Inflammatory monocytes recruited after skeletal muscle injury switch into antiinflammatory macrophages to support myogenesis

Abstract

Macrophages (MPs) are important for skeletal muscle regeneration in vivo and may exert beneficial effects on myogenic cell growth through mitogenic and antiapoptotic activities in vitro. However, MPs are highly versatile and may exert various, and even opposite, functions depending on their activation state. We studied monocyte (MO)/MP phenotypes and functions during skeletal muscle repair. Selective labeling of circulating MOs by latex beads in CX3CR1GFP/+ mice showed that injured muscle recruited only CX3CR1lo/Ly-6C+ MOs from blood that exhibited a nondividing, F4/80lo, proinflammatory profile. Then, within muscle, these cells switched their phenotype to become proliferating antiinflammatory CX3CR1hi/Ly-6C− cells that further differentiated into F4/80hi MPs. In vitro, phagocytosis of muscle cell debris induced a switch of proinflammatory MPs toward an antiinflammatory phenotype releasing transforming growth factor β1. In co-cultures, inflammatory MPs stimulated myogenic cell proliferation, whereas antiinflammatory MPs exhibited differentiating activity, assessed by both myogenin expression and fusion into myotubes. Finally, depletion of circulating MOs in CD11b–diphtheria toxin receptor mice at the time of injury totally prevented muscle regeneration, whereas depletion of intramuscular F4/80hi MPs at later stages reduced the diameter of regenerating fibers. In conclusion, injured skeletal muscle recruits MOs exhibiting inflammatory profiles that operate phagocytosis and rapidly convert to antiinflammatory MPs that stimulate myogenesis and fiber growth.

OPN‐a induces muscle inflammation by increasing recruitment and activation of pro‐inflammatory macrophages

“…These differential effects of OPN on myoblast proliferation and myotube fusion are congruent with the pro‐inflammatory effects of OPN, because inflammatory stimuli typically promote myoblast proliferation and inhibit myotube fusion (Arnold et al . 2007). As the beneficial effects of OPN ablation in dystrophic and ageing muscle are presumably attributable to inhibition of its inflammatory activities (OPN‐a is the only isoform expressed in mice), inhibiting the inflammatory action of OPN‐a while maintaining some activity of OPN‐c might serve as a useful therapy in humans.…”

Neutrophil derived CSF1 induces macrophage polarization and promotes transplantation tolerance

“…Inflammatory Ly6C hi monocytes are rapidly recruited to inflamed tissues and become alternatively activated Ly6C lo macrophages once the inciting inflammatory stimulus has been resolved (9). In organ transplantation, inflammatory Ly6C hi monocytes infiltrate the allograft early after transplantation and differentiate into suppressive Ly6C lo macrophages following costimulatory blockade (5).…”

CD4+CD25+Foxp3+regulatory T cells induce alternative activation of human monocytes/macrophages

“…These macrophages are often referred to as M2 or alternatively activated macrophages (AAM) and can be obtained in vitro after macrophage stimulation with IL-4/IL-13 (14,15), a combination of immune complexes and LPS (15), or IL-10 or glucocorticoids (16). The three different induction methods lead to more or less distinct M2 macrophage subsets (also referred to as M2a, M2b, and M2c, respectively), each with a typical cytokine/chemokine and cell surface marker profile (17), although recent data indicate that a certain degree of versatility exists between the subsets (18)(19)(20).…”