title: HMGB1 and RAGE in skeletal muscle inflammation: Implications for protein accumulation in inclusion body myositis.
abstract: Inflammation is associated with protein accumulation in IBM, but precise mechanisms are elusive. The "alarmin" HMGB1 is upregulated in muscle inflammation. Its receptor RAGE is crucial for β-amyloid-associated neurodegeneration. Relevant signaling via HMGB1/RAGE is expected in IBM pathology. By real-time-PCR, mRNA-expression levels of HMGB1 and RAGE were upregulated in muscle biopsies of patients with IBM and PM, but not in muscular dystrophy or non-myopathic controls. By immunohistochemistry, both molecules displayed the highest signal in IBM, where they distinctly co-localized to intra-fiber accumulations of β-amyloid and neurofilament/tau. In these fibers, identification of phosphorylated Erk suggested that relevant downstream activation is present upon HMGB1 signaling via RAGE. Protein expressions of HMGB1, RAGE, Erk and phosphorylated Erk were confirmed by Western blot. In a well established cell-culture model for pro-inflammatory cell-stress, exposure of human muscle-cells to IL-1β+IFN-γ induced cytoplasmic translocation of HMGB1 and subsequent release as evidenced by ELISA. Upregulation of RAGE on the cell surface was demonstrated by immunocytochemistry and flow-cytometry. Recombinant HMGB1 was equally potent as IL-1β+IFN-γ in causing amyloid-accumulation and cell-death, and both were abrogated by the HMGB1-blocker BoxA. The findings strengthen the concept of unique interactions between degenerative and inflammatory mechanisms and suggest that HMGB1/RAGE signaling is a critical pathway in IBM pathology.
authors.affiliation: Department of Neurology, University Medical Center, Göttingen, Germany.
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Muth
authors.affiliation: Department of Neurology, University Medical Center, Göttingen, Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Zschüntzsch
authors.affiliation: Department of Neurology, University Medical Center, Göttingen, Germany; Department of Neuroimmunology, Institute for Multiple Sclerosis Research and Hertie Foundation, University Medical Center, Göttingen, Germany.
authors.forename: Konstanze
authors.initials: K
authors.lastname: Kleinschnitz
authors.affiliation: Department of Neuropathology, University Medical Center, Göttingen, Germany.
authors.forename: Arne
authors.initials: A
authors.lastname: Wrede
authors.affiliation: Department of Neurodegeneration and Restorative Research, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center Göttingen, Germany.
authors.forename: Ellen
authors.initials: E
authors.lastname: Gerhardt
authors.affiliation: Department of Trauma Surgery, University Medical Center, Göttingen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Balcarek
authors.affiliation: Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilians-University of München, München, Germany.
authors.forename: Olivia
authors.initials: O
authors.lastname: Schreiber-Katz
authors.affiliation: Department of Neurology, University Hospital Halle/Saale, Halle/Saale, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Zierz
authors.affiliation: Neuroimmunology Unit, Department of Pathophysiology, University of Athens Medical School, Athens, Greece; Department of Neurology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Marinos C
authors.initials: MC
authors.lastname: Dalakas
authors.affiliation: Department of Rheumatology and Clinical Immunology, University Medical Center, Freiburg, Germany.
authors.forename: Reinhard E
authors.initials: RE
authors.lastname: Voll
authors.affiliation: Department of Neurology, University Medical Center, Göttingen, Germany; Department of Neuroimmunology, Institute for Multiple Sclerosis Research and Hertie Foundation, University Medical Center, Göttingen, Germany. Electronic address: j.schmidt@gmx.org.
authors.forename: Jens
authors.initials: J
authors.lastname: Schmidt
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism; D000704:Analysis of Variance; D001706:Biopsy; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D032342:Muscle Cells / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D018979:Myositis, Inclusion Body / Q000473:pathology* / Q000503:physiopathology*; D012333:RNA, Messenger; D000067759:Receptor for Advanced Glycation End Products / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D016875:tau Proteins / Q000378:metabolism
chemical_list: C000593871:AGER protein, human; D016229:Amyloid beta-Peptides; D016207:Cytokines; D024243:HMGB1 Protein; C585491:HMGB1 protein, human; D012333:RNA, Messenger; D000067759:Receptor for Advanced Glycation End Products; D016875:tau Proteins; D020929:Mitogen-Activated Protein Kinase Kinases
keywords: High mobility group box 1; Inclusion body myositis; Receptor for advanced glycation endproducts; β-Amyloid