The Role of Lipins in Innate Immune Signaling

Using macrophages from lipin-1-deficient animals and human macrophages deficient in the enzyme, we have found 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, activation of mitogenactivated protein kinases and AP-1. Consequently, the generation of proinflammatory cytokines like IL-6, IL-12, IL-23, or enzymes like iNOS and COX-2 was reduced. Also, 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. On the other hand, we have also investigated the role of lipin-2 in the proinflammatory action of saturated fatty acids in murine and human macrophages. Depletion of lipin-2 promotes the increased expression of the proinflammatory genes Il6, Ccl2, and Tnf, which depends on the overstimulation of the JNK1/c-Jun pathway by saturated fatty acids. In contrast, overexpression of lipin2 reduces the release of proinflammatory factors. Metabolically, the absence of lipin-2 reduces the cellular content of triacylglycerol in saturated fatty acid-overloaded macrophages. These studies demonstrate a protective role for lipin-2 in proinflammatory signaling mediated by saturated fatty acids that occurs concomitant with an enhanced cellular capacity for triacylglycerol synthesis. Transcription of the lecture presented on Monday, October 31, 2016 at the XLI Congress of the Brazilian Society of Immunology, Campos do Jordao, Brazil.