Exercise-Induced Gene Regulation in Skeletal Muscle and Its Role in Immune System Modulation

Abstract

Exercise has been reported to cause remodelling of the skeletal muscle tissue through coordinated interactions between myogenic, stromal and immune cell populations. However, cytokine-mediated mechanisms associated with immune-stromal crosstalk within the exercised muscle microenvironment remain incompletely understood. I hypothesised that exercise drives cell type-specific transcriptional reprogramming, enhancing signalling between immune cells and fibro-adipogenic progenitors (FAPs) via an IL-15 and IL-33 signalling axis. Analysing gene expression across major immune populations in skeletal muscle (NK cells, T cells, B cells, neutrophils, macrophages, ILC2s) and FAPs, I characterised the cellular sources and targets of IL-15 and IL-33. Assessing exercise-induced changes in IL-15, IL-33 and their receptor components demonstrated the effects of exercise on this signalling axis. IL-15 expression was localised to neutrophils, independent of IL-15ra. IL-33 was expressed in FAPSs, with IL-15 and IL-33 heterodimer receptors expressed predominantly in ILC2s. Exercise increased both the proportion and mean expression of IL-33, IL-15, IL-15ra expressing FAPs, suggesting enhanced sensitivity of FAPs to immune-derived cytokine cues following exercise. Across immune cell populations, exercise induced differential expression of genes associated with innate immune activation, metabolism, cytokine signalling. Notably, exercise increased stromal-immune cell interactions between FAPs and ILC2, including interactions involving IL-33. The top-ranking number of interactions into ILC2 arose from the specific FAP subtype Cxcl14+, expressing high transcripts of IL-15/IL-15ra. My data suggests a potential mechanistic framework in which exercise enhances IL-33-mediated immune-stromal crosstalk, with a potential unexplored role for IL-15 in mediating this crosstalk in the muscle microenvironment to favour immune activation and tissue remodelling.