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

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

doi:10.1038/s41467-017-01526-z

Abstract

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.

Highlights

Regeneration of skeletal muscle following injury is accompanied by transient inflammation
We made several new findings: (1) the activation of the complement cascade promotes muscle regeneration after injury; (2) the Alternative pathway (AP) plays a major role in the process while the classical and lectin pathways were apparently not critical; and (3) complement C3a–C3a receptor (C3aR), but not C5a–C5aR, signaling is required for initiating recruitment of circulating monocytes into injured muscle where they promoted muscle regeneration
After CTX treatment, damaged muscle fibers could release a number of damageassociated molecular patterns, including intracellular proteins, ATP21, heat shock protein (HSP)[22] or high mobility group box-1 protein (HMGB1)[23], as well as non-protein components derived from the extracellular matrix such as hyaluronan fragments[24], all of which were potential activators of complement

Summary

Introduction

Regeneration of skeletal muscle following injury is accompanied by transient inflammation. Depletion of the macrophage population before cardiotoxin injection or after necrotic cell removal all led to impaired muscle regeneration[9] Several chemokines, such as MCP-1/CCL2, MIP-1α/CCL3, CXCL12, CXCL16, CX3CL1, were reported to participate in muscle injury and regeneration, which could recruit the circulation monocytes to injured muscle and promote the migration of myoblast. In our previous study using a mouse model of cardiotoxin (CTX)-mediated skeletal muscle injury and regeneration, we obtained microarray data showing increased expression of complement components (C1qa, C3ar1) in injured muscle tissues at 3 days after CTX injection[20]. Exogenous administration of recombinant CCL5 rescues the defects in inflammatory cell recruitment and muscle regeneration of C3aR-deficient mice These findings reveal an important role of complement C3a pathway in the inflammation initiation and muscle regeneration

Methods

Results

Conclusion