Interleukin-10 reduces the pathology of mdx muscular dystrophy by deactivating M1 macrophages and modulating macrophage phenotype

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.

Transplanted Mesoangioblasts Require Macrophage IL-10 for Survival in a Mouse Model of Muscle Injury

“…Moreover, IL-10 regulates excessive or otherwise potentially deleterious immune effector functions. In support, Villalta and collaborators (59) have recently demonstrated a pivotal role of IL-10 expression in mdx mice, where the cytokine reduces muscle wasting: the effect on the muscle stem cell compartment was more important in the regenerative phase of muscle damage and apparently associated with an alternative polarization of muscle macrophages. Our results suggest that IL-10 is directly implicated in shielding transplanted stem cells from noxious microenvironmental signals, further adding to the array of protective actions of this "anti-inflammatory" molecule (81)(82)(83).…”

“…Macrophage infiltration is a hallmark of the injury of skeletal muscle (2,3), and these cells have been clearly shown to be involved in the natural history of primary inflammatory myopathies and genetic diseases of the tissue (Duchenne and Becker muscular dystrophies) (58,59). Several studies have characterized the macrophage role in the muscle, demonstrating that their presence is not an epiphenomenon: in contrast, they actively participate to muscle healing (3-14, 16, 17, 60).…”

Myeloid cell‐derived tumor necrosis factor‐alpha promotes sarcopenia and regulates muscle cell fusion with aging muscle fibers

“…Frozen muscles were homogenized and RNA was isolated, cDNA generated, and QPCR performed as described previously (Villalta et al, 2011). Primers used for QPCR are listed in Supporting Information Table S1.…”

Functional crosstalk of PGC-1 coactivators and inflammation in skeletal muscle pathophysiology

“…In dystrophic muscle, M1 macrophage activation and concomitant M2 macrophage repression e.g. by IFN exacerbates muscle wasting in DMD while conversely, symptoms are alleviated by IL-10, which activates M2 and represses M1 macrophages [265,266].…”

“…Reducing the inflammatory reaction in these conditions likely explains at least a part of the beneficial PGC-1 effect as other strategies to counteract inflammation have proven useful e.g. in DMD [101,265,266]. Conversely, endurance training that fosters PGC-1 expression protects against fiber damage, muscle inflammation and soreness.…”