Specialized pro-resolving lipid mediators stimulate mitochondrial metabolism in macrophages

Abstract

Abstract Chronic inflammation and sustained recruitment of classically activated macrophages (CAMs) with unchecked pro-inflammatory cytokine production is associated with disease development (e.g., atherosclerosis). Pro-inflammatory actions of CAMs are fueled by enhanced glycolysis and disruptions in the TCA cycle. Conversely, alternatively activated macrophages (AAMs) display an intact TCA cycle and mitochondrial oxidative phosphorylation (OXPHOS). Specialized pro-resolving lipid mediators (SPMs) stimulate resolution, in part, through actions on specific G-protein coupled receptors (GPCRs) in macrophages (e.g., RvD1□Fpr2). Whether SPMs exert pro-resolving effects by altering macrophage metabolism is unknown. We found that 1 hr treatment of SPMs (e.g., RvD1, RvD2, RvE1, and MaR1) enhanced basal (vehicle vs 1nM SPM; 6.11±0.1 vs RvD1 7.76±0.6 vs RvD2 9.48±0.9 vs RvE1 7.20±0.5 vs MaR1 8.73±0.9 pmol/min/μg protein; P<0.05; n=3), maximal (vehicle vs 0.1nM SPM; 9.06±1.1 vs RvD1 14.37±1.1 vs RvD2 16.54±2.7 vs RvE1 12.32±1.5 vs MaR1 13.28±1.3 pmol/min/μg protein; P<0.05; n=3), and ATP-linked respiration (vehicle vs 1nM SPM; 2.83±0.2 vs RvD1 4.50±0.3 vs RvD2 4.39±0.2 vs RvE1 4.71±0.3 vs MaR1 4.20±0.2 pmol/min/μg protein; P<0.05; n=3). Stimulation of mitochondrial metabolism with RvD1 was receptor mediated as Fpr2-deficient macrophages display no significant changes in metabolism following treatment (vehicle vs 1nM RvD1; basal 6.74±0.6 vs 6.52±0.2; maximal 11.54±1.2 vs 13.26±1.0; ATP-linked 5.84±0.8 vs 5.33±0.2 pmol/min/μg protein). Collectively, these data suggest that SPMs, despite having unique GPCRs, stimulate OXPHOS in macrophages, which could underlie their common pro-resolving properties.