Macrophages in injured skeletal muscle: a perpetuum mobile causing and limiting fibrosis, prompting or restricting resolution and regeneration

Abstract

Macrophages are present in regenerating skeletal muscles and participate in the repair process. This is due to a unique feature of macrophages, i.e., their ability to perceive signals heralding ongoing tissue injury and to broadcast the news to cells suited at regenerating the tissue such as stem and progenitor cells. Macrophages play a complex role in the skeletal muscle, probably conveying information on the pattern of healing which is appropriate to ensure an effective healing of the tissue, yielding novel functional fibers. Conversely, they are likely to be involved in limiting the efficacy of regeneration, with formation of fibrotic scars and fat replacement of the tissue when the original insult persists. In this review we consider the beneficial versus the detrimental actions of macrophages during the response to muscle injury, with attention to the available information on the molecular code macrophages rely on to guide, throughout the various phases of muscle healing, the function of conventional and unconventional stem cells. Decrypting this code would represent a major step forward toward the establishment of novel targeted therapies for muscle diseases.

Keywords: alternative activation; innate immunity; macrophages; skeletal muscle; wound healing.

Figure 1

Macrophages, recruited to the skeletal muscle after acute sterile injury, are necessary for effective tissue regeneration. Two months old C57BL/6 mice were treated i.m. with cardiotoxin (CTX). Mice were treated or not with clodronate-containing liposomes to deplete macrophages and sacrificed 15 days after CTX injection. Tibialis anterior and quadriceps muscles were collected. (A) Healthy muscles of untreated control mice. (B) The muscle of macrophage-competent mice undergoes effective and almost complete regeneration in 15 days: regenerating centronucleated fibers are evident throughout the section. (C) In the absence of macrophages, 15 days after acute sterile injury regenerating fibers are hardly evident. Degenerated fibers and cell remnants persist.

Figure 2

Environment cues control and influence macrophage polarization. Inflammatory macrophage activation is driven by stimulation with LPS or bacteria, and/or IFN-γ or GM-CSF. These molecules induce iNOS activity on macrophages and consequent production of RNI. Treatment with IL4 and/or IL13, IL10 and/or M-CSF supports the activation of tissue healing macrophages. The cytokine network activates an arginase-dependent metabolism of arginine. In macrophages, acquisition of a specific polarization state determines a differential expression of receptors and secretion of molecules. LPS, lipopolysaccharide; IFN-γ, interferon-γ; GM-CSF, granulocyte macrophage-colony stimulating factor; M-CSF, macrophage-colony stimulating factor; MHCII, major histocompatibility complex class II; GR, galactose receptor; CD163, haptoglobin–hemoglobin complex receptor; CD206, mannose receptor; TfR1, transferrin receptor 1; Fpn, ferroportin; TGF-β, transforming growth factor β; IGF1, insulin like growth factor 1; PTX-3, pentraxin 3; PGE2, prostaglandin E2; MMP-9, matrix metalloproteinase 9; Fizz, resistin like molecule; Ym1/2, chitinase like protein 1/2; TNF-α, tumor necrosis factor α; IFN, interferon type I; RNI, reactive nitrogen intermediate; ROI, reactive oxygen intermediate.