期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 214, 期 2, 页码 511-528出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20161452
关键词
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资金
- Spanish Ministry of Economy and Competitiveness [SAF2013-48201-R, BFU2013-45867-R]
- Instituto de Salud Carlos III (RIC) [RD12/0042/0006]
- Regional Government of Castile and Leon [BIO/VA22/15]
- Spanish Ministry of Science and Innovation (FPU and FPI programs)
- Regional Government of Castile and Leon
Mutations in human LPIN2 produce a disease known as Majeed syndrome, the clinical manifestations of which are ameliorated by strategies that block IL-1 beta or its receptor. However the role of lipin-2 during IL-1 beta production remains elusive. We show here that lipin-2 controls excessive IL-1 beta 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-1 beta 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-1 beta 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.
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