title: Lipin-2 regulates NLRP3 inflammasome by affecting P2X7 receptor activation.
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.
authors.affiliation: Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas, Universidad de Valladolid, 47003 Valladolid, Spain.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, 28029 Madrid, Spain.
authors.forename: Gema
authors.initials: G
authors.lastname: Lordén
authors.affiliation: Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas, Universidad de Valladolid, 47003 Valladolid, Spain.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, 28029 Madrid, Spain.
authors.forename: Itziar
authors.initials: I
authors.lastname: Sanjuán-García
authors.affiliation: Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas, Universidad de Valladolid, 47003 Valladolid, Spain.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, 28029 Madrid, Spain.
authors.forename: Nagore
authors.initials: N
authors.lastname: de Pablo
authors.affiliation: Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas, Universidad de Valladolid, 47003 Valladolid, Spain.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, 28029 Madrid, Spain.
authors.forename: Clara
authors.initials: C
authors.lastname: Meana
authors.affiliation: Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas, Universidad de Valladolid, 47003 Valladolid, Spain.|Departamento de Fisiología, Facultad de Medicina, Universidad de Valladolid, 47003 Valladolid, Spain.
authors.forename: Inés
authors.initials: I
authors.lastname: Alvarez-Miguel
authors.affiliation: Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas, Universidad de Valladolid, 47003 Valladolid, Spain.|Departamento de Fisiología, Facultad de Medicina, Universidad de Valladolid, 47003 Valladolid, Spain.
authors.forename: M Teresa
authors.identifier: 0000-0001-8540-8117
authors.initials: MT
authors.lastname: Pérez-García
authors.affiliation: Molecular Inflammation Group, Murcia Biomedical Research Institute, Hospital Virgen de la Arrixaca, Carretera Buenavista, 30120 Murcia, Spain.
authors.forename: Pablo
authors.identifier: 0000-0002-9688-1804
authors.initials: P
authors.lastname: Pelegrín
authors.affiliation: Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas, Universidad de Valladolid, 47003 Valladolid, Spain.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, 28029 Madrid, Spain.
authors.forename: Jesús
authors.identifier: 0000-0002-4157-6714
authors.initials: J
authors.lastname: Balsinde
authors.affiliation: Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas, Universidad de Valladolid, 47003 Valladolid, Spain mbalboa@ibgm.uva.es.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, 28029 Madrid, Spain.
authors.forename: María A
authors.identifier: 0000-0002-2130-5298
authors.initials: MA
authors.lastname: Balboa
mesh_terms: D000818:Animals; D020170:Caspase 1 / Q000378:metabolism; D002478:Cells, Cultured; D002784:Cholesterol / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D053583:Interleukin-1beta / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000502:physiology*; D010711:Phosphatidate Phosphatase / Q000502:physiology*; D011188:Potassium / Q000378:metabolism; D058486:Receptors, Purinergic P2X7 / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000502:physiology
chemical_list: D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D058486:Receptors, Purinergic P2X7; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D002784:Cholesterol; D048049:Extracellular Signal-Regulated MAP Kinases; D010711:Phosphatidate Phosphatase; C540254:Lipin 2 protein, mouse; D020170:Caspase 1; D011188:Potassium