Therapeutic Potential of Immunoproteasome Inhibition in Duchenne Muscular Dystrophy

Andrea Farini, Clementina Sitzia, Barbara Cassani, Letizia Cassinelli, Rosita Rigoni, Federica Colleoni, Nicola Fusco, Stefano Gatti, Pamela Bella, Chiara Villa, Filomena Napolitano, Rita Maiavacca, Silvano Bosari, Anna Villa, Yvan Torrente

Research output: Contribution to journalArticle

Abstract

Duchenne muscular dystrophy is an inherited fatal genetic disease characterized by mutations in dystrophin gene, causing membrane fragility leading to myofiber necrosis and inflammatory cell recruitment in dystrophic muscles. The resulting environment enriched in proinflammatory cytokines, like IFN-γ and TNF-α, determines the transformation of myofiber constitutive proteasome into the immunoproteasome, a multisubunit complex involved in the activation of cell-mediate immunity. This event has a fundamental role in producing peptides for antigen presentation by MHC class I, for the immune response and also for cytokine production and T-cell differentiation. Here, we characterized for the first time the presence of T-lymphocytes activated against revertant dystrophin epitopes, in the animal model of Duchenne muscular dystrophy, the mdx mice. Moreover, we specifically blocked i-proteasome subunit LMP7, which was up-regulated in dystrophic skeletal muscles, and we demonstrated the rescue of the dystrophin expression and the amelioration of the dystrophic phenotype. The i-proteasome blocking lowered myofiber MHC class I expression and self-antigen presentation to T cells, thus reducing the specific antidystrophin T cell response, the muscular cell infiltrate, and proinflammatory cytokine production, together with muscle force recovery. We suggest that i-proteasome inhibition should be considered as new promising therapeutic approach for Duchenne muscular dystrophy pathology.Molecular Therapy (2016); doi:10.1038/mt.2016.162.

Original languageEnglish
JournalMolecular Therapy
DOIs
Publication statusAccepted/In press - Sep 27 2016

Fingerprint

Duchenne Muscular Dystrophy
Proteasome Endopeptidase Complex
Dystrophin
T-Lymphocytes
Antigen Presentation
Cytokines
Inbred mdx Mouse
Muscles
Inborn Genetic Diseases
Autoantigens
Therapeutics
Epitopes
Cell Differentiation
Immunity
Skeletal Muscle
Necrosis
Animal Models
Pathology
Phenotype
Peptides

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

Cite this

Therapeutic Potential of Immunoproteasome Inhibition in Duchenne Muscular Dystrophy. / Farini, Andrea; Sitzia, Clementina; Cassani, Barbara; Cassinelli, Letizia; Rigoni, Rosita; Colleoni, Federica; Fusco, Nicola; Gatti, Stefano; Bella, Pamela; Villa, Chiara; Napolitano, Filomena; Maiavacca, Rita; Bosari, Silvano; Villa, Anna; Torrente, Yvan.

In: Molecular Therapy, 27.09.2016.

Research output: Contribution to journalArticle

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