Oxidized lipid species instigate distinct pro- and anti-inflammatory pathways
Oxidized lipids play a critical role in a variety of diseases with two faces: Pro- and anti-inflammatory. However, the molecular mechanisms of this Janus-faced activity remain largely unknown. A recent publication by the Kopf group (IMHS) shed light on the underlying mechanism.
How oxidized lipids regulate inflammatory responses is largely controversial. Investigation by Jonathan Muri et al now revealed that cyclopentenone-containing isoprostanoids such as 15d-PGJ2 possess a dual and opposing bioactivity in inflammation depending on their concentration. Exposure of DCs/macrophages to low concentrations of such lipids before TLR stimulation instigates an anti-inflammatory response mediated by Nrf2-dependent inhibition of NF-kB activation and downstream targets. By contrast, high concentrations of such lipids upon TLR activation of DCs/macrophages result in inflammatory apoptosis characterized by mitochondrial depolarization and caspase-8-mediated IL-1β maturation independently of Nrf2 and the classical inflammasome pathway. These results uncover an unexpected pro- and anti-inflammatory activity of physiologically relevant lipid species generated by enzymatic and non-enzymatic oxidation dependent on their concentration, a phenomenon known as hormesis.
Link to the paper in Cell Reports.