High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal

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Abstract
High-mobility group box 1 protein (HMGB1) is a highly conserved nuclear protein that has a surprising extracellular role. Not only does it bind DNA, increasing access to transcription factors, but it also recruits cells across endothelial barriers and promotes the local production of tumour-necrosis factor (TNF), interleukin-6 (IL-6) and interferon-γ. HMGB1 is released from necrotic cells and is secreted by activated macrophages, natural killer cells and mature dendritic cells, but it is not produced by neutrophils. HMGB1 is a 'leaderless' cytokine, requiring specialized means to gain access to the immunological synapse or to be secreted. By contrast, after DNA damage as a result of apoptotic cell death, ultraviolet-light irradiation or platination, HMGB1 is sequestered in the nucleus. During sepsis, HMGB1 release occurs considerably later than macrophage secretion of the classical early pro-inflammatory mediators TNF and IL-1. Receptors for HMGB1 include RAGE (receptor for advanced glycation end-products), Toll-like receptor 2 (TLR2) and TLR4, and possibly other as-yet-unknown receptors. RAGE is encoded in the MHC class III region and is expressed as both a transmembrane molecule — which directly interacts with extracellular-signal-regulated kinase 1 (ERK1) and/or ERK2 and drives activation of the mitogen-activated protein kinase p38 and nuclear factor-κB — and as a soluble molecule. Soluble RAGE blocks RAGE ligands, including HMGB1 and S100 proteins. The expression of RAGE by activated endothelia promotes leukocyte recruitment, through the interaction of RAGE with myeloid cells that express the β2-integrin MAC1, and this is augmented in the presence of S100 proteins. Macrophages also express HMGB1 at the cell surface when they are activated, facilitating their recruitment through interaction with RAGE expressed by endothelial cells and enabling their translocation across endothelial barriers. Controlling HMGB1 activity and release is an approach that is being developed as an experimental therapy for patients with sepsis, arthritis, cancer and other disorders.