthew</creatorcontrib><creatorcontrib>Sompallae, Ramakrishna</creatorcontrib><creatorcontrib>Kurup, Samarchith P.</creatorcontrib><creatorcontrib>Meyerholz, David K.</creatorcontrib><creatorcontrib>Sutterwala, Fayyaz S.</creatorcontrib><creatorcontrib>Narumiya, Shuh</creatorcontrib><creatorcontrib>Perlman, Stanley</creatorcontrib><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Vijay, Rahul</au><au>Fehr, Anthony R.</au><au>Janowski, Ann M.</au><au>Athmer, Jeremiah</au><au>Wheeler, Dorthea L.</au><au>Grunewald, Matthew</au><au>Sompallae, Ramakrishna</au><au>Kurup, Samarchith P.</au><au>Meyerholz, David K.</au><au>Sutterwala, Fayyaz S.</au><au>Narumiya, Shuh</au><au>Perlman, Stanley</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Virus-induced inflammasome activation is suppressed by prostaglandin D₂/DP1 signaling</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><date>2017-07-03</date><risdate>2017</risdate><volume>114</volume><issue>27</issue><spage>E5444</spage><epage>E5453</epage><pages>E5444-E5453</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>Prostaglandin D2 (PGD₂), an eicosanoid with both pro- and antiinflammatory 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.</abstract><pub>National Academy of Sciences</pub><pmid>28630327</pmid><doi>10.1073/pnas.1704099114</doi></addata></record> |
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title | Virus-induced inflammasome activation is suppressed by prostaglandin D₂/DP1 signaling |
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