Discovery of aspirin-triggered eicosanoid-like mediators in a Drosophila metainflammation blood tumor model

Abstract

Epidemiologic studies have linked the use of aspirin to a decline in chronic inflammation that underlies many human diseases, including some cancers. Aspirin reduces the levels of cyclooxygenase-mediated pro-inflammatory prostaglandins, promotes the production of proresolution molecules, and triggers the production of anti-inflammatory electrophilic mono-oxygenated (EFOX) lipid mediators. We investigated the effects of aspirin in fruit fly models of chronic inflammation. Ectopic Toll/NF-κB and JAK/STAT signaling in mutant D. melanogaster results in overproliferation of hematopoietic blood progenitors resulting in the formation of granuloma-like tumors. Ectopic JAK-STAT signaling also leads to metabolic inflammation. We report that aspirin-treated mutant flies experience reduction in metabolic inflammation, mitosis, ectopic immune signaling, and macrophage infiltration. Moreover, these flies synthesize 13-HODE, and aspirin triggers 13-oxoODE (13-EFOX-L 2) production. Providing the precursor of 13-HODE, linoleic acid, or performing targeted knockdown of the transcription factor STAT in inflammatory blood cells, boosts 13-EFOX-L 2 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 the ability of animals to resolve inflammation and repair tissue damage. These findings can help identify novel treatment targets in humans.

Drosophila melanogaster Responses against Entomopathogenic Nematodes: Focus on Hemolymph Clots

“…The remaining part of the synthetic pathway remained elusive since using the Basic Local Alignment Search Tool prevailed no obvious homologs for cyclooxygenases or lipoxygenases that could be identified in insect genomes. Still, biochemical evidence pointed towards related paths [46,55] and more recently, advanced bioinformatics and genetic evidence identified novel genes involved in eicosanoid production and novel key lipid mediators in Drosophila and the mosquito, Anopheles gambiae [58][59][60]. Functional analysis confirmed the genes' involvement in regulating inflammatory reactions in Drosophila as well as in hemocyte recruitment and immune priming upon Plasmodium infection in Anopheles.…”

Microenvironmental innate immune signaling and cell mechanical responses promote tumor growth

“…Pyrrolidine dithiocarbamates (PDTC) and aspirin are potent NF-kB signaling inhibitors; PDTC inhibits the transcription factor NF-kB, while aspirin inhibits the IKK complex (Crisostomo et al, 2008;Rö hl et al, 2004). Both inhibitors are known to be effective in human cells, mouse, and Drosophila in vivo models (Cuzzocrea et al, 2002;Moskalev and Shaposhnikov, 2011;Panettieri et al, 2019;Tanenhaus et al, 2012). With the help of the inducible escargot-flip-out system (Jiang et al, 2009), we generated GFP-marked mosaic clones expressing Mad/ Med or Shn RNAi and compared tumor cell clones in flies with or without inhibitor treatment.…”

A parasitoid wasp of Drosophila employs preemptive and reactive strategies to deplete its host’s blood cells

“…We recombined this latter insertion with the Antp-GAL4 insertion to make a UAS-mCD8GFP; Antp-GAL4 , Dome-MESO-GFP ( AntpDMG ) stock. hop Tum-l , msn-GAL4; UAS-mCD8GFP [ 87 ] uses the misshapen ( msn ) driver to mark lamellocytes [ 88 ]. For PSC-less animals, UAS-Hid [ 89 ] females were crossed with Collier-GAL4/CyO y+ males.…”