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

Abstract

Skeletal muscle is able to restore contractile functionality after injury thanks to its ability to regenerate. Following muscle necrosis, debris is removed by macrophages, and muscle satellite cells (MuSCs), the muscle stem cells, are activated and subsequently proliferate, migrate, and form muscle fibers restoring muscle functionality. In most muscle dystrophies (MDs), MuSCs fail to properly proliferate, differentiate, or replenish the stem cell compartment, leading to fibrotic deposition. However, besides MuSCs, interstitial nonmyogenic cells and inflammatory cells also play a key role in orchestrating muscle repair. A complete understanding of the complexity of these mechanisms should allow the design of interventions to attenuate MDs pathology 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). 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.

Figure 1

The complexity of the inflammatory milieu in muscle repair. During the initial phases of muscle damage, degenerating fibers release chemokines and cytokines recruiting mast cells, neutrophils (NEUT), and CD8/CD4 T cells which sustain proinflammatory M1 phenotype of recruited monocytes, thus promoting muscle fibers necrosis and debris clearing. These events are primarily mediated by IL-6, NO, TNFα, and IL-1β release. On the other hand, eosinophils are also recruited, which induce FAPs to sustain MuSCs proliferation via IL-4 release. Eosinophils-induced FAPs-produced follistatin promotes MuSCs differentiation, together with the clonally expanding mTreg which produce Areg. Areg also sustains MuSC proliferation and maintains/induces M2 anti-inflammatory/prohealing phenotype, supporting resolution of inflammation. Unbalance in the kinetics, quality, and activity of any of these actors would prevent resolution of inflammation, making muscle environment unfavourable for muscle regeneration, as it occurs in muscular dystrophies.