High-mobility group protein box-1 and its relevance to cerebral ischemia

Abstract

High-mobility group box-1 (HMGB1) was originally identified as a ubiquitously expressed, abundant, nonhistone DNA-binding protein. It has well-established functions in the maintenance of nuclear homeostasis. The HMGB1 can either be passively released into the extracellular milieu in response to necrotic signals or actively secreted in response to inflammatory signals. Extracellular HMGB1 interacts with receptors, including those for advanced glycation endproducts (RAGEs) as well as Toll-like receptor 2 (TLR2) and TLR4. The HMGB1 functions in a synergistic manner with other proinflammatory mediators and acts as a potent proinflammatory cytokine-like factor that contributes to the pathogenesis of diverse inflammatory and infectious disorders. Numerous reports point to HMGB1 as a novel player in the ischemic brain. This review provides an appraisal of the emerging roles of HMGB1 in cerebral ischemia injury, highlighting the relevance of HMGB1-blocking agents as potent therapeutic tools for neuroprotection.

Figure 1

Schematic structure of HMGB1. The basic fragment comprises Box A and B, which can function as a RAGE receptor antagonist and cytokine, respectively. The two nuclear localization signals (NLS) are also depicted. The NLS contains the hyperacetylation sites targeted by acetyltransferases that is responsible for cytoplasmic accumulation of HMGB1.

Figure 2

Pathways of HMGB1 secretion. There are two mechanisms used by cells to liberate HMGB1 into the extracellular milieu. Somatic cells contain large amounts of HMGB1 that is ‘passively released' into the extracellular milieu during cellular apoptosis or necrosis. A second mechanism is the ‘active secretion' of HMGB1 from activated immune cells or neuronal cells. The HMGB1 becomes acetylated on lysine residues within nucleus, which is thought to inhibit nuclear HMGB1 translocation, and thus, hyperacetylated HMGB1 isoforms accumulate in the cytosol where they are packaged into secretory lysosomes. The fusion of secretory lysosomes with the plasma membrane liberates HMGB1 into the extracellular environment. The molecular mechanisms underlying nuclear retention of HMGB1 and the trafficking of acetylated-HMGB1 into secretory lysosomes are still unclear. It is noteworthy that actively secreted hyperacetylated HMGB1 is molecularly different from passively released HMGB1.

Figure 3

Schematic representation of HMGB1 signaling events mediated by RAGE and TLR2/4 and therapeutic strategies for cerebral ischemia. The HMGB1 is passively released into the extracellular space, thereby allowing its interaction with RAGE and TLR2/4, as well as other unknown receptors. The TLR2/4 can then signal via MyD88, IL-1R-associated kinase 1 (IRAK), and TNF-receptor-associated factor 6 (TRAF6) to NF-κB. The RAGE can activate the Rac1 and CDC42, as well as Ras and p38. The common signaling pathway involves activation of NF-κB to induce gene expression, including that of HMGB1. The HMGB1 may be a therapeutic target for the treatment of cerebral ischemia. Therapeutic strategies include anti-HMGB1 antibodies, HMGB1 A box protein, and soluble RAGE and anti-RAGE antibodies. Open ovals indicate ‘actively secreted' acetylated HMGB1 and filled ovals indicate ‘passively released' HMGB1.