title: The immunoproteasomes are key to regulate myokines and MHC class I expression in idiopathic inflammatory myopathies.
abstract: Idiopathic inflammatory myopathies (IIMs) are diseases with muscle weakness, morphologically characterized by inflammatory infiltration and increased expression of MHC class I molecule on myofibers. Immunoproteasome, as a proteolytic complex that shapes the repertoire of antigenic peptides, has been previously demonstrated to be over-expressed in IIMs at mRNA level. In this study, we investigated the expression and the function of the immunoproteasome in IIMs in more detail. As shown by immunofluorescence staining, expression of relevant players of the immunoproteasome was detectable in the inflamed skeletal muscle tissue from IIM patients. In fact, two subunits of the immunoproteasome, β1i or β5i were upregulated in sporadic inclusion body myositis, immune-mediated necrotizing myopathies and dermatomyositis muscle biopsies and co-localized with the MHC class I expressing myofibers. Double immunofluorescence revealed that both myofibers and muscle infiltrating cells, including CD8+T-cells and CD68+macrophages in IIMs expressed β1i or β5i. In addition, we have also investigated the role of the immunoproteasome in myoblasts during in vitro inflammatory conditions. Using human primary myoblasts cultures we found that pro-inflammatory cytokines, TNF-α or IFN-γ upregulate β1i or β5i. Selective inhibition or depletion of β5i amplified the TNF-α or IFN-γ mediated expression of cytokines/chemokines (myokines) in myoblasts. Furthermore, we demonstrated that specific inhibitors of β1i or β5i reduced the cell surface expression of MHC class I in myoblasts induced by IFN-γ. Taken together, our data suggest that the immunoproteasome is involved in pathologic MHC class I expression and maintenance of myokine production in IIMs. Thus, induction of the immunoproteasome was identified as a pathomechanism underlying inflammation in IIMs.
authors: Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, Chariteplatz 1, 10117, Berlin, Germany. Electronic address: salyan.bhattarai@charite.de.
authors: Salyan
authors: S
authors: Bhattarai
authors: Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, Chariteplatz 1, 10117, Berlin, Germany.
authors: Khetam
authors: K
authors: Ghannam
authors: Friedrich Baur Institute, Ludwig Maximilians University, Marchioninistr. 17, 81377, Munich, Germany.
authors: Sabine
authors: S
authors: Krause
authors: La Pitié-Salpêtrière Hospital, Internal Medicine Department, APHP, INSERM U974, UPMC, 47-83 Boulevard de l'Hôpital, 75013, Paris, France.
authors: Olivier
authors: O
authors: Benveniste
authors: Muscle Research Unit, Experimental and Clinical Research Center, Charité-Universitätsmedizin Berlin, Lindenberger Weg 80, 13125, Berlin, Germany.
authors: Andreas
authors: A
authors: Marg
authors: Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands.
authors: Gerjan
authors: G
authors: de Bruin
authors: Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands.
authors: Bo-Tao
authors: BT
authors: Xin
authors: Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands.
authors: Hermen S
authors: HS
authors: Overkleeft
authors: Muscle Research Unit, Experimental and Clinical Research Center, Charité-Universitätsmedizin Berlin, Lindenberger Weg 80, 13125, Berlin, Germany.
authors: Simone
authors: S
authors: Spuler
authors: Department of Neuropathology, Charité-Universitätsmedizin Berlin, Chariteplatz 1, 10117, Berlin, Germany.
authors: Werner
authors: W
authors: Stenzel
authors: Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, Chariteplatz 1, 10117, Berlin, Germany.
authors: Eugen
authors: E
authors: Feist
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western; D002478:Cells, Cultured; D002675:Child, Preschool; D016207:Cytokines / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D003882:Dermatomyositis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D008297:Male; D008856:Microscopy, Fluorescence; D018482:Muscle, Skeletal / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D032446:Myoblasts / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D009220:Myositis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D019283:Pancreatitis, Acute Necrotizing / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D021122:Protein Subunits / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D055815:Young Adult
chemical_list: D016207:Cytokines; D015395:Histocompatibility Antigens Class I; D021122:Protein Subunits; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D046988:Proteasome Endopeptidase Complex
keywords: Antigen presentation; Idiopathic inflammatory myopathies; Immunoproteasome subunits; Myokine; Proteasome