gms | German Medical Science

43. Kongress der Deutschen Gesellschaft für Rheumatologie, 29. Jahrestagung der Deutschen Gesellschaft für Orthopädische Rheumatologie, 25. Wissenschaftliche Jahrestagung der Gesellschaft für Kinder- und Jugendrheumatologie

02.-05. September 2015, Bremen

HMGB1 and RAGE in skeletal muscle inflammation: implications for protein accumulation in inclusion body myositis

Meeting Abstract

  • Ingrid E. Muth - Universitätsmedizin Göttingen, Göttingen
  • Jana Zschüntzsch - Universitätsmedizin Göttingen, Göttingen
  • Konstanze Kleinschnitz - Universitätsmedizin Göttingen, Göttingen
  • Arne Wrede - Universitätsmedizin Göttingen, Göttingen
  • Ellen Gerhardt - Universitätsmedizin Göttingen, Göttingen
  • Peter Balcarek - Universitätsmedizin Göttingen, Göttingen
  • Olivia Schreiber-Katz - Friedrich-Baur-Institut, München
  • Stephan Zierz - Universitätsklinik Halle, Halle
  • Marinos C. Dalakas - University of Athens, Athen, Griechenland
  • Reinhard Voll - Universitätsklinikum Freiburg, Rheumatologie und Klinische Immunologie, Freiburg i. Br.
  • Jens Schmidt - Universitätsmedizin Göttingen, Klinik für Neurologie, Göttingen

Deutsche Gesellschaft für Rheumatologie. Deutsche Gesellschaft für Orthopädische Rheumatologie. Gesellschaft für Kinder- und Jugendrheumatologie. 43. Kongress der Deutschen Gesellschaft für Rheumatologie (DGRh); 29. Jahrestagung der Deutschen Gesellschaft für Orthopädische Rheumatologie (DGORh); 25. wissenschaftliche Jahrestagung der Gesellschaft für Kinder- und Jugendrheumatologie (GKJR). Bremen, 02.-05.09.2015. Düsseldorf: German Medical Science GMS Publishing House; 2015. DocVS.02

doi: 10.3205/15dgrh253, urn:nbn:de:0183-15dgrh2538

Veröffentlicht: 1. September 2015

© 2015 Muth et al.
Dieser Artikel ist ein Open-Access-Artikel und steht unter den Lizenzbedingungen der Creative Commons Attribution 4.0 License (Namensnennung). Lizenz-Angaben siehe http://creativecommons.org/licenses/by/4.0/.


Gliederung

Text

Background: 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.

Results: 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.

Conclusion: 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.