Inflammation balance in skeletal muscle damage and repair

Abstract

Responding to tissue injury, skeletal muscles undergo the tissue destruction and reconstruction accompanied with inflammation. The immune system recognizes the molecules released from or exposed on the damaged tissue. In the local minor tissue damage, tissue-resident macrophages sequester pro-inflammatory debris to prevent initiation of inflammation. In most cases of the skeletal muscle injury, however, a cascade of inflammation will be initiated through activation of local macrophages and mast cells and recruitment of immune cells from blood circulation to the injured site by recongnization of damage-associated molecular patterns (DAMPs) and activated complement system. During the inflammation, macrophages and neutrophils scavenge the tissue debris to release inflammatory cytokines and the latter stimulates myoblast fusion and vascularization to promote injured muscle repair. On the other hand, an abundance of released inflammatory cytokines and chemokines causes the profound hyper-inflammation and mobilization of immune cells to trigger a vicious cycle and lead to the cytokine storm. The cytokine storm results in the elevation of cytolytic and cytotoxic molecules and reactive oxygen species (ROS) in the damaged muscle to aggravates the tissue injury, including the healthy bystander tissue. Severe inflammation in the skeletal muscle can lead to rhabdomyolysis and cause sepsis-like systemic inflammation response syndrome (SIRS) and remote organ damage. Therefore, understanding more details on the involvement of inflammatory factors and immune cells in the skeletal muscle damage and repair can provide the new precise therapeutic strategies, including attenuation of the muscle damage and promotion of the muscle repair.

Keywords: complements; damage-associated molecular patterns (DAMP); immune cell; inflammation; sepsis; skeletal muscle.

Figure 1

Inflammatory activation and its triggers in the skeletal muscle. (A-C), three pathways that activate inflammatory cells. (A), proteolytic cascades of complements are triggered by the damaged tissue and released C3a and C5a recruit and activate circulating leukocytes. (B), DAMPs released into circulation are recongnized by circulating leukocytes, which are recruted to and activated in the injured site. (C), damaged tissue-activated local immune sentinel cells release cytokines and chemokines to recruit and activate circulating leukocytes. ATP, Adenosine triphospate; CCL2, C-C motif chemokine ligand 2/Monocyte chemoattractant protein-1 (MCP-1); CCR2, C-C motif chemokine receptor; CIRBP, Cold-inducible RNA-binding protein; CXCL2, C-X-C motif chemokine ligand 2/macrophage inflammatory protein 2-alpha (MIP2-α); CXCR2, C-X-C motif chemokine receptor 2; DAMPs, Damage-associated molecular patterns; HMGB1, High mobility group box-1; IL-1β, interleukin-1β; iNKT cells, Invariant natural killer T cells. LTs, Leukotrienes; MBL, Mannose-binding lectin; MASP1/2, MBL-associated serine protease-1/2; mtDNA, mitochodrial DNA; NO, Nitric oxide; PGs, Prostaglandins; P2, Purinergic preceptors (P2Rs); S100, S100 protein; RAGE, Receptor for advanced glycation endproducts; ROS, Reactive oxygen species; SRs, Scavenger receptors; 5-TH, Serotonin; TLRs, Toll-like receptors; TNFα, Tumor necrosis factor α; C1 (2, 3, 4, 5), complement component 1 (2, 3, 4, 5); C1q, C1 complex componet– recognicition molecular C1q; C1r and C1s, C1 complex componet—tetrameric protease complex C1R₂S₂; C3bBb and C4b2b, C3 convertase; C2b, smaller fragment of C2 cleaved by C1s; C3a and C3b, two fragments of cleaved C3; C4b, Complement component C4b; C4bC2b, C3 convertase; C3bBb3b and C4b2b3b, C5 convertase; C5a and C5b, two fragments of cleaved C5; C3aR, C3a receptor; C5aR, C5a receptor; Factor B, Complement factor B; Bb, Fragment of complement factor B.

Figure 2

The effects of inflammatory activation on the skeletal muscle. (A), inflammation distorys tissues; (B), inflammation promtes muscle repair; (C), a vicious cyle of the tissue damage and inflammation. C5b (6, 7, 8, 9), complement component 5b (6, 7, 8, 9); FGF2, Fibroblast growth factor 2; IGF-1, Insulin-like growth factor 1; IL-1β (6, 8, 10, 41), interleukin-1β (6, 8, 10, 41); ROS, Reactive oxygen species; TGFβ, Tranformaing growth factor-β; 5-TH, Serotonin; TNFα, Tumor necrosis factor α; TWEAK, TNF-like weak inducer of apoptosis; VEGF, Vascular endothelial growth factor.

Figure 3

Inflammation balance in skeletal muscle damage and repair. How to accurately balance the beneficial and detrimental effect of inflammation during the skeletal muscle damage and repair is a challenge for precise therapeutic strategies.