Metabolism of Docosahexaenoic Acid (DHA) Induces Pyroptosis in BV-2 Microglial Cells.

DHA is one of the most abundant fatty acids in the brain, largely present in stores of membrane phospholipids. It is readily released by the action of phospholipase A2 and is known to induce anti-inflammatory and neurotrophic effects. It is not thought to contribute to proinflammatory processes in the brain. In this study, an immortalized murine microglia cell line (BV-2) was used to evaluate the effect of DHA on neuroinflammatory cells. Pretreatment of BV-2 cells with low concentrations of DHA (30 µM) attenuates lipopolysaccharide-mediated inflammatory cytokine gene expression, consistent with known anti-inflammatory effects. However, higher (but still physiologically relevant) concentrations of DHA (200 µM) induce profound cell swelling and a reduction of viability. This is accompanied by increases in the expressions of inflammatory cytokine and lipoxygenase genes, activation of caspase-1 activity, and release of IL1β, indicating that cells were undergoing a proinflammatory cell death program known as pyroptosis. This process could be attenuated by pharmacological inhibition of 12-lipoxygenase (12-LOX, Alox12e), but not by inhibition of 5-LOX or 15-LOX. Cumulatively, these data demonstrate that DHA has an anti-inflammatory effect on microglial cells, but its metabolism by 12-LOX generates one or more products that activate a proinflammatory cell death program.