Lipin-2 regulates NLRP3 inflammasome by affecting P2X7 receptor activation
Mutations in human LPIN2 produce a disease known as Majeed syndrome, the clinical manifestations of which are ameliorated by strategies that block IL-1β or its receptor. However the role of lipin-2 during IL-1β production remains elusive. We show here that lipin-2 controls excessive IL-1β formation...
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| Veröffentlicht in: | The Journal of experimental medicine 2017-02, Vol.214 (2), p.511-528 |
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| creator | Lordén, Gema Sanjuán-García, Itziar de Pablo, Nagore Meana, Clara Alvarez-Miguel, Inés Pérez-García, M Teresa Pelegrín, Pablo Balsinde, Jesús Balboa, María A |
| description | Mutations in human LPIN2 produce a disease known as Majeed syndrome, the clinical manifestations of which are ameliorated by strategies that block IL-1β or its receptor. However the role of lipin-2 during IL-1β production remains elusive. We show here that lipin-2 controls excessive IL-1β formation in primary human and mouse macrophages by several mechanisms, including activation of the inflammasome NLRP3. Lipin-2 regulates MAPK activation, which mediates synthesis of pro-IL-1β during inflammasome priming. Lipin-2 also inhibits the activation and sensitization of the purinergic receptor P2X7 and K
efflux, apoptosis-associated speck-like protein with a CARD domain oligomerization, and caspase-1 processing, key events during inflammasome activation. Reduced levels of lipin-2 in macrophages lead to a decrease in cellular cholesterol levels. In fact, restoration of cholesterol concentrations in cells lacking lipin-2 decreases ion currents through the P2X7 receptor, and downstream events that drive IL-1β production. Furthermore, lipin-2-deficient mice exhibit increased sensitivity to high lipopolysaccharide doses. Collectively, our results unveil lipin-2 as a critical player in the negative regulation of NLRP3 inflammasome. |
| doi_str_mv | 10.1084/jem.20161452 |
| format | Article |
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efflux, apoptosis-associated speck-like protein with a CARD domain oligomerization, and caspase-1 processing, key events during inflammasome activation. Reduced levels of lipin-2 in macrophages lead to a decrease in cellular cholesterol levels. In fact, restoration of cholesterol concentrations in cells lacking lipin-2 decreases ion currents through the P2X7 receptor, and downstream events that drive IL-1β production. Furthermore, lipin-2-deficient mice exhibit increased sensitivity to high lipopolysaccharide doses. Collectively, our results unveil lipin-2 as a critical player in the negative regulation of NLRP3 inflammasome.</description><identifier>ISSN: 0022-1007</identifier><identifier>EISSN: 1540-9538</identifier><identifier>DOI: 10.1084/jem.20161452</identifier><identifier>PMID: 28031477</identifier><language>eng</language><publisher>United States: Rockefeller University Press</publisher><subject>Acid phosphatase ; Animals ; Apoptosis ; Caspase ; Caspase 1 - metabolism ; Caspase-1 ; Cell activation ; Cells, Cultured ; Cholesterol ; Cholesterol - pharmacology ; Efflux ; Extracellular Signal-Regulated MAP Kinases - metabolism ; IL-1β ; Inflammasomes ; Interleukin-1beta - biosynthesis ; Ion currents ; Lipopolysaccharides ; Machinery and equipment ; Macrophages ; MAP kinase ; Mice ; Mice, Inbred C57BL ; Mutation ; NLR Family, Pyrin Domain-Containing 3 Protein - physiology ; Oligomerization ; Phosphatidate Phosphatase - physiology ; Phosphatidic acid ; Potassium - metabolism ; Priming ; Receptor mechanisms ; Receptors, Purinergic P2X7 - physiology ; Restoration ; Signal Transduction - physiology ; Toll-Like Receptor 4 - physiology</subject><ispartof>The Journal of experimental medicine, 2017-02, Vol.214 (2), p.511-528</ispartof><rights>2017 Lordén et al.</rights><rights>Copyright Rockefeller University Press Feb 2017</rights><rights>2017 Lordén et al. 2017</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3932-6cc2584ed7cce4326e7c7bf426ea25e7d055d8b2fe114fd85ba5c20853f0145d3</citedby><cites>FETCH-LOGICAL-c3932-6cc2584ed7cce4326e7c7bf426ea25e7d055d8b2fe114fd85ba5c20853f0145d3</cites><orcidid>0000-0002-9688-1804 ; 0000-0002-2130-5298 ; 0000-0001-8540-8117 ; 0000-0002-4157-6714</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28031477$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lordén, Gema</creatorcontrib><creatorcontrib>Sanjuán-García, Itziar</creatorcontrib><creatorcontrib>de Pablo, Nagore</creatorcontrib><creatorcontrib>Meana, Clara</creatorcontrib><creatorcontrib>Alvarez-Miguel, Inés</creatorcontrib><creatorcontrib>Pérez-García, M Teresa</creatorcontrib><creatorcontrib>Pelegrín, Pablo</creatorcontrib><creatorcontrib>Balsinde, Jesús</creatorcontrib><creatorcontrib>Balboa, María A</creatorcontrib><title>Lipin-2 regulates NLRP3 inflammasome by affecting P2X7 receptor activation</title><title>The Journal of experimental medicine</title><addtitle>J Exp Med</addtitle><description>Mutations in human LPIN2 produce a disease known as Majeed syndrome, the clinical manifestations of which are ameliorated by strategies that block IL-1β or its receptor. However the role of lipin-2 during IL-1β production remains elusive. We show here that lipin-2 controls excessive IL-1β formation in primary human and mouse macrophages by several mechanisms, including activation of the inflammasome NLRP3. Lipin-2 regulates MAPK activation, which mediates synthesis of pro-IL-1β during inflammasome priming. Lipin-2 also inhibits the activation and sensitization of the purinergic receptor P2X7 and K
efflux, apoptosis-associated speck-like protein with a CARD domain oligomerization, and caspase-1 processing, key events during inflammasome activation. Reduced levels of lipin-2 in macrophages lead to a decrease in cellular cholesterol levels. In fact, restoration of cholesterol concentrations in cells lacking lipin-2 decreases ion currents through the P2X7 receptor, and downstream events that drive IL-1β production. Furthermore, lipin-2-deficient mice exhibit increased sensitivity to high lipopolysaccharide doses. Collectively, our results unveil lipin-2 as a critical player in the negative regulation of NLRP3 inflammasome.</description><subject>Acid phosphatase</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Caspase</subject><subject>Caspase 1 - metabolism</subject><subject>Caspase-1</subject><subject>Cell activation</subject><subject>Cells, Cultured</subject><subject>Cholesterol</subject><subject>Cholesterol - pharmacology</subject><subject>Efflux</subject><subject>Extracellular Signal-Regulated MAP Kinases - metabolism</subject><subject>IL-1β</subject><subject>Inflammasomes</subject><subject>Interleukin-1beta - biosynthesis</subject><subject>Ion currents</subject><subject>Lipopolysaccharides</subject><subject>Machinery and equipment</subject><subject>Macrophages</subject><subject>MAP kinase</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mutation</subject><subject>NLR Family, Pyrin Domain-Containing 3 Protein - physiology</subject><subject>Oligomerization</subject><subject>Phosphatidate Phosphatase - physiology</subject><subject>Phosphatidic acid</subject><subject>Potassium - metabolism</subject><subject>Priming</subject><subject>Receptor mechanisms</subject><subject>Receptors, Purinergic P2X7 - physiology</subject><subject>Restoration</subject><subject>Signal Transduction - physiology</subject><subject>Toll-Like Receptor 4 - physiology</subject><issn>0022-1007</issn><issn>1540-9538</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkc1r3DAQxUVJaDZpbjkHQy45xFt9WvKlUJZ8srShtJCbkOXRVottbSV7If99VLJZ2pxmmPnxeI-H0BnBc4IV_7yGfk4xqQgX9AOaEcFxWQumDtAMY0pLgrE8QscprTEmnIvqIzqiCjPCpZyhh6Xf-KGkRYTV1JkRUvFt-eORFX5wnel7k0IPRfNcGOfAjn5YFY_0SWbcwmYMsTD5uDWjD8MndOhMl-B0N0_Qr5vrn4u7cvn99n7xdVlaVjNaVtZSoTi00lrgjFYgrWwcz4uhAmSLhWhVQx0Qwl2rRGOEpVgJ5rJ_0bIT9OVVdzM1PbQWhjGaTm-i70181sF4_f9n8L_1Kmy1oDVXFc4ClzuBGP5MkEbd-2Sh68wAYUqaKMEJrrisM3rxDl2HKQ45nia1YpxVRJJMXb1SNoaUIri9GYL135J0Lkm_lZTx838D7OG3VtgLjKaMaw</recordid><startdate>20170201</startdate><enddate>20170201</enddate><creator>Lordén, Gema</creator><creator>Sanjuán-García, Itziar</creator><creator>de Pablo, Nagore</creator><creator>Meana, Clara</creator><creator>Alvarez-Miguel, Inés</creator><creator>Pérez-García, M Teresa</creator><creator>Pelegrín, Pablo</creator><creator>Balsinde, Jesús</creator><creator>Balboa, María A</creator><general>Rockefeller University Press</general><general>The Rockefeller University Press</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QL</scope><scope>7QP</scope><scope>7T5</scope><scope>7TK</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-9688-1804</orcidid><orcidid>https://orcid.org/0000-0002-2130-5298</orcidid><orcidid>https://orcid.org/0000-0001-8540-8117</orcidid><orcidid>https://orcid.org/0000-0002-4157-6714</orcidid></search><sort><creationdate>20170201</creationdate><title>Lipin-2 regulates NLRP3 inflammasome by affecting P2X7 receptor activation</title><author>Lordén, Gema ; Sanjuán-García, Itziar ; de Pablo, Nagore ; Meana, Clara ; Alvarez-Miguel, Inés ; Pérez-García, M Teresa ; Pelegrín, Pablo ; Balsinde, Jesús ; Balboa, María A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3932-6cc2584ed7cce4326e7c7bf426ea25e7d055d8b2fe114fd85ba5c20853f0145d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Acid phosphatase</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Caspase</topic><topic>Caspase 1 - metabolism</topic><topic>Caspase-1</topic><topic>Cell activation</topic><topic>Cells, Cultured</topic><topic>Cholesterol</topic><topic>Cholesterol - pharmacology</topic><topic>Efflux</topic><topic>Extracellular Signal-Regulated MAP Kinases - metabolism</topic><topic>IL-1β</topic><topic>Inflammasomes</topic><topic>Interleukin-1beta - biosynthesis</topic><topic>Ion currents</topic><topic>Lipopolysaccharides</topic><topic>Machinery and equipment</topic><topic>Macrophages</topic><topic>MAP kinase</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mutation</topic><topic>NLR Family, Pyrin Domain-Containing 3 Protein - physiology</topic><topic>Oligomerization</topic><topic>Phosphatidate Phosphatase - physiology</topic><topic>Phosphatidic acid</topic><topic>Potassium - metabolism</topic><topic>Priming</topic><topic>Receptor mechanisms</topic><topic>Receptors, Purinergic P2X7 - physiology</topic><topic>Restoration</topic><topic>Signal Transduction - physiology</topic><topic>Toll-Like Receptor 4 - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lordén, Gema</creatorcontrib><creatorcontrib>Sanjuán-García, Itziar</creatorcontrib><creatorcontrib>de Pablo, Nagore</creatorcontrib><creatorcontrib>Meana, Clara</creatorcontrib><creatorcontrib>Alvarez-Miguel, Inés</creatorcontrib><creatorcontrib>Pérez-García, M Teresa</creatorcontrib><creatorcontrib>Pelegrín, Pablo</creatorcontrib><creatorcontrib>Balsinde, Jesús</creatorcontrib><creatorcontrib>Balboa, María A</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of experimental medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lordén, Gema</au><au>Sanjuán-García, Itziar</au><au>de Pablo, Nagore</au><au>Meana, Clara</au><au>Alvarez-Miguel, Inés</au><au>Pérez-García, M Teresa</au><au>Pelegrín, Pablo</au><au>Balsinde, Jesús</au><au>Balboa, María A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Lipin-2 regulates NLRP3 inflammasome by affecting P2X7 receptor activation</atitle><jtitle>The Journal of experimental medicine</jtitle><addtitle>J Exp Med</addtitle><date>2017-02-01</date><risdate>2017</risdate><volume>214</volume><issue>2</issue><spage>511</spage><epage>528</epage><pages>511-528</pages><issn>0022-1007</issn><eissn>1540-9538</eissn><abstract>Mutations in human LPIN2 produce a disease known as Majeed syndrome, the clinical manifestations of which are ameliorated by strategies that block IL-1β or its receptor. However the role of lipin-2 during IL-1β production remains elusive. We show here that lipin-2 controls excessive IL-1β formation in primary human and mouse macrophages by several mechanisms, including activation of the inflammasome NLRP3. Lipin-2 regulates MAPK activation, which mediates synthesis of pro-IL-1β during inflammasome priming. Lipin-2 also inhibits the activation and sensitization of the purinergic receptor P2X7 and K
efflux, apoptosis-associated speck-like protein with a CARD domain oligomerization, and caspase-1 processing, key events during inflammasome activation. Reduced levels of lipin-2 in macrophages lead to a decrease in cellular cholesterol levels. In fact, restoration of cholesterol concentrations in cells lacking lipin-2 decreases ion currents through the P2X7 receptor, and downstream events that drive IL-1β production. Furthermore, lipin-2-deficient mice exhibit increased sensitivity to high lipopolysaccharide doses. Collectively, our results unveil lipin-2 as a critical player in the negative regulation of NLRP3 inflammasome.</abstract><cop>United States</cop><pub>Rockefeller University Press</pub><pmid>28031477</pmid><doi>10.1084/jem.20161452</doi><tpages>18</tpages><orcidid>https://orcid.org/0000-0002-9688-1804</orcidid><orcidid>https://orcid.org/0000-0002-2130-5298</orcidid><orcidid>https://orcid.org/0000-0001-8540-8117</orcidid><orcidid>https://orcid.org/0000-0002-4157-6714</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Acid phosphatase Animals Apoptosis Caspase Caspase 1 - metabolism Caspase-1 Cell activation Cells, Cultured Cholesterol Cholesterol - pharmacology Efflux Extracellular Signal-Regulated MAP Kinases - metabolism IL-1β Inflammasomes Interleukin-1beta - biosynthesis Ion currents Lipopolysaccharides Machinery and equipment Macrophages MAP kinase Mice Mice, Inbred C57BL Mutation NLR Family, Pyrin Domain-Containing 3 Protein - physiology Oligomerization Phosphatidate Phosphatase - physiology Phosphatidic acid Potassium - metabolism Priming Receptor mechanisms Receptors, Purinergic P2X7 - physiology Restoration Signal Transduction - physiology Toll-Like Receptor 4 - physiology |
| title | Lipin-2 regulates NLRP3 inflammasome by affecting P2X7 receptor activation |
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