The Immune System in Duchenne Muscular Dystrophy Pathogenesis

Abstract

Growing evidence demonstrates the crosstalk between the immune system and the skeletal muscle in inflammatory muscle diseases and dystrophic conditions such as Duchenne Muscular Dystrophy (DMD), as well as during normal muscle regeneration. The rising of inflammation and the consequent activation of the immune system are hallmarks of DMD: several efforts identified the immune cells that invade skeletal muscle as CD4+ and CD8+ T cells, Tregs, macrophages, eosinophils and natural killer T cells. The severity of muscle injury and inflammation dictates the impairment of muscle regeneration and the successive replacement of myofibers with connective and adipose tissue. Since immune system activation was traditionally considered as a consequence of muscular wasting, we recently demonstrated a defect in central tolerance caused by thymus alteration and the presence of autoreactive T-lymphocytes in DMD. Although the study of innate and adaptive immune responses and their complex relationship in DMD attracted the interest of many researchers in the last years, the results are so far barely exhaustive and sometimes contradictory. In this review, we describe the most recent improvements in the knowledge of immune system involvement in DMD pathogenesis, leading to new opportunities from a clinical point-of-view.

Identification of Auxiliary Biomarkers and Description of the Immune Microenvironmental Characteristics in Duchenne Muscular Dystrophy by Bioinformatical Analysis and Experiment

“…The levels of infiltration for active B cells, CD56dim natural killer cells and type 17 T helper cells were decreased in DMD. These differences might be associated with DMD occurrence and progression, which were in good agreement with those from previous studies (Tripodi et al, 2021) and further confirmed the importance of the immune response in the pathogenesis of DMD. It is generally known that macrophages are an essential component of human innate immunity, and these cells can also exert potential influence on the pathogenesis of DMD.…”

Smad8 Is Increased in Duchenne Muscular Dystrophy and Suppresses miR-1, miR-133a, and miR-133b

“…In contrast, IL-6 mRNA was attenuated with Smad8 silencing. IL-6 is a pro-inflammatory cytokine that exacerbates the dystrophic process by promoting the recruitment of neutrophils and other immune cells to sustain an inflammatory milieu [ 52 , 53 ]. This impedes muscle regeneration and promotes fibrosis.…”

Identification of immune-related features involved in Duchenne muscular dystrophy: A bidirectional transcriptome and proteome-driven analysis

“…It includes destruction of muscle fiber membrane, imbalance of calcium balance, muscle necrosis and exhaustion, accompanied by adipose tissue proliferation and immune cell infiltration ( 28 , 29 ). Moreover, growing evidence demonstrates the crosstalk between the immune system and the skeletal muscle in inflammatory muscle diseases, including DMD ( 15 , 30 , 31 ). However, these downstream pathways cannot elucidate the pathogenesis of DMD alone.…”

“…Furthermore, weighted gene coexpression network analysis (WGCNA) can describe the connections among various genes by constructing a co–expression network and identify phenotype-related modules, which is more effective to investigate the key pathways and genes in many human disorders ( 13 , 14 ). In addition, most immune system components are demonstrated in the initiation and progression of DMD ( 15 ). Therefore, our goal was to perform a detailed analysis of molecular mechanisms, diagnostic and therapeutic targets underlying DMD with the transcriptome, proteome, and immune-related features.…”