TIPE2 gene transfer with adeno-associated virus 9 ameliorates dystrophic pathology in mdx mice.

Duchenne muscle dystrophy (DMD), characterized by progressive loss of muscle architecture and function, is caused by lack of dystrophin expression in the sarcolemma of myofibers. Recurrent muscle damages in DMD patients and DMD mouse model, mdx, lead to chronic inflammation, which further exacerbate the muscle histopathology. It is critical to find a successful therapy that will improve the histopathology of muscles of DMD patients and restore skeletal muscle function. TIPE2 (tumor necrosis factor α-induced-protein 8-like 2), identified as a negative regulator of immune response, has been found to be expressed in various types of immune cells including macrophages. However, whether and how TIPE2 plays a role in the DMD-related inflammation remains unknown. In this study, we found the basal expression levels of TIPE2 in skeletal muscle from mdx mice are significantly lower than wild-type (WT) mice. To investigate the potential beneficial effect of TIPE2 in muscular dystrophy, we performed intramuscular injection of adeno-associated virus 9 carrying the TIPE2 gene in mdx mice. Our results indicate that the restoration of TIPE2 ameliorates muscular dystrophy phenotype through a reduction in inflammation and fibrosis. In addition, TIPE2 overexpression dramatically decreased the proliferation and migration rate of macrophages, as well as repressed the secretion of pro-inflammatory factors induced by tumor necrotic factor alpha. Taken together, our results indicate that a reduction of TIPE2 expression is observed in dystrophic skeletal muscle, when compared to WT and more importantly that TIPE2 gene delivery may provide as a novel anti-inflammatory therapy to alleviate the muscle weakness in DMD patients.