Abstract
Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. We identify High Mobility Group Box 1 (HMGB1) as a novel causative factor in the development of cerebral oedema, mediating coagulation, preventing secondary brain damage as well as serving as a novel therapeutic target to limit secondary neurological injury after TBI. As a prototypical danger associated molecular patterns (DAMP), HMGB1 is released from necrotic neurons via a NR2B-mediated mechanism during TBI. The secretion of HMGB1 requires severe injury and tissue hypoperfusion, and is associated with posttraumatic coagulation abnormalities, activation of complement and severe systemic inflammatory response. HMGB1 is clinically associated with elevated intracranial pressure (ICP) in patients and functionally promoted cerebral edema after TBI. The detrimental effects of HMGB1 is mediated at least in part between activation of microglial toll-like receptor 4 (TLR4) and the subsequent expression of the astrocytic water channel aquaporin-4 (AQP4). Anti-HMGB1mAb remarkably inhibited fluid percussion-induced brain edema by inhibiting HMGB1 translocation, protection of blood-brain barrier (BBB) integrity, suppression of inflammatory molecule expression and improvement of motor function. Our review demonstrates the pathological role of HMGB1 as well as the possible therapeutic valve of HMGB1 in patients with TBI.
Highlights
We identify High Mobility Group Box 1 (HMGB1) as a novel causative factor in the development of cerebral oedema, mediating coagulation, preventing secondary brain damage as well as serving as a novel therapeutic target to limit secondary neurological injury after Traumatic brain injury (TBI)
Laird and colleagues proposed that toll-like receptor 4 (TLR4) mediates innate immune activation and edema development after TBI by using a translational research approach that incorporates patient Cerebrospinal fluid (CSF), human tissue culture, and pre-clinical TBI models to explicate the complex role of HMGB1-TLR4 signaling in the development of secondary neurovascular injury after TBI [27]
Okuma and associates demonstrated that the treatment of TBI rats with anti-HMGB1-neutralizing mAb fiercely subdued acute brain edema, as notice on T2-weighted MRI, associated with the collateral reduction in blood-brain barrier (BBB) permeability, structural changes in capillary blood vessels, up-regulation of matrix metalloproteinase-2/9 (MMP2/9) activity, and elucidation of inflammatory molecules which was initial proposed by other researchers [34]
Summary
Traumatic Brain Injury (TBI) is the major cause of death and disability worldwide, with survivors living the rest of their lives with cognitive, motor, behav-. It is well known that intracellular functions of HMGB1 include stabilization of nucleosome formation and facilitation of gene transcription as well as co-transcriptional factor with the ability to serve as a structural DNA-binding protein [8]. The secret HMGB1 interacts with receptor for advanced glycation end (RAGE) products and members of the toll-like family of receptors (TLRs) including TLR2 and TLR4 mobilizes HMGB1 intracellularly into the extracellular compartments [14], which serves as a danger signal that activates the immune system to the ubiquity of injured cells. The mobilization of HMGB1 from intracellular milieu into the extracellular milieu involves its release by immune cells. A study by Klune et al indicated that, in the Extracellular space, HMGB1 trigger the immune system by promoting dendritic cell maturation, accelerating release of inflammatory cytokines, activating neutrophils and monocytes, as well as natural killer (NK) cells [14]. We evaluated the role of HMGB1 in secondary brain injury
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