High mobility group box chromosomal protein 1, a DNA binding cytokine, induces arthritis

Abstract

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 g or 5 g 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 B (NF-B) 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-B, 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-B activation.High mobility group box chromosomal protein 1 (HMGB-1), named for its rapid mobility on electrophoresis gels, is a ubiquitous, nonhistone, chromatinassociated 215-amino acid protein with highly conserved amino acid sequence identity between rodents and humans (1-3). Nuclear HMGB-1 has been identified and studied for a long time as a DNA binding protein. It participates in maintenance of nucleosomal structure and stability and facilitates the binding of transcription factors to their cognate DNA sequences (4). HMGB-1 also has functions in DNA transcription, recombination (5,6), repair, cell replication, cell migration, and tumor growth (7,8).In contrast to its intranuclear role, extracellular HMGB-1 was recently shown to act as a cytokine mediating delayed endotoxin lethality (9) as well as acute lung injury in mice (10). Moreover, high levels of HMGB-1 have been detected in the blood of patients with sepsis (9) and in the synovial fluid of rheumatoid arthritis (RA) patients (11). Proinflammatory mediators, such as tumor necrosis factor ␣ (TNF␣) and interleukin-1 (IL-1), can dose-dependently induce the release of HMGB-1 from monocytes and macrophages

Mitochondrial hyperpolarization: a checkpoint of T-cell life, death and autoimmunity

“…High-mobility group B1 (HMGB1) protein, an abundant DNA-binding protein, remains immobilized on chromatin of apoptotic bodies, but is released from necrotic cells [53]. HMGB1 stimulates human monocytes to release TNF-α, IL-1α, IL-1β, IL-1 receptor antagonist (IL-1RA), IL-6, IL-8, macrophage inflammatory protein (MIP)-1α, and MIP-1β, but not IL-10 or IL-12 [54], and induces arthritis [55]. Necrotic, but not apoptotic, cells also release heat shock proteins (HSPs) HSPgp96, HSP90, HSP70 and calreticulin.…”

High-Mobility Group Box-1 Protein (HMGB1) Is Increased in Antineutrophilic Cytoplasmatic Antibody (ANCA)-Associated Vasculitis with Renal Manifestations

“…In animal models of arthritis, a strict nuclear HMGB-1 pattern was observed in synovial cells of healthy mice and rats. In contrast, a distinct pattern of extracellular expression in the cytoplasm of macrophages and synoviocytes has been identified with immunohistochemical staining in animals with arthritis (18,19). Targeting HMGB1 has been demonstrated to confer protection in animal models of sepsis, endotoxemia and arthritis (10,20,21).…”

Targeting DAMP Activation of Toll-Like Receptors: Novel Pathways to Treat Rheumatoid Arthritis?

“…A number of approaches have been taken to examine the effect of DAMP administration, deletion or blockade in animal models of arthritis and data supporting the role of specific molecules in such models are summarized in Table 4. In particular, the administration of the fibronectin EDA domain (FNEDA), fibrinogen, HMGB-1 and tenascin-C intra-articularly to mice provokes pathological inflammation in vivo, (Pullerits et al, 2003;Gondokaryono et al, 2007;Midwood et al, 2009). Moreover, targeted deletion of tenascin-C protects mice from experimental disease; synovial inflammation is induced but is transient and little tissue destruction occurs in contrast to wild type mice (Midwood et al, 2009) suggesting that tenascin-C plays a crucial role in disease chronicity.…”