Grant: Discovery Grants Program - Individual

Macrophages are highly versatile tissue-resident cells that play important roles beyond their well-known immune functions. Their diverse functions vary by tissue and are essential for maintaining tissue homeostasis, supporting tissue repair, and contributing to overall physiological health. They include, tissue maintenance, development and remodeling, lipid metabolism, iron recycling, and bone remodeling. This ongoing research program will investigate the long-lasting effects of chronic exercise on the physiological and homeostatic role of macrophages in non-immune tissues. In the proposed research, we will employ in vivo and in vitro experimental approaches - in humans and mice - designed to elucidate the molecular mechanisms through which regular moderate exercise triggers persistent adaptations in tissue resident macrophages. Regular, moderate exercise has been shown to modulate the inflammatory response, promoting a more balanced and beneficial inflammatory profile. Funded by an NSERC Discovery grant, we have explored how moderate exercise promotes persistent adaptations in mouse bone marrow derived macrophages. We showed that following 8 weeks of exercise, bone marrow derived macrophages (BMDM) were metabolically and functionally reprogrammed, which dampened their inflammatory responses. Importantly, other studies have showed that exercise can promote an anti-inflammatory state in macrophages in liver and adipose tissue. However, whether exercise induces adaptations in tissue resident macrophages and/or in their monocyte precursors has not been studied. Therefore, we hypothesize that the exercise-mediated anti-inflammatory adaptations of macrophages that occurred in the bone marrow also alters their monocyte progenitors before their migration to populate peripheral tissues. The goal of this proposal is to investigate the effect of exercise on the physiological and homeostatic function of tissue-resident macrophages as well as on recently recruited macrophages and their monocyte precursors in various non-immune tissues. In the first study, we will employ an 8-week moderate exercise protocol in mice to evaluate the effects on tissue resident macrophage function in various non-immune tissues, including muscle, liver, lungs, heart, adipose and brain will be harvested. In the second study, we will employ a moderate exercise training in healthy human volunteers and evaluate the effects on blood monocyte and muscle macrophage adaptations over a 12-week period. These studies will have a significant impact on our understanding of the fundamental role of exercise in reprogramming macrophages prior to and after they reside in tissue and how that alters their physiological functions in maintaining tissue homeostasis. This knowledge improves our ability to fine tune and modify physical activity patterns that can cause specific adaptations in resident macrophages that better maintains tissue homeostasis and function.