Abstract
High-mobility group box 1 (HMGB1) protein is a highly abundant protein that can promote the pathogenesis of inflammatory and autoimmune diseases once it is in an extracellular location. This translocation can occur with immune cell activation as well as cell death, with the conditions for release associated with the expression of different isoforms. These isoforms result from post-translational modifications, with the redox states of three cysteines at positions 23, 45 and 106 critical for activity. Depending on the redox states of these residues, HMGB1 can induce cytokine production via toll-like receptor 4 (TLR4) or promote chemotaxis by binding the chemokine CXCL12 for stimulation via CXCR4. Fully oxidized HMGB1 is inactive. During the course of inflammatory disease, HMGB1 can therefore play a dynamic role depending on its redox state. As a mechanism to generate alarmins, cell death is an important source of HMGB1, although each major cell death form (necrosis, apoptosis, pyroptosis and NETosis) can lead to different isoforms of HMGB1 and variable levels of association of HMGB1 with nucleosomes. The association of HMGB1 with nucleosomes may contribute to the pathogenesis of systemic lupus erythematosus by producing nuclear material whose immunological properties are enhanced by the presence of an alarmin. Since HMGB1 levels in blood or tissue are elevated in many inflammatory and autoimmune diseases, this molecule can serve as a unique biomarker as well as represent a target of novel therapies to block its various activities.
Highlights
High mobility group box 1 (HMGB1)protein is a highly abundant and conserved protein that has important biological activities inside as well as outside the cell
In addition to the intrinsic activity of HMGB1, the extracellular actions of this molecule are extended by interaction with pathogen-associated molecular patterns (PAMPs), cytokines and chemokines [3]
HMGB1 showed acetylation with or without LPS priming. These results suggest that immune activation can lead to different forms of HMGB1 depending upon which pathway—TLR or inflammasome—is activated [52,53]
Summary
Protein is a highly abundant and conserved protein that has important biological activities inside as well as outside the cell. In addition to the intrinsic activity of HMGB1, the extracellular actions of this molecule are extended by interaction with pathogen-associated molecular patterns (PAMPs), cytokines and chemokines [3]. HMGB1 can play multiple roles in the pathogenesis of inflammatory and autoimmune disease and mediate processes that range from inflammation to repair [4]. Species with a fixed structure; (b) the function of HMGB1 can evolve over time because of posttranslational modification; and (c) cell death, a major source of extracellular HMGB1 in immune-mediated disease, has multiple forms whose immunological activities vary. Evidence for a key role of HMGB1 in immune-mediated disease is compelling and has come from studies demonstrating (a) increased HMGB1 levels in the blood or other biological fluid (for example, synovial fluid, urine); (b) increased HMGB1 expression in diseased tissue, especially outside the cell; (c) induction
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