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

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 media...

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Bibliographic Details
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
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Summary: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.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.1400238