The Roles of High Mobility Group Box 1 in Cerebral Ischemic Injury

Abstract

High mobility group box 1 (HMGB1) is a ubiquitous nuclear protein that plays an important role in stabilizing nucleosomes and DNA repair. HMGB1 can be passively released from necrotic neurons or actively secreted by microglia, macrophages/monocytes, and neutrophils. Cerebral ischemia is a major cause of mortality and disability worldwide, and its outcome depends on the number of neurons dying due to hypoxia in the ischemic area. HMGB1 contributes to the pathogenesis of cerebral ischemia via mediating neuroinflammatory responses to cerebral ischemic injury. Extracellular HMGB1 regulates many neuroinflammatory events by interacting with its different cell surface receptors, such as receptors for advanced glycation end products, toll-like receptor (TLR)-2, and TLR-4. Additionally, HMGB1 can be redox-modified, thus exerting specific cellular functions in the ischemic brain and has different roles in the acute and late stages of cerebral ischemic injury. However, the role of HMGB1 in cerebral ischemia is complex and remains unclear. Herein, we summarize and review the research on HMGB1 in cerebral ischemia, focusing especially on the role of HMGB1 in hypoxic ischemia in the immature brain and in white matter ischemic injury. We also outline the possible mechanisms of HMGB1 in cerebral ischemia and the main strategies to inhibit HMGB1 pertaining to its potential as a novel critical molecular target in cerebral ischemic injury.

Keywords: cerebral; high-mobility group box 1; ischemia; receptor for advanced glycation end products; therapeutic strategy; toll-like receptor.

Figure 1

Schematic structure of the HMGB1 protein. HMGB1 is a single polypeptide chain consisting of 215 amino acids, containing two DNA binding domains (HMG boxes A, B), a N-terminal and a C-terminal. A box and B box function as RAGE receptor antagonist and cytokine, respectively.

Figure 2

Mechanisms of HMGB1 release in cerebral ischemia. There are two mechanisms of HMGB1 from intracellular to extracellular in cerebral ischemic injury: (A) passive release, occurring mainly in necrotic cells (e.g., neurons, oligodendrocytes), pyrocytes, and ischemic brain tissue; (B) active secretion, which occurs mainly in activated microglia cells, astrocytes, and innate immune cells such as macrophages. Extracellular HMGB1 functions as a proinflammatory factor, leading to neuroinflammatory events.

Figure 3

HMGB1/TLR/RAGE signaling pathways in cerebral ischemia. The primary HMGB1 receptors involved in ischemic brain injury include RAGE, toll-like receptor (TLR)-2, and TLR-4. HMGB1 directly interacts with TLR2 and stimulates increase in TLR2-mediated activation of NF-κB. Disulfide HMGB1 combines with MD-2, which forms a complex with TLR4, triggering an inflammatory response. TLR downstream signal regulators include p38, MyD88, TGF-β activated kinase 1 (TAK1), and TAK1-binding protein 2 (TAB2). They activate NF-κB to trigger an inflammatory response. Two major pathways of HMGB1-induced RAGE activation are CDC42 / Rac1 and multiple mitogen-activated protein kinases (MAPKs), which ultimately lead to NF-κB activation. NF-κB translocates to the nucleus and initiates the transcription of several pro-inflammatory genes, including TNF-α, iNOS, ICAM-1, IL-1β, IL-6, IL-8, and COX-2.