High-mobility group box protein 1 (HMGB1): an alarmin mediating the pathogenesis of rheumatic disease - PubMed (original) (raw)
Review
High-mobility group box protein 1 (HMGB1): an alarmin mediating the pathogenesis of rheumatic disease
David S Pisetsky et al. Arthritis Res Ther. 2008.
Abstract
High-mobility group box protein 1 (HMGB1) is a non-histone nuclear protein that has a dual function. Inside the cell, HMGB1 binds DNA, regulating transcription and determining chromosomal architecture. Outside the cell, HMGB1 can serve as an alarmin to activate the innate system and mediate a wide range of physiological and pathological responses. To function as an alarmin, HMGB1 translocates from the nucleus of the cell to the extra-cellular milieu, a process that can take place with cell activation as well as cell death. HMGB1 can interact with receptors that include RAGE (receptor for advanced glycation endproducts) as well as Toll-like receptor-2 (TLR-2) and TLR-4 and function in a synergistic fashion with other proinflammatory mediators to induce responses. As shown in studies on patients as well as animal models, HMGB1 can play an important role in the pathogenesis of rheumatic disease, including rheumatoid arthritis, systemic lupus erythematosus, and polymyositis among others. New approaches to therapy for these diseases may involve strategies to inhibit HMGB1 release from cells, its interaction with receptors, and downstream signaling.
Figures
Figure 1
The effects of high-mobility group box protein 1 (HMGB1) are dependent on complex formation with different ligands. The figure depicts a possible, highly simplified scenario for the mechanisms for the various functions of HMGB1. During initiation of inflammation from infection, the abundant presence of Toll-like receptor (TLR) ligands will induce signaling through TLR, resulting in strong, proinflammatory cytokine production. The limited presence of HMGB1 at this stage will lead to weak signaling through receptor for advanced glycation endproducts (RAGE), thereby inducing only limited cell migration, proliferation, and differentiation. During the expansion phase of inflammation, an increased concentration of HMGB1, released from both activated and dead cells, occurs at the same time that TLR ligands are still present. Immune complexes formed between HMGB1 and TLR ligands can induce signaling through RAGE and TLR receptors in close proximity to each other. This signaling can increase and possibly prolong cytokine production as well as enhance cell migration, proliferation, and differentiation. During the regeneration/repair phase of inflammation, TLR ligands decrease in amount while HMGB1 is still abundant. This situation will cause signaling primarily through RAGE alone, leading to cell migration, proliferation, and differentiation while cytokine production diminishes. The illustration above shows complex formation between HMGB1 and TLR ligands. It is also possible that endogenous, non-TLR signaling, danger molecules can form complexes with HMGB1 and affect HMGB1 function in a similar way. HMGB1 can also enhance cytokine production when complexed to either lipopolysaccharide or interleukin-1β. The scenario described for the regeneration and repair phase of inflammation would also pertain to the function of HMGB1 during nerve sprouting, muscle cell regeneration, and other non-inflammatory circumstances in which the presence of HMGB1 has been described.
Figure 2
High-mobility group box protein 1 (HMGB1) expression in collagen-induced arthritis. The presence of cells expressing HMGB1 in the invading pannus of collagen-induced arthritis is shown. In this experiment, the section was stained for HMGB1 using affinity-purified polyclonal rabbit anti-HMGB1 antibodies (BD Pharmingen, San Diego, CA, USA) followed by biotin-labeled Fab2 fragments of a donkey anti-rabbit antibody (Jackson ImmunoResearch Laboratories, Inc., West Grove, PA, USA). The sections then were exposed to avidin-biotin-horseradish peroxidase (Vectastain Elite, ABC kit; Vector Laboratories, Burlingame, CA, USA), and color reaction was generated with diaminobenzidine (DAB). Reproduced with permission from Nature Insight 2002, 420: 845–846
. Copyright 2002, Macmillan Publishers Ltd.
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