ROLE OF PLA2-DERIVED BIOACTIVE LIPIDS IN NEUROINFLAMMATION

Abstract

Phospholipase A2 (PLA2) is an enzyme that is highly enriched in the brain and hydrolyzes glycerophospholipids to polyunsaturated fatty acids and lysophospholipids. Arachidonic acid, docosahexaenoic acid (DHA) and lysophosphatidic acid (LPA) are the major signaling lipid species produced by PLA2. In the present study, we provide evidence that the inflammomodulatory effects of DHA on BV-2 microglial cells are concentration-dependent with concentrations below 100μM exerting anti-inflammatory effects and those above, inducing pyroptosis. Since chronic neuroinflammation is a driver of chronic pain, we examined the involvement of LPA in pain transmission. We observed a decrease in mechanical allodynia in LPA1 receptor deficient mice, accompanied by a reduction in phosphorylated CREB expression in the brain, which is a critical player in central sensitization of chronic pain states. Thus, this project has helped identify LPA1 as a potential drug target for pain management and characterize a novel, DHA-mediated immunomodulatory phenomenon in microglia.