Macrophage plasticity and the role of inflammation in skeletal muscle repair

Abstract

Effective repair of damaged tissues and organs requires the coordinated action of several cell types, including infiltrating inflammatory cells and resident cells. Recent findings have uncovered a central role for macrophages in the repair of skeletal muscle after acute damage. If damage persists, as in skeletal muscle pathologies such as Duchenne muscular dystrophy (DMD), macrophage infiltration perpetuates and leads to progressive fibrosis, thus exacerbating disease severity. Here we discuss how dynamic changes in macrophage populations and activation states in the damaged muscle tissue contribute to its efficient regeneration. We describe how ordered changes in macrophage polarization, from M1 to M2 subtypes, can differently affect muscle stem cell (satellite cell) functions. Finally, we also highlight some of the new mechanisms underlying macrophage plasticity and briefly discuss the emerging implications of lymphocytes and other inflammatory cell types in normal versus pathological muscle repair.

Figure 1

Inflammation and macrophage polarization in skeletal muscle injury and repair. Satellite cells are muscle-resident stem cells which are located underneath the basal lamina of myofibers and are normally quiescent (top right). Upon muscle injury, satellite cells get activated, start to proliferate as myoblasts, and subsequently fuse and differentiate into myotubes that later grow thereby replacing damaged muscle. Several cell types influence the outcome of regeneration, in particular inflammatory cells released from the blood (top left). Proinflammatory monocytes and neutrophils (not shown) extravasate shortly after damage, invading the injured areas where they differentiate into proinflammatory macrophages that phenotypically resemble M1 macrophages. These cells clear the damage and release a number of cytokines that stimulate myoblast proliferation. M2-like macrophages are present locally at later stages of regeneration acting as promoters of myoblast differentiation and fusion. Other cell types such as mast cells and lymphocytes also have less defined roles in muscle repair (not shown).