Abstract

The skeletal muscle represents a unique site from the immunological point of view. Leukocytes are virtually absent in healthy conditions. However they are quickly recruited upon muscle injury, persist during the regenerative phases to disappear again after tissue healing. Thus, it represents and ideal scenario to study the involvement of the innate immune system in the homeostatic response either to the conventional programmed death of multinucleated myofibers and to the parallel occurrence of “non-canonical” cell death and survival programs, including necrosis and autophagy. Recruited phagocytes are responsible of the clearance of damaged myofibers and of dying muscle stem/progenitor cells, stromal cells and leukocytes. Muscle macrophages in particular are endowed with remarkable plasticity throughout regeneration and healing, switching from activated cells that generate inflammatory cytokines to reparative assets, that play a non redundant role during the resolution phases of the damage and regulate the termination of the inflammatory responses. This dynamic transition between is increasingly felt to be the key to muscle homeostasis. Conversely defects in the process favour maladaptive remodeling with deposition of collagen and fat accumulation and in predisposed individuals autoimmunity leading to inflammatory idiopathic myopathies. A specialized population of regulatory T (Treg) cells, which control the inflammatory response by promoting the M1-to-M2 switch, and the activation of the muscle stem cells, satellite cells is receiving increasing attention for their central role in tissue homeostasis. Thus, the immunological perception of muscle cell death and regeneration – in turn influenced by environmental cues, including mitophagy and alteration of the redox balance - determines whether these events foster successful tissue healing or persisting inflammatory myopathies. The insights that are progressively become available on this original scenario hold promises to develop new approaches for disease treatment. Thus, immunologic perception of death and regeneration of muscle cells determine whether these events promote healing of tissues or persistent inflammatory myopathies. The insights that are becoming increasingly available on this original scenario hold promise for the development of new approaches to the treatment of persistent human muscle disease.