HMGB1 release by inflammasomes

Abstract

High-mobility group box 1 (HMGB1) was originally identified as a highly conserved nuclear DNA-binding protein that participates in DNA replication, repair and transcriptional regulation of gene expression. Although the nuclear role of HMGB1 is not quite understood, recent studies characterized the emerging role of extracellular HMGB1 as a prototypical danger signal that regulates inflammatory and repair responses. Under conditions of infection, injury and sterile inflammation, HMGB1 can be passively released from damaged cells or actively secreted from activated immune cells. Inflammasomes, large caspase-1-activating protein complexes, were recently shown to play a critical role in mediating the extracellular release of HMGB1 from activated and infected immune cells.

Figure 1

Structure of HMGB1 and its functions in the extracellular environment. (A) Human HMGB1 is a protein of 216 amino acids that is composed of two homologous DN A-binding domains called ‘A and B boxes’ that are followed by a negatively charged acidic tail in the carboxyl-terminus. (B) HMGB1 can be secreted through non-canonical mechanisms along with pro-inflammatory cytokines such as IL-1β and IL-18 following inflammasome activation in stimulated and/or infected immune cells, or it may be passively released from damaged and infected cells undergoing necrotic or pyroptotic cell death. Extracellular HMGB1 can bind to its receptors RAGE and TLR2/4 on effector cells in order to induce inflammation, chemotaxis and repair responses.