Macrophages recruited via CCR2 produce insulin-like growth factor-1 to repair acute skeletal muscle injury.
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.
Lu
Haiyan
H
Neuroinflammation Research Center, Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Ave./S90, Cleveland, OH 44195, USA.
Huang
Danping
D
Saederup
Noah
N
Charo
Israel F
IF
Ransohoff
Richard M
RM
Zhou
Lan
L
D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D017609:Barium Compounds / Q000633:toxicity; D002712:Chlorides / Q000633:toxicity; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D007150:Immunohistochemistry; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000502:physiology; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010587:Phagocytosis; D054390:Receptors, CCR2 / Q000235:genetics / Q000378:metabolism*; D012038:Regeneration / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
D000950:Antigens, Ly; D017609:Barium Compounds; C515335:Ccr2 protein, mouse; D002712:Chlorides; C494192:Ly-6C antigen, mouse; D054390:Receptors, CCR2; C024986:barium chloride; D007334:Insulin-Like Growth Factor I