Macrophage Migration Inhibitory Factor in Normal Human Skeletal Muscle and Inflammatory Myopathies (original) (raw)
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PLoS ONE, 2012
Transplantation of muscle precursor cells is of therapeutic interest for focal skeletal muscular diseases. However, major limitations of cell transplantation are the poor survival, expansion and migration of the injected cells. The massive and early death of transplanted myoblasts is not fully understood although several mechanisms have been suggested. Various attempts have been made to improve their survival or migration. Taking into account that muscle regeneration is associated with the presence of macrophages, which are helpful in repairing the muscle by both cleansing the debris and deliver trophic cues to myoblasts in a sequential way, we attempted in the present work to improve myoblast transplantation by coinjecting macrophages. The present data showed that in the 5 days following the transplantation, macrophages efficiently improved: i) myoblast survival by limiting their massive death, ii) myoblast expansion within the tissue and iii) myoblast migration in the dystrophic muscle. This was confirmed by in vitro analyses showing that macrophages stimulated myoblast adhesion and migration. As a result, myoblast contribution to regenerating host myofibres was increased by macrophages one month after transplantation. Altogether, these data demonstrate that macrophages are beneficial during the early steps of myoblast transplantation into skeletal muscle, showing that coinjecting these stromal cells may be used as a helper to improve the efficiency of parenchymal cell engraftment.
The pathogenesis of inflammatory muscle diseases
Autoimmunity Reviews, 2002
Inflammatory muscle diseases (IMD), including dermatomyositis (DM) and polymyositis (PM), affect skeletal muscle, leading to profound tissue modification. The etiology of IMD is unknown, but multiple steps of the disease pathogenesis have been identified. The main alterations involve the immune response. Cellular infiltrates found in the muscle provide strong evidence for the involvement of a preferential immune mechanism of muscle damage. The pathologic differences found between PM and DM indicate a different role played by cell-mediated and humoral immune alterations. It is well accepted that in the pathogenetic pathway both host genes and environmental factors are involved. Apoptosis, or programmed cell death, is a complex process that plays a key role in many physiological events. It regulates the turnover of immune cells and is one of the mechanisms involved in ensuring a competent, non-autoreactive repertoire of lymphocytes. Apoptosis as a mechanism of muscle fibre death has been described in several neuromuscular disorders and muscular dystrophies, and evidence of a lack of apoptosis in IMD suggests a failure of apoptotic clearance of inflammatory cells playing a role in the maintenance of chronic cytotoxic muscle fibre damage. Most likely, the failure of apoptosis seems to be the main hallmark of the pathogenesis of IMD.
Cellular & Molecular Biology Letters, 2002
We tested whether intramuscular injections of dermatomyositis (DM) patients' sera into guinea pig muscles can be used to transfer myositic alterations to these animals. Additionally, similar tests were performed using neoplastic patients' sera and sera from non-neoplastic, non-myositic patients. The DM patients' sera induced idiopathic inflammatory myopathy (IIM) type histological changes in muscle fibres in guinea pig quadriceps muscles, which were especially evident 72 h after sera injections. Immunohistochemical stainings of myositic guinea pig muscles were done for guinea pig panT cells , monocytes/macrophages, the neuronal marker-protein gene product 9.5 (PGP 9.5) and protein S-100. Our studies proved that the factor(s) responsible for the appearance of characteristic alterations in diseased muscles during the course of DM is/are present in patient sera.
Basic Appl Myol, 2004
Macrophages drive muscle regeneration and repair by removing necrotic material and producing key signaling molecules. The array of cytokines/growth factors produced by macrophages and myogenic cells stimulates the proliferation, migration and differentiation of satellite cells. Although the details of such processes are only partially understood, it is known that the administration of purified growth factors can improve the final outcome after traumatic muscle injuries. Also, such approach has proved to be beneficial in myoblast transplantation experiments in animal models. The translation of such procedures into therapeutic protocols is, however, hampered by high costs and the somewhat oversimplified biochemical input compared to the physiological signal network. We have previously reported that peritoneal macrophages could secrete factors capable of increasing the myoblast/myotube yield in cultures of primary rat myoblasts. Recently, we observed that a macrophage cell line could be stimulated to produce a conditioned medium that specifically enhances the proliferation of cultured neonatal primary myoblasts from mouse, rat, chicken, and human fetal myoblasts. The factors did not inhibit differentiation and led to a striking increase in the rate of contractile myotube formation. The factors could also enhance muscle regenerative processes in vivo, thereby suggesting a potential role as an economical and effective tool for the treatment of traumatic and disease-related muscle injuries. Further experiments in this direction and the biochemical characterization of the macrophage-produced myogenic factors are presently underway. The possibility to use the macrophage factors to improve the myoblast yield from diseased-muscle biopsies is also under investigation. Abbreviations: MCM: macrophage-conditioned medium.
The diagnosis and classification of Idiopathic Inflammatory Myopathies (IIM) remain complex because of the lack of information about their pathogeny. Scanning Electron Microscopy (SEM) allows a histological analysis with better resolution, which together with the immunological profile, is useful for a better understanding of physiopathology. For immunological profile characterization, we identified the presence of autoantibodies (Ro-52, OJ, EJ, PL7, PL12, SRP, Jo-1, PMScl75, PMScl100, Ku, SAE1, NXP2, MDA5, TIF1γ, Mi-2α, Mi-2β) and quantified cytokines (IL-1β, IFN-α2, IFN-γ, TNF-α, IL-6, IL-10, IL-12p70, IL-17A, IL-18, IL-23, IL-33) and chemokines (CCL2, CXCL8). The histological analysis was made by hematoxylin-eosin staining while the muscle fiber was characterized by SEM. We observed changes in the morphology and structure of the muscle fiber according to muscle strength and muscle enzymes. We were able to find and describe muscle fiber ultrastructure with marked irregularities, po...
Muscle Cell and Tissue [Working Title], 2019
Inflammatory myopathies, also called idiopathic inflammatory myopathy or myositis, are rare conditions characterized by the involvement of various organs in addition to muscle tissue. These changes can lead to severe impairments and adversely impact the quality of life of affected individuals. The diagnosis and treatment of inflammatory myopathies involve the participation of an interdisciplinary team, due to the complexity of the disease and the high variety of possible signs and symptoms. In this chapter we will discuss the epidemiology and characteristics of the main subtypes of inflammatory myopathies, such as polymyositis, dermatomyositis, necrotizing myopathy, overlap myositis, and myositis of inclusion bodies. Next, we will discuss the existence of crosstalk between inflammatory processes in the oral cavity and their consequences on skeletal muscle. As oral inflammation can increase infiltration of macrophages in muscle tissue and this increase is related to the production of proinflammatory cytokines in this tissue, these cytokines can cause muscle weakness. It is important to consider the prevention of chronic inflammatory processes in order to maintain muscle integrity or even prevent the worsening of the clinical condition of patients with inflammatory muscle diseases.
The immune system and the repair of skeletal muscle
Pharmacological Research, 2008
Skeletal muscle injury, despite the initial trigger, leads to a stereotypical cascade of events mediated by cells of the immune system. Acute damage recruits cells of the innate immune system (polymorphonuclear leukocytes and monocytes/macrophages) that initially release noxious molecules and clear the cellular debris. Macrophages in particular display two distinct differentiation patterns. At early times after acute damage inflammatory macrophages are predominant, and play a non-redundant role in the clearance of cellular debris. At later time points, when fibre regeneration occurs, macrophages acquire a de-activated phenotype, which has been associated to tissue remodelling. A role for cells of the acquired immune system, in particular antigen-specific T and B cells, in muscle regeneration has been envisaged, but still needs to be elucidated. Similar events possibly play a role during persistent muscle damage in which fibres never completely heal. As a consequence infiltrating leukocytes stay alive and are continuously activated. Their effector function in situ contributes to perpetuate the damage and results in the deposition of collagen with interstitial fibrosis and fat accumulation. In this review we will discuss the events characterising acute and persistent damage in stretch-induced injury, autoimmune polymyositis, inclusion bodies myositis and muscular dystrophies. We will focus on the molecular interactions involved in the positive and negative regulation of the inflammatory damage, with specific attention to their exploitation in the context of strategies to limit muscle wasting and supporting fibre regeneration.