Macrophages recruited via CCR2 produce insulin-like growth factor-1 to repair acute skeletal muscle injury. FASEB J

Neuroinflammation Research Center, Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Ave./S90, Cleveland, OH 44195, USA.
The FASEB Journal (Impact Factor: 5.48). 10/2010; 25(1):358-69. DOI: 10.1096/fj.10-171579
Source: PubMed

ABSTRACT CC chemokine receptor 2 (CCR2) is essential to acute skeletal muscle injury repair. We studied the subpopulation of inflammatory cells recruited via CCR2 signaling and their cellular functions with respect to muscle regeneration. Mobilization of monocytes/macrophages (MOs/MPs), but not lymphocytes or neutrophils, was impaired from bone marrow to blood and from blood to injured muscle in Ccr2(-/-) mice. While the Ly-6C(+) but not the Ly-6C(-) subset of MOs/MPs was significantly reduced in blood, both subsets were drastically reduced in injured muscle of Ccr2(-/-) mice. Expression of insulin-like growth factor-1 (IGF-I) was markedly up-regulated in injured muscle of wild-type but not Ccr2(-/-) mice. IGF-I was strongly expressed by macrophages within injured muscle, more prominently by the Ly-6C(-) subset. A single injection of IGF-I, but not PBS, into injured muscle to replace IGF-I remarkably improved muscle regeneration in Ccr2(-/-) mice. CCR2 was not detected in myogenic cells or capillary endothelial cells in injured muscle to suggest its direct involvement in muscle regeneration or angiogenesis. We conclude that CCR2 is essential to acute skeletal muscle injury repair primarily by recruiting Ly-6C(+) MOs/MPs. Within injured muscle, these cells conduct phagocytosis, contribute to accumulation of intramuscular Ly-6C(-) macrophages, and produce a high level of IGF-I to promote muscle regeneration.

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    • "After skeletal muscle injury, monocytes with a proinflammatory profile migrate from the blood into the muscle tissue and differentiate into pro-inflammatory cytokine producing macrophages , which clear necrotic tissue and stimulate muscle progenitor proliferation (Arnold et al., 2007; Tidball & Wehling-Henricks, 2007). Two days after injury, pro-inflammatory macrophages in mice change into macrophages with an anti-inflammatory phenotype to stimulate further differentiation of muscle progenitor cells and fusion of myotubes (Arnold et al., 2007; Lu et al., 2011). "
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    ABSTRACT: In mice, monocytes that exhibit a pro-inflammatory profile enter muscle tissue after muscle injury and are crucial for clearance of necrotic tissue and stimulation of muscle progenitor cell proliferation and differentiation. The aim of this study was to test if pro-inflammatory capacity of classically activated (M1) monocytes relates to muscle mass and strength in humans. This study included 191 male and 195 female subjects (mean age 64.2 years (SD 6.4) and 61.9 ±6.4 respectively) of the Leiden Longevity Study. Pro-inflammatory capacity of M1 monocytes was assessed by ex vivo stimulation of whole blood with Toll-like receptor (TLR) 4 agonist lipopolysaccharide (LPS) and TLR-2/1 agonist tripalmitoyl- S-glycerylcysteine (Pam3 Cys-SK4 ), both M1 phenotype activators. Cytokines that stimulate M1 monocyte response (IFN-γ and GM-CSF) as well as cytokines that are secreted by M1 monocytes (IL-6, TNF-α, IL-12 and IL-1β) were measured. Analyses were adjusted for age, height and body fat mass. Upon stimulation with LPS, the cytokine production capacity of INF-y, GM-CSF, and TNF-α was significantly positively associated with lean body mass, appendicular lean mass and handgrip strength in men, but not in women. Upon stimulation with Pam3 Cys-SK4 , IL-6, TNF-α and Il-1β was significantly positively associated with lean body mass and appendicular lean in women, but not in men. Taken together, this study shows that higher pro-inflammatory capacity of M1 monocytes upon stimulation is associated with muscle characteristics and sex dependent. This article is protected by copyright. All rights reserved.
    Aging cell 04/2013; 12(4). DOI:10.1111/acel.12095 · 5.94 Impact Factor
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    • "This fits with a sharp increase in wound macrophages following IGF-1R antagonism over and above that observed in Ovx mouse wounds (Figure 2g). IGF-1 has been linked to inflammation in numerous tissue systems, contributing to tissue repair in injured muscle (Lu et al., 2011) and heart (Kluge et al., 1995), and associated with inflammation of the airway in asthma patients (Yamashita et al., 2005) and the intestine in inflammatory bowel disorder patients (Eivindson et al., 2005). Moreover, local IGF-1 attenuates tumor necrosis factor-a and interleukin-1b production in rat burn wounds (Spies et al., 2001), whereas cerebral IGF-1 reduces proinflammatory cytokine expression in lipopolysaccharide-treated mice (Park et al., 2011). "
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    ABSTRACT: Although it is understood that endogenous IGF-1 is involved in the wound repair process, the effects of exogenous IGF-1 administration on wound repair remain largely unclear. In addition, the signaling links between IGF-1 receptor (IGF-1R) and estrogen receptors (ERs), which have been elucidated in other systems, have yet to be explored in the context of skin repair. In this study, we show that locally administered IGF-1 promotes wound repair in an estrogen-deprived animal model, the ovariectomized (Ovx) mouse, principally by dampening the local inflammatory response and promoting re-epithelialization. Using specific IGF-1R and ER antagonists in vivo, we reveal that IGF-1-mediated effects on re-epithelialization are directly mediated by IGF-1R. By contrast, the anti-inflammatory effects of IGF-1 are predominantly via the ERs, in particular ERα. Crucially, in ERα-null mice, IGF-1 fails to promote healing, and local inflammation is increased. Our findings illustrate the complex interactions between IGF-1 and estrogen in skin. The fact that IGF-1 may compensate for estrogen deficiency in wound repair, and potentially other contexts, is an important consideration for the treatment of postmenopausal pathology.Journal of Investigative Dermatology advance online publication, 19 July 2012; doi:10.1038/jid.2012.228.
    Journal of Investigative Dermatology 07/2012; 132(12). DOI:10.1038/jid.2012.228 · 6.37 Impact Factor
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    • "This observation suggests that macrophages regulate muscle healing through IGF1. Indeed, in CCR2 −/− mice, local IGF1 injection at least partially makes up for the lack of recruited macrophages (Lu et al., 2011b). In vitro, IGF1 elicits in muscle cells a biphasic response, first stimulating cell proliferation and subsequently enhancing myogenic differentiation (Rosenthal and Cheng, 1995), a sequence of events that could be teleologically suited to sustain the repair of damaged tissue. "
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    ABSTRACT: Macrophages are present in regenerating skeletal muscles and participate in the repair process. This is due to a unique feature of macrophages, i.e., their ability to perceive signals heralding ongoing tissue injury and to broadcast the news to cells suited at regenerating the tissue such as stem and progenitor cells. Macrophages play a complex role in the skeletal muscle, probably conveying information on the pattern of healing which is appropriate to ensure an effective healing of the tissue, yielding novel functional fibers. Conversely, they are likely to be involved in limiting the efficacy of regeneration, with formation of fibrotic scars and fat replacement of the tissue when the original insult persists. In this review we consider the beneficial versus the detrimental actions of macrophages during the response to muscle injury, with attention to the available information on the molecular code macrophages rely on to guide, throughout the various phases of muscle healing, the function of conventional and unconventional stem cells. Decrypting this code would represent a major step forward toward the establishment of novel targeted therapies for muscle diseases.
    Frontiers in Immunology 11/2011; 2:62. DOI:10.3389/fimmu.2011.00062
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