High Mobility Group Box-1 and Blood–Brain Barrier Disruption

Abstract

Increasing evidence suggests that inflammatory responses are involved in the progression of brain injuries induced by a diverse range of insults, including ischemia, hemorrhage, trauma, epilepsy, and degenerative diseases. During the processes of inflammation, disruption of the blood–brain barrier (BBB) may play a critical role in the enhancement of inflammatory responses and may initiate brain damage because the BBB constitutes an interface between the brain parenchyma and the bloodstream containing blood cells and plasma. The BBB has a distinct structure compared with those in peripheral tissues: it is composed of vascular endothelial cells with tight junctions, numerous pericytes surrounding endothelial cells, astrocytic endfeet, and a basement membrane structure. Under physiological conditions, the BBB should function as an important element in the neurovascular unit (NVU). High mobility group box-1 (HMGB1), a nonhistone nuclear protein, is ubiquitously expressed in almost all kinds of cells. HMGB1 plays important roles in the maintenance of chromatin structure, the regulation of transcription activity, and DNA repair in nuclei. On the other hand, HMGB1 is considered to be a representative damage-associated molecular pattern (DAMP) because it is translocated and released extracellularly from different types of brain cells, including neurons and glia, contributing to the pathophysiology of many diseases in the central nervous system (CNS). The regulation of HMGB1 release or the neutralization of extracellular HMGB1 produces beneficial effects on brain injuries induced by ischemia, hemorrhage, trauma, epilepsy, and Alzheimer’s amyloidpathy in animal models and is associated with improvement of the neurological symptoms. In the present review, we focus on the dynamics of HMGB1 translocation in different disease conditions in the CNS and discuss the functional roles of extracellular HMGB1 in BBB disruption and brain inflammation. There might be common as well as distinct inflammatory processes for each CNS disease. This review will provide novel insights toward an improved understanding of a common pathophysiological process of CNS diseases, namely, BBB disruption mediated by HMGB1. It is proposed that HMGB1 might be an excellent target for the treatment of CNS diseases with BBB disruption.

Meta-Analysis of Methamphetamine Modulation on Amyloid Precursor Protein through HMGB1 in Alzheimer’s Disease

“…Our meta-analysis found that METH increased expression of HMGB1, which, in turn, leads to disruption of the blood brain barrier (BBB), neuronal damage, formation of amyloid-beta plaques, and an overall increase in APP expression ( Figure 10 ). These data were in line with prior findings on the relationship between HMGB1 and its effects on the BBB and APP [ 10 , 11 , 12 , 13 , 32 , 33 ] to demonstrate METH modulation on APP, the precursor of beta amyloid, through HMGB1 in AD development.…”

“…Furthermore, HMGB1 is seen on the Aβ plaques in AD brains [ 10 ] and enhances the neurotoxicity of Aβ [ 11 ]. HMGB1 has also been found to mediate disruption of the blood-brain barrier (BBB) [ 12 , 13 ].…”

“…sAPPα is a well-studied neuroprotective factor involved in enhancing long-term potentiation and memory [ 27 ]. In traumatic brain injuries, HMGB1 level is increased and contributes to the disruption of BBB integrity [ 12 , 13 ]. There have been very few studies examining the relationship between METH and HMGB1.…”

Understanding of COVID-19 Pathology: Much More Attention to Plasma Proteins

“…High mobility group box-1 (HMGB1), a highly conserved nonhistone nuclear protein, plays a particularly important role as proinflammatory factor in the extracellular space through the stimulation of plural receptors: receptor for advanced glycation end products, toll-like receptor-4/2 (35). HMGB1 is released from not only necrotic cells but also many kinds of living cells under different conditions of stress including hypoxia, ischemia, and stimulation by cytokines (36,37). The neutralization of extracellular HMGB1 by specific monoclonal antibody (mAb) was reported to inhibit influenza virus (H1N1)-induced pneumonia and improve the survival of infected mice (38,39).…”

Modulation of α7nAchR by Melatonin Alleviates Ischemia and Reperfusion-Compromised Integrity of Blood–Brain Barrier Through Inhibiting HMGB1-Mediated Microglia Activation and CRTC1-Mediated Neuronal Loss

“…High mobility group box 1(HMGB1) not only plays a critical role as a nuclear DNA-binding protein, but also as a cytokine-like mediator of systemic in ammation, for example, HMGB1 plays an important role in BBB damage after stroke (Nishibori et al 2020). In addition, serum HMGB1 levels were signi cantly elevated in patients with cerebral ischemia (Goldstein et al 2006) and HMGB1 has been reported to be released from neurons early following ischemic injury, and acts as a mediator linking acute brain damage and subsequent in ammatory processes (Qiu et al 2008).…”