From innate to adaptive immune response in muscular dystrophies and skeletal muscle regeneration: the role of lymphocytes

Skeletal muscle is able to restore contractile functionality after injury thanks to a tightly regulated process named muscle regeneration. During this process a large number of different cells skillfully participate at muscle fibers re-building. Following muscle necrosis, debris is removed by macrophages, and Muscle Satellite Cells (MuSCs), the muscle stem cells, are activated and subsequently proliferate, migrate and fuse together to form initially small centro-nucleated fibers. These small fibers become mature after an intense protein synthesis and restore muscle functionality. Besides MuSCs, many other cell populations participate in this complex process, including interstitial non-myogenic cells. In addition, inflammatory cells also play a key role in orchestrating muscle repair. In most muscle dystrophies (MDs), MuSCs fail to properly proliferate, differentiate or replenish the stem cell compartment leading to fibrotic deposition that compromises the contractile ability of muscle. Thus, a complete understanding of the complexity of muscle repair mechanisms and the cell populations involved should allow the design of interventions that attenuate pathogenetic mechanisms without disrupting regenerative processes. In this review we will focus on the contribution of immune cells in the onset and progression of MDs, with particular emphasis on Duchenne Muscular Dystrophy (DMD). In the past years, much has been learned about the crucial role of macrophages and their subtypes in MDs and healthy muscle regeneration. Much less is known about other inflammatory cells, and their eventual cross-talk, although recent observations have highlighted the role of previously under-appreciated cell populations. We will briefly summarize the current knowledge and recent advances made in our understanding of the involvement of different innate immune cells in MDs, and will move on to critically evaluate the possible role of cell populations within the acquired immune response. Revisiting previous observations in the light of recent evidence will likely change our current view of the onset and progression of the disease.