Regular physical activity results in a phenotypic switch in resident macrophages in muscle and prevents development of chronic pain through release of IL-10

Abstract

Regular physical activity reduces chronic pain and may prevent the transition from acute to chronic pain. We show that regular physical activity prevents the development of chronic pain. Levels of IL-10, an anti-inflammatory cytokine which can reduce nociceptor sensitization, are increased during regular exercise. Since macrophages play a major role in cytokine production and are present in muscle tissue, we hypothesized there would be a phenotypic switch from classical macrophages (pro-inflammatory cytokines) in sedentary mice to regulatory macrophages (anti-inflammatory cytokines) in physically activity mice. We further hypothesized that IL-10 released from muscle macrophages is critical for the prevention of chronic pain in physically active animals. The current study tested if: 1) macrophage populations is different in sedentary vs. physically active mice; 2) administering IL-10 mimics the protective effects of regular physical activity; 3) blocking IL-10 receptors prevents protective effects of regular physical activity; and 4) if silencing the IL-10 gene in macrophages prevents the protective effects of regular physical activity. Physical activity was induced by placing C57BL/6J mice in cages with running wheels and compared to mice with no running wheels (sedentary) for 8 weeks. Immunohistochemistry analysis of the gastrocnemius muscle revealed a significant increase in regulatory macrophages in the muscle of physically active (68.5+/-4.6%) compared to sedentary (45.8+/-7.1%) mice. Furthermore, administration of IL-10 prevented the development of chronic pain (elicited by repeated acid injections), and blockade of IL-10 receptors in physically activity mice prevented the protective effects of regular physical activityonchronic pain. These resultsshowthat regular physical activity is associated with increases in regulatory macrophages, and that IL- 10 plays a critical role in preventing the development of chronic pain by regular physical activity.