Protective targeting of high mobility group box chromosomal protein 1 in a spontaneous arthritis model

Therese Östberg, Kohki Kawane, Shigekazu Nagata, Huan Yang, Sangeeta Chavan, Lena Klevenvall, Marco E. Bianchi, Helena Erlandsson Harris, Ulf Andersson, Karin Palmblad

Research output: Contribution to journalArticle

Abstract

Objective. High mobility group box chromosomal protein 1 (HMGB-1) is a DNA binding nuclear protein that can be released from dying cells and activated myeloid cells. Extracellularly, HMGB-1 promotes inflammation. Clinical and experimental studies demonstrate that HMGB-1 is a pathogenic factor in chronic arthritis. Mice with combined gene deficiency for DNase II and IFNRI spontaneously develop chronic, destructive polyarthritis with many features shared with rheumatoid arthritis. DNase II is needed for macrophage degradation of engulfed DNA. The aim of this study was to evaluate a potential pathogenic role of HMGB-1 in this novel murine model. Methods. The course of arthritis, assessed by clinical scoring and histology, was studied in DNase II -/- x IFNRI-/- mice, in comparison with heterozygous and wild-type mice. Synovial HMGB-1 expression was analyzed by immunohistochemistry. Serum levels of HMGB-1 were determined by Western immunoblotting and enzyme-linked immunosorbent assay (ELISA), and anti - HMGB-1 autoantibodies were detected by ELISA. Macrophage activation was studied by immunostaining for intracellular interleukin-1β and HMGB-1. HMGB-1 was targeted with truncated HMGB-1 - derived BoxA protein, acting as a competitive antagonist, with intraperitoneal injections every second day for 5 weeks. Results. DNase II -/- x IFNRI-/- mice developed symmetric polyarthritis with strong aberrant cytosolic and extracellular HMGB-1 expression in synovial tissue, in contrast to that observed in control animals. Increased serum levels of HMGB-1 and HMGB-1 auto-antibodies were recorded in DNase II-/- x IFNRI-/- mice, both prior to and during the establishment of disease. Systemic HMGB-1 - specific blockade significantly ameliorated the clinical disease course, and a protective effect on joint destruction was demonstrated by histologic evaluation. Conclusion. HMGB-1 is involved in the pathogenesis of this spontaneous polyarthritis, and intervention with an HMGB-1 antagonist can mediate beneficial effects.

Original languageEnglish
Pages (from-to)2963-2972
Number of pages10
JournalArthritis and Rheumatism
Volume62
Issue number10
DOIs
Publication statusPublished - Oct 2010

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Rheumatology
  • Pharmacology (medical)

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    Östberg, T., Kawane, K., Nagata, S., Yang, H., Chavan, S., Klevenvall, L., Bianchi, M. E., Harris, H. E., Andersson, U., & Palmblad, K. (2010). Protective targeting of high mobility group box chromosomal protein 1 in a spontaneous arthritis model. Arthritis and Rheumatism, 62(10), 2963-2972. https://doi.org/10.1002/art.27590