Lipin-1 integrates lipid synthesis with proinflammatory responses during TLR activation in macrophages

• Published in: The Journal of immunology (1950) 2014-11, Vol.193 (9), p.4614-4622
• Main Authors: Meana, Clara, Peña, Lucía, Lordén, Gema, Esquinas, Esperanza, Guijas, Carlos, Valdearcos, Martín, Balsinde, Jesús, Balboa, María A
• Format: Article
• Language: English
• Subjects: Animals; Cluster Analysis; Cytokines - metabolism; Endotoxins - administration & dosage; Female; Gene Expression; Gene Expression Profiling; Humans; Inflammation - genetics; Inflammation - immunology; Inflammation Mediators - metabolism; Lipids - biosynthesis; Macrophage Activation - genetics; Macrophage Activation - immunology; Macrophages - immunology; Macrophages - metabolism; Male; Mice; Mice, Knockout; Nuclear Proteins - deficiency; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Phosphatidate Phosphatase - deficiency; Phosphatidate Phosphatase - genetics; Phosphatidate Phosphatase - metabolism; Signal Transduction; Toll-Like Receptors - agonists; Toll-Like Receptors - metabolism; Transcriptome
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1400238

Lipin-1 is a Mg(2+)-dependent phosphatidic acid phosphatase involved in the de novo synthesis of phospholipids and triglycerides. Using macrophages from lipin-1-deficient animals and human macrophages deficient in the enzyme, we show in this work that this phosphatase acts as a proinflammatory mediator during TLR signaling and during the development of in vivo inflammatory processes. After TLR4 stimulation lipin-1-deficient macrophages showed a decreased production of diacylglycerol and activation of MAPKs and AP-1. Consequently, the generation of proinflammatory cytokines like IL-6, IL-12, IL-23, or enzymes like inducible NO synthase and cyclooxygenase 2, was reduced. In addition, animals lacking lipin-1 had a faster recovery from endotoxin administration concomitant with a reduced production of harmful molecules in spleen and liver. These findings demonstrate an unanticipated role for lipin-1 as a mediator of macrophage proinflammatory activation and support a critical link between lipid biosynthesis and systemic inflammatory responses.