CX ₃ CR1 deficiency delays acute skeletal muscle injury repair by impairing macrophage functions

Abstract

Adequate inflammatory response predominated by macrophage infiltration is essential to acute skeletal muscle injury repair. The majority of intramuscular macrophages express the chemokine receptor CX 3 CR1. We studied the role of CX 3 CR1 in regulating intramuscular macrophage number and function in acute injury repair by using a loss-of-function approach. Muscle injury repair was delayed in CX 3 CR1GFP/GFP mice as compared with wild-type (WT) controls. CX 3 CR1 was predominantly expressed by macrophages but not by myogenic cells or capillary endothelia cells in injured muscles. Intramuscular macrophage number and subset composition were not altered by CX 3 CR1 deficiency. Intramuscular macrophage phagocytosis function was impaired by CX 3 CR1 deficiency as demonstrated by increased number of necrotic fibers (+115%) and percentage of necrotic area (+204%) at 7 d, increased number of intramuscular neutrophils at 3 (+89%) but not 1 d, reduced number of phagocytosing macrophages (212%) and phagocytosed beads within macrophages (215%) in CX 3 CR1 GFP/GFP mice as compared with WT controls. The mRNA expression of CD36 (250%), CD14 (243%), IGF-1 (253%), and IL-6 (240%) was reduced in CX 3 CR1-deficient macrophages as compared with WT controls. We conclude that CX 3 CR1 is important to acute skeletal muscle injury repair by regulating macrophage phagocytosis function and trophic growth factor production.-Zhao, W., Lu, H., Wang, X., Ransohoff, R. M., Zhou, L. CX 3 CR1 deficiency delays acute skeletal muscle injury repair by impairing macrophage functions. FASEB J. 30, 380-393 (2016). www.fasebj.org

Regulation of muscle growth and regeneration by the immune system

“…For many years, those studying muscle regeneration noted that perturbations that slow phagocytic removal of apoptotic cells and other debris were associated with delayed regeneration 17,19,57,66,67 . On the one hand, defective regeneration among large amounts of persistent debris was not surprising; the prolonged accumulation of debris could provide a physical obstacle to the regeneration.…”

Monocytes and macrophages in tissue repair: Implications for immunoregenerative biomaterial design

“…73,74 Nevertheless, CX3CR1 was important for macrophage phagocytosis functions, regulation of apolipoprotein E (ApoE) production, secretion of the inflammatory cytokine IL-6, and the trophic factor IGF-1. 73,74 …”

Snapshot: Targeting Macrophages as a Candidate for Tissue Regeneration

“…(Zhao et al, 2016) Brain Mouse Recruitment of MOs/MPs via CCR2 and activating TGF-β1 signaling pathway.…”

“…Next, these macrophages switched into the CX3CR1 hi / Ly-6C low subtype to produce cytokines to accomplish muscle regeneration (Arnold et al, 2007;Contreras-Shannon et al, 2007;Sun et al, 2009;Lu et al, 2011;Lu et al, 2011). Inspired by this discovery, instead of using the macrophageknock-out system, Zhao and colleagues (Zhao et al, 2016) generated CX3CR1 mutant transgenic mice as models, in which the function of macrophage was impaired. In barium chloride (BaCl2)-injected acute muscle injury mouse models, both the number of necrotic fibers and percentage of the necrotic area at 7 d were significantly augmented compared with the WT controls, indicating unsuccessful injury repair.…”

“…Phenotypes lacking macrophage fractalkine receptor CX3CR1, exhibiting inefficient phagocytosis and abnormal cytokine secretion, has therapeutic actions in arthrosclerosis (Lesnik et al, 2003), acute spinal cord injury (Donnelly et al, 2011;Freria et al, 2017) and acute colitis (Kostadinova et al, 2010). However, Zhao et al (Zhao et al, 2016) and Ishida et al (Ishida et al, 2008) found that CX3CR1 deficiency mice showed delayed repair of acute skeletal muscle injury. These findings provide another vision to explore the dual function of macrophages in different tissue/organ/ species during regeneration process.…”