A Drosophila metainflammation-blood tumor model links aspirin-triggered eicosanoid-like mediators to immune signaling

Abstract

Accumulating data from epidemiologic studies are linking aspirins use to a decline in chronic and metabolic inflammation that underlies many human diseases including some cancers. Aspirin reduces cyclooxygenase-mediated pro-inflammatory prostaglandins and promotes the production of pro-resolution molecules. Aspirin also triggers the production of anti-inflammatory electrophilic mono-oxygenated lipid mediators implicated in human pathologies. With the goal of developing a model system for studying the mechanisms of aspirin in reducing inflammation, we investigated aspirins effects in fruit fly models of chronic inflammation. Ectopic Toll/NF-{kappa}B and JAK/STAT signaling in D. melanogaster results in an overproliferation of hematopoietic blood progenitors coupled with metabolic inflammation in adipocytes. We report that, like mammals, flies are sensitive to aspirin treatment and it modulates the Toll-NF-{kappa}B axis. Aspirin-treated mutants simultaneously experience reduction in metabolic inflammation, mitosis, ectopic immune signaling, and macrophage infiltration. Moreover, flies synthesize 13-HODE, and aspirin triggers 13-EFOX-L2 production in mutants. In such flies with ectopic immune signaling, providing 13-HODEs precursor linoleic acid or performing targeted knockdown of transcription factor STAT in inflammatory blood cells boosts 13-EFOX-L2 levels while decreasing metabolic inflammation. Thus, hematopoietic cells regulate metabolic inflammation in flies, and their effects can be reversed by pharmaceutical or dietary intervention, suggesting deep phylogenetic conservation in animals ability to resolve systemic inflammation and repair tissue damage. This model system brings the power of Drosophila genetics to bear on immuno-metabolic mechanisms that boost systemic health and healing, with the potential to identify new targets for the treatment of chronic diseases in humans.