title: Acute skeletal muscle injury: CCL2 expression by both monocytes and injured muscle is required for repair.
abstract: 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.
authors.affiliation: Neuroinflammation Research Center, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Ave/S90, Cleveland, OH 44195, USA.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Lu
authors.forename: Danping
authors.initials: D
authors.lastname: Huang
authors.forename: Richard M
authors.initials: RM
authors.lastname: Ransohoff
authors.forename: Lan
authors.initials: L
authors.lastname: Zhou
mesh_terms: D000818:Animals; D017609:Barium Compounds / Q000633:toxicity; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D054410:Chemokine CCL7 / Q000235:genetics / Q000378:metabolism; D002712:Chlorides / Q000633:toxicity; D005786:Gene Expression Regulation / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018945:Monocyte Chemoattractant Proteins / Q000235:genetics / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000293:injuries* / Q000378:metabolism*; D009135:Muscular Diseases / Q000139:chemically induced / Q000378:metabolism; D054390:Receptors, CCR2 / Q000235:genetics / Q000378:metabolism
chemical_list: D017609:Barium Compounds; C491224:Ccl12 protein, mouse; C491768:Ccl2 protein, mouse; C515451:Ccl7 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D054410:Chemokine CCL7; D002712:Chlorides; D018945:Monocyte Chemoattractant Proteins; D054390:Receptors, CCR2; C024986:barium chloride; D007334:Insulin-Like Growth Factor I