Abstract
M1 macrophages play a major role in worsening muscle injury in the mdx mouse model of Duchenne muscular dystrophy. However, mdx muscle also contains M2c macrophages that can promote tissue repair, indicating that factors regulating the balance between M1 and M2c phenotypes could influence the severity of the disease. Because interleukin-10 (IL-10) modulates macrophage activation in vitro and its expression is elevated in mdx muscles, we tested whether IL-10 influenced the macrophage phenotype in mdx muscle and whether changes in IL-10 expression affected the pathology of muscular dystrophy. Ablation of IL-10 expression in mdx mice increased muscle damage in vivo and reduced mouse strength. Treating mdx muscle macrophages with IL-10 reduced activation of the M1 phenotype, assessed by iNOS expression, and macrophages from IL-10 null mutant mice were more cytolytic than macrophages isolated from wild-type mice. Our data also showed that muscle cells in mdx muscle expressed the IL-10 receptor, suggesting that IL-10 could have direct effects on muscle cells. We assayed whether ablation of IL-10 in mdx mice affected satellite cell numbers, using Pax7 expression as an index, but found no effect. However, IL-10 mutation significantly increased myogenin expression in vivo during the acute and the regenerative phase of mdx pathology. Together, the results show that IL-10 plays a significant regulatory role in muscular dystrophy that may be caused by reducing M1 macrophage activation and cytotoxicity, increasing M2c macrophage activation and modulating muscle differentiation.
Highlights
Duchenne muscular dystrophy (DMD) is caused by genetic deletion of dystrophin, a subsarcolemmal protein that strengthens the muscle cell membrane [1,2]
Because interleukin-10 (IL-10) modulates macrophage activation in vitro and its expression is elevated in mdx muscles, we tested whether IL-10 influenced the macrophage phenotype in mdx muscle and whether changes in IL-10 expression affected the pathology of muscular dystrophy
The results show that IL-10 plays a significant regulatory role in muscular dystrophy that may be caused by reducing M1 macrophage activation and cytotoxicity, increasing M2c macrophage activation and modulating muscle differentiation
Summary
Duchenne muscular dystrophy (DMD) is caused by genetic deletion of dystrophin, a subsarcolemmal protein that strengthens the muscle cell membrane [1,2]. Inhibiting the immune response in dystrophic muscle can delay the progression of muscular dystrophy and prolong ambulation. Longterm use of glucocorticoids produces unwanted side effects, including weight gain, susceptibility to infection and cushingoid appearance [10,11], which has led to our interest in identifying better-tolerated, immune-based interventions to reduce inflammatory cell-mediated damage to dystrophic muscle. IL-10 greatly inhibited the expression of interferon-gamma (IFN-g) [14] and tumor necrosis factor-alpha (TNF-a) [14], both of which drive pro-inflammatory responses and activate cytotoxic, M1 macrophages [13]. Once activated to the M1 phenotype, macrophages express cytokines such as TNF-a, IL-1b and IL-6 [15] that further promote inflammation and the M1 phenotype
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