Abstract
BackgroundThe idiopathic inflammatory myopathies represent a group of autoimmune diseases that are characterized by lymphocyte infiltration of muscle and muscle weakness. Insulin-like 6 (Insl6) is a poorly characterized member of the insulin-like/relaxin family of secreted proteins, whose expression is upregulated upon acute muscle injury.MethodsIn this study, we employed Insl6 gain or loss of function mice to investigate the role of Insl6 in a T cell-mediated model of experimental autoimmune myositis (EAM). EAM models in rodents have involved immunization with human myosin-binding protein C with complete Freund’s adjuvant (CFA) emulsions and pertussis toxin.ResultsInsl6-deficiency in mice led to a worsened myositis phenotype including increased infiltration of CD4 and CD8 T cells and the elevated expression of inflammatory cytokines. Insl6-deficient mice show significant motor function impairment when tested with treadmill or Rotarod devices. Conversely, muscle-specific overexpression of Insl6 protected against the development of myositis as indicated by reduced lymphocyte infiltration in muscle, diminished inflammatory cytokine expression and improved motor function. The improvement in myositis by Insl6 could also be demonstrated by acute hydrodynamic delivery of a plasmid encoding murine Insl6. In cultured cells, Insl6 inhibits Jurkat cell proliferation and activation in response to phytohemagglutinin/phorbol 12-myristate 13-acetate stimulation. Insl6 transcript expression in muscle was reduced in a cohort of dermatomyositis and polymyositis patients.ConclusionsThese data suggest that Insl6 may have utility for the treatment of myositis, a condition for which few treatment options exist.
Highlights
The idiopathic inflammatory myopathies represent a group of autoimmune diseases that are characterized by lymphocyte infiltration of muscle and muscle weakness
To further investigate the role of Insulin-like 6 (Insl6) in muscle regeneration, we analyzed the response of Insl6-deficient mice (Insl6-KO) in this model
Since muscle injury with CTX elicits a T cell response [7], sections were stained for CD4 and CD8 cells
Summary
The idiopathic inflammatory myopathies represent a group of autoimmune diseases that are characterized by lymphocyte infiltration of muscle and muscle weakness. Idiopathic inflammatory myositis is a category of autoimmune muscle disorders that include polymyositis, dermatomyositis and inclusion body myositis. Features common to all of the subtypes include muscle weakness, histological evidence of muscle inflammation and elevated levels of creatine kinase. Muscle damage stimulates massive infiltration of immune cells into the injury site, including neutrophils, macrophages, and T cells. These cells function in the phagocytosis of necrotic muscle fibers, express pro-inflammatory cytokines and participate in satellite cell activation [7]. We sought to extend these studies and explore the utility of Insl in the setting of inflammatory muscle injury using a rodent model of myositis
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