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J Exp Med. 2017 Feb;214(2):511-528. doi: 10.1084/jem.20161452. Epub 2016 Dec 28.

Lipin-2 regulates NLRP3 inflammasome by affecting P2X7 receptor activation.

Author information

1
Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas, Universidad de Valladolid, 47003 Valladolid, Spain.
2
Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, 28029 Madrid, Spain.
3
Departamento de Fisiología, Facultad de Medicina, Universidad de Valladolid, 47003 Valladolid, Spain.
4
Molecular Inflammation Group, Murcia Biomedical Research Institute, Hospital Virgen de la Arrixaca, Carretera Buenavista, 30120 Murcia, Spain.
5
Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas, Universidad de Valladolid, 47003 Valladolid, Spain mbalboa@ibgm.uva.es.

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.

PMID:
28031477
PMCID:
PMC5294860
DOI:
10.1084/jem.20161452
[Indexed for MEDLINE]
Free PMC Article

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