A recipe for myositis : nuclear factor κB and nuclear factor of activated T-cells transcription factor pathways spiced up by cytokines

Nuclear factor κB (NF-κB) is a well-known pro-inflammatory transcription factor that regulates the expression of the tissue’s immune-active components, which include cytokines, chemokines and adhesion molecules. In addition, the versatile nuclear factor of activated T-cells (NFAT) family of transcription factors plays a crucial role in the development and function of the immune system, integrating calcium signaling with other signaling pathways. NF-κB and NFAT share many structural and functional characteristics and likely regulate gene expression through shared enhancer elements. This review describes recent research data that has led to new insights into the involvement of NFκB- and NFAT-mediated pathways in the different idiopathic inflammatory myopathies. The general activation of NF-κB p65 in blood vessel endothelium, seems to flag down inflammatory cells that subsequently accumulate mostly at perimysial sites in dermatomyositis. The joint activation of p65 and NFAT5 in myofibers specifically at perifascicular areas reflects the characteristic tissue damage pattern observed in that particular subgroup of patients. In immune cells actively invading nonnecrotic muscle fibers in polymyositis and sporadic inclusion body myositis on the other hand, p65 activation is an important aspect of their cytotoxic and chemoattactant properties. In addition, both transcription factor families are generally upregulated in regenerating muscle fibers as components of the differentiation process. It can be concluded that the two transcription factor families function in close relationship with each other, representing two-edged swords for muscle disease: on the one hand promoting cell growth and regeneration, while on the other hand actively participating in inflammatory cell damage. In this respect, cytokines function as important go-betweens at the crossroads of the pathways. Beyond NF-κB and NFAT, many fascinating winding roads relevant to inflammatory myopathy disease management still lie ready for the exploring

Scanning for therapeutic targets within the cytokine network of idiopathic inflammatory myopathies

The idiopathic inflammatory myopathies (IIM) constitute a heterogeneous group of chronic disorders that include dermatomyositis (DM), polymyositis (PM), sporadic inclusion body myositis (IBM) and necrotizing autoimmune myopathy (NAM). They represent distinct pathological entities that, most often, share predominant inflammation in muscle tissue. Many of the immunopathogenic processes behind the IIM remain poorly understood, but the crucial role of cytokines as essential regulators of the intramuscular build-up of inflammation is undisputed. This review describes the extensive cytokine network within IIM muscle, characterized by strong expression of Tumor Necrosis Factors (TNF, LT, BAFF), Interferons (IFN//), Interleukins (IL-1/6/12/15/18/23) and Chemokines (CXCL9/10/11/13, CCL2/3/4/8/19/21). Current therapeutic strategies and the exploration of potential disease modifying agents based on manipulation of the cytokine network are provided. Reported responses to anti-TNF treatment in IIM are conflicting and new onset DM/PM has been described after administration of anti-TNF agents to treat other diseases, pointing to the complex effects of TNF neutralization. Treatment with anti-IFN has been shown to suppress the IFN type 1 gene signature in DM/PM patients and improve muscle strength. Beneficial effects of anti-IL-1 and anti-IL-6 therapy have also been reported. Cytokine profiling in IIM aids the development of therapeutic strategies and provides approaches to subtype patients for treatment outcome prediction

Cytokines and chemokines as regulators of skeletal muscle inflammation: presenting the case of Duchenne muscular dystrophy

Duchenne muscular dystrophy is a severe inherited muscle disease that affects 1 in 3500 boys worldwide. Infiltration of skeletal muscle by inflammatory cells is an important facet of disease pathophysiology and is strongly associated with disease severity in the individual patient. In the chronic inflammation that characterizes Duchenne muscle, cytokines and chemokines are considered essential activators and recruiters of inflammatory cells. In addition, they provide potential beneficiary effects on muscle fiber damage control and tissue regeneration. In this review, current knowledge of cytokine and chemokine expression in Duchenne muscular dystrophy and its relevant animal disease models is listed, and implications for future therapeutic avenues are discussed

Osmolytes as mediators of the muscle tissue’s responses to inflammation : emerging regulators of myositis with therapeutic potential

Chronic inflammation of skeletal muscle tissues termed myositis is associated with inherited muscular dystrophy and with acquired inflammatory myopathy. In this review, the role of the organic osmolytes taurine, betaine, myo-inositol and sorbitol in skeletal muscle in general and in myositis in particular, is discussed. Evidence indicates that regulated osmolyte pathway activation contributes to normal muscle functioning, which becomes further activated in myositis as part of the tissue’s program of damage control. On the one hand, osmolytes seem to act as protein stabilizers in muscle fibers counteracting tissue injury but, on the other hand, these compounds also regulate immune cell function. The possibilities for treating myositis through boosting of beneficial or targeting of adversary effects are explored

Sporadic inclusion body myositis : an acquired mitochondrial disease with extras

The sporadic form of inclusion body myositis (IBM) is the most common late-onset myopathy. Its complex pathogenesis includes degenerative, inflammatory and mitochondrial aspects. However, which of those mechanisms are cause and which effect, as well as their interrelations, remain partly obscured to this day. In this review the nature of the mitochondrial dysregulation in IBM muscle is explored and comparison is made with other muscle disorders. Mitochondrial alterations in IBM are evidenced by histological and serum biomarkers. Muscular mitochondrial dynamics is disturbed, with deregulated organelle fusion leading to subsequent morphological alterations and muscle displays abnormal mitophagy. The tissue increases mitochondrial content in an attempt to compensate dysfunction, yet mitochondrial DNA (mtDNA) alterations and mild mtDNA depletion are also present. Oxidative phosphorylation defects have repeatedly been shown, most notably a reduction in complex IV activities and levels of mitokines and regulatory RNAs are perturbed. Based on the cumulating evidence of mitochondrial abnormality as a disease contributor, it is therefore warranted to regard IBM as a mitochondrial disease, offering a feasible therapeutic target to be developed for this yet untreatable condition

Progressive skeletal muscle atrophy in muscular dystrophies : a role for toll-like receptor-signaling in disease pathogenesis

Muscle atrophy is an active process controlled by specific transcriptional programs, in which muscle mass is lost by increased protein degradation and/or decreased protein synthesis. This review explores the involvement of Toll-like receptors (TLRs) in the muscle atrophy as it is observed in muscular dystrophies, disorders characterized by successive bouts of muscle fiber degeneration and regeneration in an attempt to repair contraction-induced damage. TLRs are defense receptors that detect infection and recognize self-molecules released from damaged cells. In muscular dystrophies, these receptors become over-active, and are firmly involved in the sustained chronic inflammation exhibited by the muscle tissue, via their induction of pro-inflammatory cytokine expression. Taming the exaggerated activation of TLR2/4 and TLR7/8/9, and their downstream effectors in particular, comes forward as a therapeutic strategy with potential to slow down disease progression