The Role of High Mobility Group Box 1 in Ischemic Stroke

Abstract

High-mobility group box 1 protein (HMGB1) is a novel, cytokine-like, and ubiquitous, highly conserved, nuclear protein that can be actively secreted by microglia or passively released by necrotic neurons. Ischemic stroke is a leading cause of death and disability worldwide, and the outcome is dependent on the amount of hypoxia-related neuronal death in the cerebral ischemic region. Acting as an endogenous danger-associated molecular pattern (DAMP) protein, HMGB1 mediates cerebral inflammation and brain injury and participates in the pathogenesis of ischemic stroke. It is thought that HMGB1 signals via its presumed receptors, such as toll-like receptors (TLRs), matrix metalloproteinase (MMP) enzymes, and receptor for advanced glycation end products (RAGEs) during ischemic stroke. In addition, the release of HMGB1 from the brain into the bloodstream influences peripheral immune cells. However, the role of HMGB1 in ischemic stroke may be more complex than this and has not yet been clarified. Here, we summarize and review the research into HMGB1 in ischemic stroke.

Keywords: high-mobility group box 1 protein (HMGB1); inflammatory response; ischemic stroke; signaling pathways; stroke-induced immunodepression.

Figure 1

Structure of high-mobility group box 1 protein (HMGB1; 30 kD, 214 amino acids). HMGB1 is divided into three distinct structural domains: A box, B box, and C tail. The three regions have their respective positions. The three cysteines (C23, C45, and C106) in the molecular structure of HMGB1 contribute to its redox state.

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 space during cell apoptosis or necrosis. A second mechanism is the active secretion of HMGB1 from activated immune or nerve cells.

Figure 3

Potential mechanisms by which HMGB1 contributes to stroke pathogenesis. HMGB1 acts as an early mediator at the initial stages of stroke. An ischemia causes nerve cell injury, which leads to the passive release of the disulfide form of hypoacetylated HMGB1 from damaged cells. Extracellular HMGB1, which is either acetylated or oxidized at residues 23 and 45 to its the disulfide form, stimulates inflammatory signaling by binding to cell-surface receptors TRL4, receptor for advanced glycation end product (RAGE), and CXCR4 on microglia. Acetylated or disulfide HMGB1, together with cytokines and danger-associated molecular patterns (DAMPs), is also actively released from activated immune cells, causing additional nerve cell damage and microglia activation via positive feedback, thereby acting as a late inflammatory mediator.