Lu, H., Huang, D., Ransohoff, R.M. & Zhou, L. Acute skeletal muscle injury: CCL2 expression by both monocytes and injured muscle is required for repair. FASEB J. 25, 3344-3355

Neuroinflammation Research Center, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Ave/S90, Cleveland, OH 44195, USA.
The FASEB Journal (Impact Factor: 5.04). 06/2011; 25(10):3344-55. DOI: 10.1096/fj.10-178939
Source: PubMed


CC chemokine ligand 2 (CCL2), a ligand of CC chemokine receptor 2 (CCR2), is essential to mount an adequate inflammatory response to repair acute skeletal muscle injury. We studied the mechanisms by which CCL2 regulates muscle inflammation and regeneration. Mobilization of monocytes/macrophages (MOs/MPs) but not lymphocytes or neutrophils was impaired from bone marrow to blood and from blood to injured muscles in Ccl2(-/-) mice. This was accompanied by poor phagocytosis, reduced up-regulation of insulin-like growth factor-1 (IGF-1), and impaired muscle regeneration. Bone marrow transfer from wild-type mice to irradiated Ccr2(-/-) but not Ccl2(-/-) mice restored muscle inflammation. Intravenously injected CCL2-deficient bone marrow monocytes could not enter wild-type injured muscles as well as wild-type bone marrow monocytes. Intravenously injected wild-type bone marrow monocytes could not enter CCL2-deficient injured muscles as well as wild-type injured muscles. CCL2 stimulated IGF-1 expression by wild-type but not CCR2-deficient intramuscular macrophages. A single intramuscular injection of IGF-1, but not PBS, markedly improved muscle regeneration in Ccl2(-/-) mice. We conclude that CCL2 is a major ligand of CCR2 to recruit MOs/MPs into injured muscles to conduct phagocytosis and produce IGF-1 for injury repair. CCL2 needs to be expressed by bone marrow cells, circulating monocytes, and injured muscle tissue cells to recruit MOs/MPs into injured muscles. CCL2/CCR2 signaling also up-regulates IGF-1 expression by intramuscular macrophages to promote acute skeletal muscle injury repair.

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    • "Resident macrophages are associated with the release of neutrophil chemoattractant and monocyte chemoattractant 1 (MCP-1) in response to deep skeletal muscle injury in mice [8]. MCP-1 has previously been demonstrated to recruit monocytes to areas of active inflammation [1] and is required for the recruitment of macrophages [30]. "
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    ABSTRACT: Skeletal muscle has recently been described as an endocrine organ, capable of releasing cytokines and regulators of metabolism. Microdialysis of the interstitial space of skeletal muscle enables analysis of the release of such cytokines. The purpose of this study was to determine the transient changes in concentration of metabolites and cytokines in human skeletal muscle in a 7h period following the insertion of a microdialysis probe. In total, sixteen microdialysis catheters were inserted into the vastus lateralis of male participants (age 26.2±1.35y, height 180.8±3.89cm, mass 83.9±3.86kg, BMI 25.7±0.87kgm(-2), body fat 26.1±3.0%). Serial samples were analyzed by micro-enzymatic and multiplexed immunoassay. Muscle interstitial glucose and lactate levels remained stable throughout, amino acid concentrations stabilized after 2.5h, however, insertion of a microdialysis catheter induced a 29-fold increase in peak IL-6 (p<0.001) and 35-fold increase in peak IL-8 concentrations (p<0.001) above basal levels 6h post insertion. In contrast to stable amino acid, glucose and lactate concentrations after 2h, commonly reported markers of tissue homeostasis in in vivo microdialysis, the multi-fold increase in IL-6 and IL-8 following insertion of a microdialysis catheter is indicative of a sustained disturbance of tissue homeostasis. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Cytokine 12/2014; 71(2):327-333. DOI:10.1016/j.cyto.2014.10.022 · 2.66 Impact Factor
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    • "Critical for this role of the innate immune system are monocytes infiltrating muscle tissue after injury (Lu et al., 2011; Nguyen et al., 2011) and producing pro-inflammatory cytokines, of which most notably TNF-a (Warren et al., 2002; Chen et al., 2005). As a counterbalance, the rs4072226CT rs6667202CA rs6676671TA rs10494879CG rs1800890TA rs6703630CT rs1800893GA rs1800896AG rs1800871CT rs1800872CA rs3024490GT rs1554286CT rs1878672CG rs3024496TC rs3024498AG rs4844553CT rs7548373GT rs7512090CT rs13376708GA rs4390174AG "
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    ABSTRACT: Recently, it has been shown that the capacity of the innate immune system to produce cytokines relates to skeletal muscle mass and strength in older persons. The interleukin-10 (IL-10) gene regulates the production capacities of IL-10 and tumour necrosis factor-α (TNF-α). In rural Ghana, IL-10 gene variants associated with different production capacities of IL-10 and TNF-α are enriched compared with Caucasian populations. In this setting, we explored the association between these gene variants and muscle strength. Among 554 Ghanaians aged 50 years and older, we determined 20 single nucleotide polymorphisms in the IL-10 gene, production capacities of IL-10 and TNF-α in whole blood upon stimulation with lipopolysaccharide (LPS) and handgrip strength as a proxy for skeletal muscle strength. We distinguished pro-inflammatory haplotypes associated with low IL-10 production capacity and anti-inflammatory haplotypes with high IL-10 production capacity. We found that distinct haplotypes of the IL-10 gene associated with handgrip strength. A pro-inflammatory haplotype with a population frequency of 43.2% was associated with higher handgrip strength (P = 0.015). An anti-inflammatory haplotype with a population frequency of 7.9% was associated with lower handgrip strength (P = 0.006). In conclusion, variants of the IL-10 gene contributing to a pro-inflammatory cytokine response associate with higher muscle strength, whereas those with anti-inflammatory response associate with lower muscle strength. Future research needs to elucidate whether these effects of variation in the IL-10 gene are exerted directly through its role in the repair of muscle tissue or indirectly through its role in the defence against infectious diseases.
    Aging cell 07/2014; 13(5). DOI:10.1111/acel.12244 · 6.34 Impact Factor
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    • "Although molecules are secreted by immune cells shape regeneration, the muscle is not a passive bystander. Indeed it releases a series of cytokines and chemokines collectively referred to as " myokines " [37] which also include IL-6, TNFí µí»¼, and CCL2 [38] [39]. Aside from proinflammatory functions, IL-6 was demonstrated to have both an autocrine function on satellite cell proliferation and muscle hypertrophy [40] and paracrine effects when released into the circulation (on glucose metabolism and lipolysis) [41]. "
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    ABSTRACT: Treating muscle disorders poses several challenges to the rapidly evolving field of regenerative medicine. Considerable progress has been made in isolating, characterizing, and expanding myogenic stem cells and, although we are now envisaging strategies to generate very large numbers of transplantable cells (e.g., by differentiating induced pluripotent stem cells), limitations directly linked to the interaction between transplanted cells and the host will continue to hamper a successful outcome. Among these limitations, host inflammatory and immune responses challenge the critical phases after cell delivery, including engraftment, migration, and differentiation. Therefore, it is key to study the mechanisms and dynamics that impair the efficacy of cell transplants in order to develop strategies that can ultimately improve the outcome of allogeneic and autologous stem cell therapies, in particular for severe disease such as muscular dystrophies. In this review we provide an overview of the main players and issues involved in this process and discuss potential approaches that might be beneficial for future regenerative therapies of skeletal muscle.
    BioMed Research International 06/2014; 2014(4):964010. DOI:10.1155/2014/964010 · 3.17 Impact Factor
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