The role of P2X7 receptor in NLRP3 inflammasome activation by lipin-2

Abstract

Mutations in LPIN2 produce in humans a disease known as Majeed Syndrome, whose clinical manifestations are ameliorated by strategies that block IL-1b or its receptor. However the role of lipin-2 during IL-1b production remains elusive. We show here that lipin-2 controls excessive IL-1b formation in primary human and mouse macrophages by several mechanisms that include activation of the inflammasome NLRP3. Lipin-2 regulates MAPK activation which mediates synthesis of pro-IL-1b during inflammasome priming. Lipin-2 also inhibits the activation and sensitization of the purinergic receptor P2X7 and K+ efflux, ASC 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-1b production. Furthermore, lipin-2-deficient mice exhibit increased sensitivity to high LPS doses. Collectively, our results unveil lipin-2 as a critical player in the negative regulation of NLRP3 inflammasome.