Fig. 8. Model for cross-talk between dystrophic skeletal muscle and bone marrow leading to a reprogrammed macrophage phenotype.

According to the model, chronic systemic exposure to damage-associated molecular patterns (DAMPs) acting as ligands for innate immune receptors such as TLR4, induces the hallmark features of trained immunity (cytokine hyperresponsiveness, metabolic alterations, epigenetic rewiring) in macrophage precursor cells residing in the bone marrow. A more open chromatin state for both pro-inflammatory and anti-inflammatory genes enhances the ability of future macrophages to adopt different phenotypes once the cells home to damaged dystrophic muscle tissue. The ultimate macrophage functional phenotype and impact (adaptive or maladaptive) are dependent on the combination of signals received at the bone marrow level and within the dystrophic muscle milieu.