The role of the immune system in response to muscle damage

Abstract

Following skeletal muscle damage, complex cellular events are required that coordinate the restoration of the functional environment of muscle fibers. Theimmune system fulfills important roles in recognizing the damaged environment and mediating muscle regeneration. Two time-dependent and functionally distinct phases of muscle regeneration can be distinguished. › The first pro-inflammatory response involves the expression of cytokines that mediate the early invasion of M1-phenotype macrophages after muscle damage. Within the first three days after damage, these macrophages are functionally involved in the removal of cell debris associated with the expression of cytokines that induce proliferation of satellite cells (SCs). A time-dependent change in the expression of cytokines within three to seven days after injury initiates the type 2 immune response associated with increased accumulation of regulatory T-cells. › Within this time frame, the shift of macrophages to a pro-re-generative M2 phenotype occurs, associated with extracellular matrix production, inhibition of SC proliferation and the onset of differentiation. M2 macrophages further activate fibro-adipogenic precursor cells (FAP) that contribute to extracellular matrix production. The crucial switch of macrophage phenotypes is induced by the release of IL-10 and TGF-β cytokines, but also supported by the activation of AMPK. Localized IGF-1 release by macrophages essentially supports the myogenic program and subjects satellite cells to differentiation. Myotube formation, extracellular matrix production and angiogenesis finally contribute to the restoration of the skeletal muscle functional environment. Here, we give a short overview of the major cytokines, modulators and interacting cells that contribute to and coordinate immune responses to promote muscle regeneration.