| First Author | Lordén G | Year | 2017 |
| Journal | J Exp Med | Volume | 214 |
| Issue | 2 | Pages | 511-528 |
| PubMed ID | 28031477 | Mgi Jnum | J:240100 |
| Mgi Id | MGI:5882428 | Doi | 10.1084/jem.20161452 |
| Citation | Lorden G, et al. (2017) Lipin-2 regulates NLRP3 inflammasome by affecting P2X7 receptor activation. J Exp Med 214(2):511-528 |
| abstractText | Mutations in human LPIN2 produce a disease known as Majeed syndrome, the clinical manifestations of which are ameliorated by strategies that block IL-1beta or its receptor. However the role of lipin-2 during IL-1beta production remains elusive. We show here that lipin-2 controls excessive IL-1beta 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-1beta 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-1beta 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. |
