MCP-1 deficiency causes altered inflammation with impaired skeletal muscle regeneration

Abstract

We examined the role of MCP-1, a potent chemotactic and activating factor for macrophages, in perfusion, inflammation, and skeletal muscle regeneration post-ischemic injury. MCP-1-/- or C57Bl/6J control mice [wild-type (WT)] underwent femoral artery excision (FAE). Muscles were collected for histology, assessment of tissue chemokines, and activity measurements of lactate dehydrogenase (LDH) and myeloperoxidase. In MCP-1-/- mice, restoration of perfusion was delayed, and LDH and fiber size, indicators of muscle regeneration, were decreased. Altered inflammation was observed with increased neutrophil accumulation in MCP-1-/- versus WT mice at Days 1 and 3 (P< or =0.003), whereas fewer macrophages were present in MCP-1-/- mice at Day 3. As necrotic tissue was removed in WT mice, macrophages decreased (Day 7). In contrast, macrophage accumulation in MCP-1-/- was increased in association with residual necrotic tissue and impaired muscle regeneration. Consistent with altered inflammation, neutrophil chemotactic factors (keratinocyte-derived chemokine and macrophage inflammatory protein-2) were increased at Day 1 post-FAE. The macrophage chemotactic factor MCP-5 was increased significantly in WT mice at Day 3 compared with MCP-1-/- mice. However, at post-FAE Day 7, MCP-5 was significantly elevated in MCP-1-/- mice versus WT mice. Addition of exogenous MCP-1 did not induce proliferation in murine myoblasts (C2C12 cells) in vitro. MCP-1 is essential for reperfusion and the successful completion of normal skeletal muscle regeneration after ischemic tissue injury. Impaired muscle regeneration in MCP-1-/- mice suggests an important role for macrophages and MCP-1 in tissue reparative processes.

Interleukin-6/Signal Transducer and Activator of Transcription 3 (STAT3) Pathway Is Essential for Macrophage Infiltration and Myoblast Proliferation during Muscle Regeneration

“…3). It was reported that muscle regeneration was impaired in CCL2 Ϫ/Ϫ mice with less macrophage infiltration (8), which was consistent with our result that there was less CCL2 production in IL-6 Ϫ/Ϫ mice with less macrophage infiltration.…”

“…Depletion of the macrophage population before cardiotoxin injection or after necrotic cell removal all lead to an impaired regeneration (6,7). Knock-out of chemokine CCL2 (Ϫ/Ϫ) or its receptor CCR2 (Ϫ/Ϫ) would result in impaired muscle regeneration with macrophages infiltration deficiency (8,9). We also previously reported that lack of chemokine CXCL16 leads to reduced macrophage infiltration, which causes poor muscle regeneration (10).…”

Transplanted Mesoangioblasts Require Macrophage IL-10 for Survival in a Mouse Model of Muscle Injury

“…The molecular pathways by which macrophages sustain muscle regeneration are still unclear (7,8,65). Notably, macrophages secrete both signals such as TNF-a that worsen muscle wasting via activation of the FOXO transcription factor (66, 67) and molecules that have an opposite function, such as IGF-1, a central regulator of muscle regeneration (7,56,57), or IL-10 (59, 68, 69).…”

Inflammatory monocytes recruited after skeletal muscle injury switch into antiinflammatory macrophages to support myogenesis

“…Depending on the context, MPs may have supportive or deleterious eff ects on cells: in chronic diseases, including those aff ecting skeletal muscle, MPs are deleterious (62, 63), whereas they support tissue repair in muscle and other various tissues, including the liver, brain, peripheral nerve, and epithelium (19)(20)(21)(22)(64)(65)(66)(67). With the exception of regulation of infl ammation, studies documenting a direct role of MPs on cell behavior are scant and include intestinal progenitor proliferation (65), erythroblast proliferation and maturation (68), and oligodendrocytic diff erentiation and myelination (69).…”