Lipin‐1 Links Lipid Signaling with Inflammation

Abstract

Lipins are Mg2+‐dependent phosphatidic acid phosphatases involved in the de novo synthesis of phospholipids and triglycerides. Although they regulate cellular levels of important signaling lipids, little is known about the role of lipins in the immune response. Using lipin‐1‐deficient animals, we show in this work that this phosphatase acts as a proinflammatory modulator during TLR signaling and also in the developmentof in vivo inflammatory processes. After stimulation with lipopolysaccharide (LPS), lipin‐1 deficient macrophages had a decreased production of DAG, activation of MAPKs and phosphorylation of the AP‐1 transcription factor c‐jun. Consequently, the generation of cytokines like IL‐6, IL12, IL23, or proteins like iNOS and COX‐2 was reduced. In the same line, responses to Salmonella were diminished, although no differences in phagocytosis rates were found. During the development of chemically‐induced colitis these animals exhibited reduced inflammatory responses and were protected against tissue damage and disease severity. These effects correlated with a lower generation of gut pathogenic factors like IL‐17 and IFNg and increased production of the gut protective factor TGFa. These findings demonstrate an unanticipated role for lipin‐1 as a mediator of inflammatory‐based pathological states and support a critical link between lipid signaling and inflammatory responses.Supported by Grant SAF2013‐48201‐R from the Spanish Ministry of Economy and Competitiveness.