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.
High-mobility group box 1 protein (HMGB1), which previously was thought to function only as a nuclear factor that enhances transcription, was recently discovered to be a crucial cytokine that mediates the response to infection, injury and inflammation. These observations have led to the emergence of a new field in immunology that is focused on understanding the mechanisms of HMGB1 release, its biological activities and its pathological effects in sepsis, arthritis, cancer and other diseases. Here, we discuss these features of HMGB1 and summarize recent advances that have led to the preclinical development of therapeutics that modulate HMGB1 release and activity.
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Careful review and comment on the manuscript by A. Rubartelli and M. Albert is appreciated.
Kevin Tracey is a consultant on HMGB1 for Critical Therapeutics, Inc.
- RHEUMATOID ARTHRITIS
An immunological disorder that is characterized by symmetrical polyarthritis, often progressing to crippling deformation after years of synovitis. It is associated with systemic immune activation. Acute-phase reactants are present in the peripheral blood, as well as rheumatoid factor (immunoglobulins specific for IgG), which forms immune complexes that are deposited in many tissues.
- CROHN'S DISEASE
One of two idiopathic inflammatory bowel diseases that are characterized by chronic intestinal inflammation. The inflammatory lesions of Crohn's disease can occur in any part of the gastrointestinal tract. By contrast, ulcerative colitis is typically confined to the colon and the distal small bowel.
- SICKNESS BEHAVIOUR
During infection, production of cytokines is stimulated, and individuals develop symptoms that include fatigue, sleepiness, malaise, listlessness, inability to focus, a subjective sense of poor memory, fever and decreased appetite. The administration of cytokines often results in similar responses.
The fundamental structural unit of eukaryotic chromosomes. It consists of pairs of each of the core histones (H2A, H2B, H3 and H4), thereby creating the histone octamer, and a single molecule of the linker histone H1. The nucleosome spans ∼180 base pairs of DNA. During apoptotic cell death, cleavage of nuclear DNA typically occurs at these nucleosomal intervals.
- DAMAGE-ASSOCIATED MOLECULAR PATTERN
(DAMP). Several molecules have been identified that are associated with damage or injury. These molecules interact with cellular receptors expressed by various cells: by endothelial cells, resulting in inflammatory-cell recruitment; by epithelial cells, promoting the epithelial to mesenchymal transition that is important in wound healing and migratory behaviour, which closes gaps in epithelial barriers; and by immune cells, promoting pathogen recognition or, in the absence of pathogens, tissue repair. During 'unscheduled' cell death, prototypical DAMPs are released from the degraded stroma (for example, hyaluronan), from the nucleus (high-mobility group box 1 protein) and from the cytosol (ATP, uric acid, S100 proteins and heat-shock proteins). Interestingly, many of these molecules promote the maturation of either tolerogenic or immunogenic myeloid DCs, depending on the nature of the other signals that are present.
Genetic elements that can be transposed from one site to another, such as the 'jumping genes' in corn that were reported by Barbara McClintock. The Tc1/mariner superfamily of transposable elements found in vertebrates is inactive, but one such element derived from fish has been reconstructed and is known as Sleeping Beauty. This element is increased in its transposable activity by about threefold in the presence of HMGB1. HMGB1 increases the activity of a transpositional enhancer in Sleeping Beauty, catalysing cut-and-paste transposition in tissue culture and in the germline of mice and zebrafish in vivo.
The late effects occurring during bacterial infection that are associated with multi-organ dysfunction and death. These are now attributable, at least in part, to release of high-mobility group box 1 protein.
A common form of cell death that frequently results from toxic injury, hypoxia or stress. Necrosis involves cell swelling, dysregulation of cell-membrane ion and water fluxes, mitochondrial swelling and the eventual release of cell contents into the interstitium. This form of cell death usually occurs together with inflammation. Cells that are exposed to the high concentrations of purified perforin that are typically delivered by cytolytic cells, such as natural killer cells and cytotoxic T lymphocytes, usually die by osmotic lysis, a form of necrotic cell death.
- IMMUNOLOGICAL SYNAPSE
A large junctional structure that is formed at the cell surface between a T cell and an antigen-presenting cell. It is also known as the supramolecular activation cluster. Important molecules that are involved in T-cell activation — including the T-cell receptor, numerous signal-transduction molecules and molecular adaptors — accumulate in an orderly manner at this site. Immunological synapses are now known to also form between other types of immune cell: for example, between dendritic cells and natural killer cells.
A common form of cell death, which is also known as intrinsic or programmed cell death. Many physiological and developmental stimuli cause apoptosis, and this mechanism is frequently used to remove unwanted, superfluous or potentially harmful cells, such as those undergoing transformation. Apoptosis involves cell shrinkage, chromatin condensation in the periphery of the nucleus, cell-membrane blebbing and DNA fragmentation into multiples of ∼180 base pairs. Eventually, the cell breaks up into many membrane-bound apoptotic bodies, which are phagocytosed by neighbouring cells.
- TYPE B CpG ODNS
Synthetic oligodeoxynucleotides containing unmethylated CpG motifs (CpG ODNs) that can activate immunity through stimulation of cytosolic Toll-like receptor 9 in human B cells and plasmacytoid DCs, as well as in mouse myeloid DCs. Two main types of CpG ODN have been identified. A/D-type CpG ODNs enhance the production of type I interferons by plasmacytoid DCs. B/K-type CpG ODNs activate human B cells, promoting the upregulation of expression of co-stimulatory molecules and the survival of these cells.
A class of transferases that catalyse transfer of an amino group from an amino acid to another compound. The levels of serum aspartate aminotransferase (also known as oxaloacetate) and alanine aminotransferase are increased in the plasma or serum after damage or injury to the liver.
- ACUTE-PHASE REACTANTS
Proteins that increase in serum concentration by 25% or more during inflammation, often increasing by as much as 3 logs. They include C-reactive protein, serum amyloid A, fibrinogen and α1-acid glycoprotein. Infection, trauma, surgical procedures, cancer, burns, and other acute and chronic inflammatory diseases prompt their production, largely by the liver.
- SEPTIC SHOCK
The acute haemodynamic effects occurring during bacterial infection that are associated with release of cytokine mediators — typically tumour-necrosis factor and interleukin-1 — that drive hypotension, reflex tachycardia and peripheral vasodilation, and are possibly associated with the secondary production of nitric oxide, owing to the induction of nitric-oxide synthase.
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Lotze, M., Tracey, K. High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal. Nat Rev Immunol 5, 331–342 (2005). https://doi.org/10.1038/nri1594
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