Abstract
The mechanisms by which regular exercise prevents the development and progression of chronic inflammatory diseases are largely unknown. We find that exercise (Exe) enhances resolution of acute inflammation by promoting macrophage (MФ) phagocytosis and by augmenting resolvin D1 (RvD1) levels. When compared with sedentary controls (Sed), mice adapted to a 4-week treadmill exercise regimen displayed 1.48-fold higher MФ phagocytotic activity, enhanced RvD1 levels (Sed 28.08±1.5 vs Exe 48.01±8.6 pg/mL, n=6), and earlier neutrophilic clearance (ΔR i ~7 h) during peritonitis. Peritonitis cell extracts from exercise-adapted mice showed elevated expression of Alox15 (48 h: Sed 0.97±0.15 vs Exe 1.5±0.16 relative expression, n=8-9), Alox5 (48 h: Sed 0.77±0.15 vs Exe 1.7±0.27 relative expression, n=4-5), and RvD1 levels (48 h: 29.0±2.1 vs 52.6±8.9 pg/mL, n=5). Because exercise stimulates epinephrine (Epi) release, which has immunomodulatory effects, we questioned if Epi exerts pro-resolving actions on macrophages. Epi-treated macrophages displayed higher 15-lipoxygenase 1 expression and RvD1 levels, which were prevented by incubation with the α1 adrenergic receptor (AR-α1) blocker, Prazosin (Praz). During zymosan-induced peritonitis, Praz abrogated exercise-enhanced neutrophilic clearance (48 h: Exe+Veh 2.07±0.41 vs Exe+Praz 5.2±1.04 x10 6 PMN, n=5), MФ phagocytosis (Exe+Veh 33463.0±2174.0 vs Exe+Praz 8303.0±2748.0 MFI, n=5-7), and RvD1 biosynthesis (Exe+Veh 211.0±55.4 vs Exe+Praz 81.79±11.8 pg/mL, n=6). These results suggest that exercise-stimulated Epi release enhances resolution of acute inflammation in an AR-α1 dependent manner. These findings provide new mechanistic insights into the pro-resolving effects of exercise and may lead to the identification of novel pathways to stimulate resolution biology.
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