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.—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 (2011). www.fasebj.org