Protective activities of distinct omega-3 enriched oils are linked to their ability to upregulate specialized pro-resolving mediators

Abstract

Clinical studies using a range of omega-3 supplements have yielded conflicting results on their efficacy to control inflammation. Omega-3 fatty acids are substrate for the formation of potent immune-protective mediators, termed as specialized pro-resolving mediators (SPM). Herein, we investigated whether observed differences in the potencies of distinct omega-3 supplements were linked with their ability to upregulate SPM formation. Using lipid mediator profiling we found that four commercially available supplements conferred a unique SPM signature profile to human macrophages, with the overall increases in SPM concentrations being different between the four supplements. These increases in SPM concentrations were linked with an upregulation of macrophage phagocytosis and a decreased uptake of oxidized low-density lipoproteins. Pharmacological inhibition of two key SPM biosynthetic enzymes 5-Lipoxygenase or 15-Lipoxygenase reversed the macrophage-directed actions of each of the omega-3 supplements. Furthermore, administration of the two supplements that most potently upregulated macrophage SPM formation and reprogrammed their responses in vitro, to APOE-/- mice fed a western diet, increased plasma SPM concentrations and reduced vascular inflammation. Together these findings support the utility of SPM as potential prognostic markers in determining the utility of a given supplement to regulate macrophage responses and inflammation.

Quantitative profiling of inflammatory and pro-resolving lipid mediators in human adolescents and mouse plasma using UHPLC-MS/MS

“…This increased SPM concentrations and the reduction of n-6 PUFA based pro-inflammatory lipid mediators like LTB4 and PGD2 in OV treated mouse plasma may well contribute to the beneficial effects of n-3 PUFA based lipid emulsions. Several of these identified SPMs, like MaR1, PD1 and RvD5, have been shown to reduce lethality in mouse models of bacterial sepsis [46][47][48], and MaR1 has been shown to reduce inflammation in murine models of ulcerative colitis [49], following lung injury [50], and to reduce acute pancreatitis [51]. In addition, further support for a role for these SPMs in the beneficial effects of n-3 PUFA supplementation comes from two recent investigations, showing that blocking the metabolism of n-3 PUFAs to their respective SPMs reduces the beneficial PUFA mediated enhanced phagocytosis and efferocytosis of human and mouse macrophages [45,52].…”

The diverse roles of macrophages in metabolic inflammation and its resolution

“…Several SPMs have been directly implicated in improving atherosclerotic plaque inflammation ( Gerlach et al, 2020 ). Along these lines, increased SPMs in human monocyte-derived macrophages by omega-3 supplements were linked with an upregulation of macrophage phagocytosis and a decreased uptake of oxidized LDL ( Sobrino et al, 2020 ).…”

Structured Long-Chain Omega-3 Fatty Acids for Improvement of Cognitive Function during Aging

“…EPA produces E-series resolvins (RvE), whereas DHA produces protectins, D-series resolvins (RvD) and maresins (MaR) [ 14 , 40 ]. Some of these SPMs were proven to reduce chronic inflammation states characteristic of elderly in preclinical and clinical studies [ 40 , 41 ] through their inflammatory revolving effects acting as senomorphic agents [ 42 , 43 , 44 ].…”