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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Bibliographic Details
Published in:The Journal of experimental medicine 2017-02, Vol.214 (2), p.511-528
Main Authors: Lordén, Gema, Sanjuán-García, Itziar, de Pablo, Nagore, Meana, Clara, Alvarez-Miguel, Inés, Pérez-García, M Teresa, Pelegrín, Pablo, Balsinde, Jesús, Balboa, María A
Format: Article
Language:English
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
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Summary: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.
ISSN:0022-1007
1540-9538
DOI:10.1084/jem.20161452