title: Autophagy, inflammation and innate immunity in inflammatory myopathies.
abstract: Autophagy has a large range of physiological functions and its dysregulation contributes to several human disorders, including autoinflammatory/autoimmune diseases such as inflammatory myopathies (IIMs). In order to better understand the pathogenetic mechanisms of these muscular disorders, we sought to define the role of autophagic processes and their relation with the innate immune system in the three main subtypes of IIM, specifically sporadic inclusion body myositis (sIBM), polymyositis (PM), dermatomyositis (DM) and juvenile dermatomyositis (JDM). We found that although the mRNA transcript levels of the autophagy-related genes BECN1, ATG5 and FBXO32 were similar in IIM and controls, autophagy activation in all IIM subgroups was suggested by immunoblotting results and confirmed by immunofluorescence. TLR4 and TLR3, two potent inducers of autophagy, were highly increased in IIM, with TLR4 transcripts significantly more expressed in PM and DM than in JDM, sIBM and controls, and TLR3 transcripts highly up-regulated in all IIM subgroups compared to controls. Co-localization between autophagic marker, LC3, and TLR4 and TLR3 was observed not only in sIBM but also in PM, DM and JDM muscle tissues. Furthermore, a highly association with the autophagic processes was observed in all IIM subgroups also for some TLR4 ligands, endogenous and bacterial HSP60, other than the high-mobility group box 1 (HMGB1). These findings indicate that autophagic processes are active not only in sIBM but also in PM, DM and JDM, probably in response to an exogenous or endogenous 'danger signal'. However, autophagic activation and regulation, and also interaction with the innate immune system, differ in each type of IIM. Better understanding of these differences may lead to new therapies for the different IIM types.
authors.affiliation: Neurology IV, Neuroimmunology and Neuromuscular Diseases Unit, Fondazione Istituto Neurologico Carlo Besta, Milan, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Cappelletti
authors.affiliation: Neurology IV, Neuroimmunology and Neuromuscular Diseases Unit, Fondazione Istituto Neurologico Carlo Besta, Milan, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Galbardi
authors.affiliation: Neurology IV, Neuroimmunology and Neuromuscular Diseases Unit, Fondazione Istituto Neurologico Carlo Besta, Milan, Italy.
authors.forename: Dimos
authors.initials: D
authors.lastname: Kapetis
authors.affiliation: Section of Clinical Neurology, Department of Neurological and Movement Sciences, University of Verona, Verona, Italy.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Vattemi
authors.affiliation: Section of Clinical Neurology, Department of Neurological and Movement Sciences, University of Verona, Verona, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Guglielmi
authors.affiliation: Section of Clinical Neurology, Department of Neurological and Movement Sciences, University of Verona, Verona, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Tonin
authors.affiliation: Neurology IV, Neuroimmunology and Neuromuscular Diseases Unit, Fondazione Istituto Neurologico Carlo Besta, Milan, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Salerno
authors.affiliation: Neurology IV, Neuroimmunology and Neuromuscular Diseases Unit, Fondazione Istituto Neurologico Carlo Besta, Milan, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Morandi
authors.affiliation: Section of Clinical Neurology, Department of Neurological and Movement Sciences, University of Verona, Verona, Italy.
authors.forename: Giuliano
authors.initials: G
authors.lastname: Tomelleri
authors.affiliation: Neurology IV, Neuroimmunology and Neuromuscular Diseases Unit, Fondazione Istituto Neurologico Carlo Besta, Milan, Italy.
authors.forename: Renato
authors.initials: R
authors.lastname: Mantegazza
authors.affiliation: Neurology IV, Neuroimmunology and Neuromuscular Diseases Unit, Fondazione Istituto Neurologico Carlo Besta, Milan, Italy.
authors.forename: Pia
authors.initials: P
authors.lastname: Bernasconi
mesh_terms: D001343:Autophagy / Q000235:genetics / Q000276:immunology; D015415:Biomarkers; D018834:Chaperonin 60 / Q000235:genetics / Q000378:metabolism; D006684:HLA-DR Antigens / Q000276:immunology / Q000378:metabolism; D024002:HMGB Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009220:Myositis / Q000175:diagnosis / Q000209:etiology* / Q000473:pathology; D010588:Phagosomes / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D012038:Regeneration / Q000235:genetics / Q000276:immunology; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D015415:Biomarkers; D018834:Chaperonin 60; D006684:HLA-DR Antigens; D024002:HMGB Proteins; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D051193:Toll-Like Receptors