P.21.1 Autophagy as a link between immunity and inflammation in idiopathic inflammatory myopathies

Abstract

Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of immune-mediated muscle disorders characterized by muscle inflammation and weakness. They comprise inclusion body myositis (IBM), polymyositis (PM), juvenile dermatomyositis (JDM) and adult dermatomyositis (DM). Autophagic pathway impairment has been well documented in sporadic IBM, where it has been suggested to be responsible for the accumulation of multiple-protein aggregates, typical of the myopathy. The main candidates responsible for this impairment are suggested to be TLRs. We evaluated the autophagic process also in PM and DM, in particular the interaction between autophagosome maturation and innate immune system. LC3 and other autophagic molecules, together with TLR3, TLR4, HSP60 and HMGB1/2 were analyzed in IIM and control muscles by qPCR, immunohistochemistry and immunoblot. Myoblasts and myotubes from PM, DM and control muscle biopsies were analyzed to evaluate changes in TLR and HMGB1/2 expression after induction or inhibition of autophagy. Gene expression analysis showed a dysregulation of autophagy in all IIM subgroups. A tight correlation between autophagy and innate immunity in myopathic muscles compared to controls was highlighted by confocal microscopy; activation of stress response and the presence of bacterial infection were observed connected with an abnormal accumulation of autophagosomes in IIM myofibers. These findings demonstrate the involvement of the autophagic process in the pathogenesis of all subtypes of IIMs; it is not clear if this mechanism represents a consequence or a cause of the induction of immune response and inflammation. Autophagic machinery components might represent a possible target for new therapeutic approaches for IIM.