IL-10 Triggers Changes in Macrophage Phenotype That Promote Muscle Growth and Regeneration

Abstract

We examined the function of interleukin-10 (IL-10) in regulating changes in macrophage phenotype during muscle growth and regeneration following injury. Our findings showed that the Th1 cytokine response in inflamed muscle is characterized by high levels of expression of CD68, CCL-2, TNF-α and IL-6 at 1-day post-injury. During transition to the Th2 cytokine response, expression of those transcripts declined while CD163, IL-10, IL-10 receptor-1 and arginase-1 increased. Ablation of IL-10 amplified the Th1 response at 1-day post-injury, causing increases in IL-6 and CCL2, while preventing a subsequent increase in CD163 and arginase-1. Reductions in muscle damage that normally occurred between 1 and 4-days post-injury did not occur in IL-10 mutants. In addition, muscle regeneration and growth were greatly slowed by loss of IL-10. Furthermore, myogenin expression increased in IL-10 mutant muscle at 1-day post-injury, suggesting that the mutation amplified the transition from the proliferative to the early differentiation stages of myogenesis. In vitro assays showed that stimulation of muscle cells with IL-10 had no effect on cell proliferation or expression of MyoD or myogenin. However, co-culturing muscle cells with macrophages activated with IL-10 to the M2 phenotype increased myoblast proliferation affecting MyoD or myogenin expression, showing that M2 macrophages promote the early, proliferative stage of myogenesis. Collectively, these data show that IL-10 plays a central role in regulating the switch of muscle macrophages from a M1 to M2 phenotype in injured muscle in vivo and this transition is necessary for normal growth and regeneration of muscle.

Osteopontin, inflammation and myogenesis: influencing regeneration, fibrosis and size of skeletal muscle

“…The importance of different macrophage phenotypes in the early, inflammatory, T h 1 dominated phase and the later, regenerative T h 2 dominated phase of the response of skeletal muscle to injury has only recently been described (Deng et al 2012;Tidball 2011;Villalta et al 2011). The possibility that osteopontin influences macrophage phenotype and therefore inflammation and regeneration in injured and diseased muscle warrants further investigation.…”

Shared signaling systems in myeloid cell-mediated muscle regeneration

“…However, phagocytosis of muscle debris by macrophages is sufficient to induce M1 to M2 phenotype switching in the absence of IL-4 or IL-13 (Arnold et al, 2007;Mounier et al, 2013). In addition, IL-10 signaling is sufficient for transition to the M2 macrophage phenotype that drives muscle regeneration in other injury models (Deng et al, 2012), and there might be a similar IL-10-mediated role in muscle regeneration following injury by toxins.Much of the beneficial effect of eosinophil-derived IL-4 in regeneration appears to be mediated through a population of stromal cells called fibro/adipogenic progenitors (FAPs), which normally reside in mature muscle in a quiescent state. FAPs derive from a non-myogenic lineage and do not form muscle fibers, but they can nonetheless have a tremendous influence on myogenesis following injury by modulating the microenvironment (Joe et al, 2010).…”

CD163, a Hemoglobin/Haptoglobin Scavenger Receptor, After Intracerebral Hemorrhage: Functions in Microglia/Macrophages Versus Neurons

“…CD163 is involved in anti-inflammatory signaling following binding of certain forms of haptoglobin, including triggering interleukin-10 (IL-10) responses via phosphatidylinositol-3 kinase-dependent Akt signaling [9]. IL-10 is involved in the polarization of macrophages to the M2 (CD163 + ) phenotype [10,11], resulting in a positive feedback loop of IL-10 and CD163 expression. However, proinflammatory signals such as tumor necrosis factor-α, interferon-γ, transforming growth factor-β, and lipopolysaccharide lead to decreased levels of CD163 expression [5].…”