Journal Article

Complement C3a signaling facilitates skeletal muscle regeneration by regulating monocyte function and trafficking

Zhang, Congcong, Cui, Wei, Song, Wen-Chao, Li, Yulin, Miwa, Takashi, Wang, Chunxiao, Du, Jie, Liu, Chang

2017

Overview

Regeneration of skeletal muscle following injury is accompanied by transient inflammation. Here we show that complement is activated in skeletal muscle injury and plays a key role during regeneration. Genetic ablation of complement C3 or its inactivation with Cobra Venom Factor (CVF) result in impaired muscle regeneration following cardiotoxin-induced injury in mice. The effect of complement in muscle regeneration is mediated by the alternative pathway and C3a receptor (C3aR) signaling, as deletion of Cfb , a key alternative pathway component, or C3aR leads to impaired regeneration and reduced monocyte/macrophage infiltration. Monocytes from C3aR -deficient mice express a reduced level of adhesion molecules, cytokines and genes associated with antigen processing and presentation. Exogenous administration of recombinant CCL5 to C3aR -deficient mice rescues the defects in inflammatory cell recruitment and regeneration. These findings reveal an important role of complement C3a in skeletal muscle regeneration, and suggest that manipulating complement system may produce therapeutic benefit in muscle injury and regeneration. Regeneration of skeletal muscle is accompanied by a transitory inflammatory phase. Here the authors show that the complement C3 component is activated following muscle injury, and signals through the alternative complement pathway to regulate immune cell infiltration and muscle regeneration.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/250/2501 / 631/532/2439 / 692/698/1671/1668/1973 / Alternative pathway / Animals / Antigen presentation / Antigen processing / Auditory defects / Bone Marrow Transplantation / Cardiotoxins - toxicity / Cell Movement - physiology / Cells, Cultured / Chemokine CCL5 - metabolism / Chimera - physiology / Clonal deletion / Cobra venom factor / Complement / Complement activation / Complement C3a - antagonists & inhibitors / Complement C3a - physiology / Complement component C3 / Complement component C3a / Complement Pathway, Alternative - physiology / Complement receptors / Cytokines / Deactivation / Disease Models, Animal / Elapid Venoms - pharmacology / Humanities and Social Sciences / Humans / Inactivation / Infiltration / Inflammation / Inflammation - immunology / Injuries / Macrophages / Macrophages - physiology / Male / Mice / Mice, Knockout / Monocytes / Monocytes - physiology / multidisciplinary / Muscle, Skeletal - drug effects / Muscle, Skeletal - injuries / Muscle, Skeletal - physiology / Muscles / Musculoskeletal system / Receptors, Complement - deficiency / Receptors, Complement - physiology / Recruitment / Regeneration / Regeneration - drug effects / Regeneration - immunology / Rodents / Science / Science (multidisciplinary) / Signal transduction / Signal Transduction - physiology / Signaling / Skeletal muscle / Venom / Wound Healing - physiology