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High mobility group box chromosomal protein 1, a DNA binding cytokine, induces arthritis
Rille Pullerits1, Ing-Marie Jonsson, Margareta Verdrengh
1Department of Rheumatology and Inflammation Research, Sahlgrenska University Hospital, University of Göteborg, Gothenburg, Sweden. rille.pullerits@rheuma.gu.se
Objective:
To examine the potential role of high mobility group box chromosomal protein 1 (HMGB-1) in the pathogenesis of arthritis.
Methods:
Mice were injected intraarticularly with 1 microg or 5 microg of HMGB-1. Joints were dissected on days 4, 7, and 28 after injection and were evaluated histopathologically and immunohistochemically. To investigate the importance of different white blood cell populations for the development of arthritis, in vivo cell depletion procedures were performed. In addition, spleen cells were cultured in the presence of HMGB-1, and nuclear factor kappaB (NF-kappaB) activation was detected by electrophoretic mobility shift assay.
Results:
Injection of recombinant HMGB-1 (rHMGB-1) into different mouse strains resulted in an overall frequency of arthritis in 80% of the animals. The inflammation was characterized by mild to moderate synovitis and lasted for at least 28 days. The majority of cells found in the inflamed synovium were Mac-1+ macrophages, whereas only a few CD4+ lymphocytes were detected. Pannus formation was observed in some cases 7 and 28 days after HMGB-1 injection. No significant differences were found with respect to incidence and severity of arthritis between mice depleted of monocytes, granulocytes, or lacking T/B lymphocytes. However, combined removal of monocytes and neutrophils resulted in a 43% lower incidence of arthritis. Mice rendered deficient in the interleukin-1 (IL-1) receptor did not develop inflammation upon challenge with HMGB-1. In vitro data corroborate this finding, showing that rHMGB-1 activated NF-kappaB, a major pathway leading to IL-1 production.
Conclusion:
Our results indicate that HMGB-1 is not a mere expression of inflammatory responses, but on its own, it triggers joint inflammation by activating macrophages and inducing production of IL-1 via NF-kappaB activation.
Insights
High mobility group box 1 (HMGB-1) directly triggers arthritis by activating macrophages and inducing interleukin-1 (IL-1) production through nuclear factor kappaB (NF-kappaB) signaling.
Area of Science:
- Immunology
- Molecular Biology
- Rheumatology
Background:
- High mobility group box chromosomal protein 1 (HMGB-1) is implicated in inflammatory processes.
- Its specific role in arthritis pathogenesis requires further elucidation.
Purpose of the Study:
- To investigate the role of HMGB-1 in inducing arthritis.
- To explore the cellular and molecular mechanisms underlying HMGB-1-mediated joint inflammation.
Main Methods:
- Intra-articular injection of recombinant HMGB-1 (rHMGB-1) in mice.
- Histopathological and immunohistochemical analysis of joint tissues.
- In vivo cell depletion studies and in vitro NF-kappaB activation assays.
Main Results:
- rHMGB-1 injection induced arthritis in 80% of mice, characterized by synovitis and pannus formation.
- Macrophages were the predominant inflammatory cells; combined depletion of monocytes and neutrophils reduced arthritis incidence.
- Mice lacking IL-1 receptor did not develop inflammation; rHMGB-1 activated NF-kappaB, leading to IL-1 production.
Conclusions:
- HMGB-1 acts as a direct trigger for joint inflammation, not merely a marker.
- HMGB-1 activates macrophages and induces IL-1 production via NF-kappaB signaling, driving arthritis development.