Lipin-2 regulates NLRP3 inflammasome by affecting P2X7 receptor activation

Author:

Lordén Gema12,Sanjuán-García Itziar12,de Pablo Nagore12,Meana Clara12,Alvarez-Miguel Inés13,Pérez-García M. Teresa13ORCID,Pelegrín Pablo4ORCID,Balsinde Jesús12ORCID,Balboa María A.12ORCID

Affiliation:

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

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.

Funder

Spanish Ministry of Economy and Competitiveness

Instituto de Salud Carlos III

Spanish Ministry of Science and Innovation

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

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