DHA-derived oxylipins, neuroprostanes and protectins, differentially and dose-dependently modulate the inflammatory response in human macrophages: putative mechanisms through PPAR activation
Résumé
Whereas the anti-inflammatory properties and mechanisms of action of long chain. 3 PUFAs
have been abundantly investigated, research gaps remain regarding the respective contribution and mechanisms of action of their oxygenated metabolites collectively known as oxylipins. A dose-dependent and comparative study was conducted using human primary macrophages. The aim was to compare the anti-inflammatory activity of two types of DHA- derived oxylipins including protectins (NPD1 and PDX), formed through lipoxygenase pathway and the neuroprostanes (14-A4t- and 4-F4t-NeuroP) formed through free-radical mediated oxygenation and suspected to be new anti-inflammatory mediators. Considering the potential ability of these lipid mediators to bind PPARs and knowing the central role of PPARs in the regulation of macrophage inflammatory response, transactivation assays was performed to compare the ability of protectins and neuroprostanes to activate PPARs. All molecules significantly reduced LPS-stimulated expression of cytokines but not at the same doses. Notably, NPD1 showed the most effect at 0.1 µM (IL-6:-14.9%, p<0.05 and TNF-α:-26.7%, p<0.05) while the other oxylipins had greater effects at 10 µM, with the strongest result obtained with the cyclopentenone neuroprostane 14-A4t-NeuroP (IL-6:-49.8%, p<0.001 and TNF-α:-40.8%, p<0.001, respectively). Concerning their binding to PPARs, Neuroprostanes and notably 14-A4t-NeuroP preferentially activate PPARγ while Protectins, especially PDX mainly activate PPARα. Combined together, these results bring new insights to the understanding of the role and mechanisms of action of DHA-derived oxylipins in the regulation of the macrophage inflammatory response