HMGB1 Translocation in Neurons after Ischemic Insult: Subcellular Localization in Mitochondria and Peroxisomes

Wang, Dengli; Liu, Keyue; Fukuyasu, Yusuke; Takamatsu, Kiyoshi; Fu, Li; Wake, Hidenori; Ohtsuka, Aiji; Nishibori, Masahiro

doi:10.3390/cells9030643

Cited by 20 publications

(15 citation statements)

References 33 publications

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“…Recently, Wang et al reported the subcellular localizations of HMGB1 in neurons after ischemic insults in adult rats 65 . They found that HMGB1 was co‐localized with mitochondria and peroxisomes in the cytosolic compartment when HMGB1 formed granular structures, suggesting a possible role for HMGB1 in energy metabolism of neurons.…”

Section: Discussionmentioning

confidence: 99%

High‐mobility group box‐1 and inter‐alpha inhibitor proteins: In vitro binding and co‐localization in cerebral cortex after hypoxic‐ischemic injury

et al. 2021

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The high‐mobility group box‐1 (HMGB1) protein is a transcription‐regulating protein located in the nucleus. However, it serves as a damage‐associated molecular pattern protein that activates immune cells and stimulates inflammatory cytokines to accentuate neuroinflammation after release from damaged cells. In contrast, Inter‐alpha Inhibitor Proteins (IAIPs) are proteins with immunomodulatory effects including inhibition of pro‐inflammatory cytokines. We have demonstrated that IAIPs exhibit neuroprotective properties in neonatal rats exposed to hypoxic‐ischemic (HI) brain injury. In addition, previous studies have suggested that the light chain of IAIPs, bikunin, may exert its anti‐inflammatory effects by inhibiting HMGB1 in a variety of different injury models in adult subjects. The objectives of the current study were to confirm whether HMGB1 is a target of IAIPs by investigating the potential binding characteristics of HMGB1 and IAIPs in vitro, and co‐localization in vivo in cerebral cortices after exposure to HI injury. Solid‐phase binding assays and surface plasmon resonance (SPR) were used to determine the physical binding characteristics between IAIPs and HMGB1. Cellular localizations of IAIPs‐HMGB1 in neonatal rat cortex were visualized by double labeling with anti‐IAIPs and anti‐HMGB1 antibodies. Solid‐phase binding and SPR demonstrated specific binding between IAIPs and HMGB1 in vitro. Cortical cytoplasmic and nuclear co‐localization of IAIPs and HMGB1 were detected by immunofluorescent staining in control and rats immediately and 3 hours after HI. In conclusion, HMGB1 and IAIPs exhibit direct binding in vitro and co‐localization in vivo in neonatal rats exposed to HI brain injury suggesting HMGB1 could be a target of IAIPs.

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Section: Discussionmentioning

confidence: 99%

High‐mobility group box‐1 and inter‐alpha inhibitor proteins: In vitro binding and co‐localization in cerebral cortex after hypoxic‐ischemic injury

et al. 2021

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“…It is possible that secretion-ready cytosolic HMGB1 is packed into a secretory lysosome or autophagosome and secreted via non-conventional secretion mechanisms, requiring a very complex, as yet unknown, packaging mechanism. Conversely, a recent article by Wang et al observed HMGB1 localization in mitochondria and peroxisome in neuron cells via electron microscopy and immunofluorescence, but not in lysosomes (121). In macrophages or macrophage lineages, the release of HMGB1 occurred through a lysosomal pathway after acetylation of the HMGB1 (16).…”

Section: Hmgb1 Secretion Kineticsmentioning

confidence: 91%

Immunological Significance of HMGB1 Post-Translational Modification and Redox Biology

et al. 2020

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Most extracellular proteins are secreted via the classical endoplasmic reticulum (ER)/Golgi-dependent secretion pathway; however, some proteins, including a few danger-associated molecular patterns (DAMPs), are secreted via non-classical ER/Golgi-independent secretion pathways. The evolutionarily conserved high mobility group box1 (HMGB1) is a ubiquitous nuclear protein that can be released by almost all cell types. HMGB1 lacks signal peptide and utilizes diverse non-canonical secretion mechanisms for its extracellular export. Although the post-translational modifications of HMGB1 were demonstrated, the oxidation of HMGB1 and secretion mechanisms are not highlighted yet. We currently investigated that peroxiredoxins I and II (PrxI/II) induce the intramolecular disulfide bond formation of HMGB1 in the nucleus. Disulfide HMGB1 is preferentially transported out of the nucleus by binding to the nuclear exportin chromosome-region maintenance 1 (CRM1). We determined the kinetics of HMGB1 oxidation in bone marrow-derived macrophage as early as a few minutes after lipopolysaccharide treatment, peaking at 4 h while disulfide HMGB1 accumulation was observed within the cells, starting to secrete in the late time point. We have shown that HMGB1 oxidation status, which is known to determine the biological activity in extracellular HMGB1, is crucial for the secretion of HMGB1 from the nucleus. This review summarizes selected aspects of HMGB1 redox biology relevant to the induction and propagation of inflammatory diseases. We implicate the immunological significance and the need for novel HMGB1 inhibitors through mechanism-based studies.

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“…Recent work on the translocation of HMGB1 in neurons after ischemic insult indicated that the HMGB1 translocated from nuclei to cytoplasm was colocalized with mitochondria and peroxisomes [ 73 ] during the release process. Moreover, HMGB1 was colocalized with Drp-1, a protein involved in the fission of mitochondria, suggesting that HMGB1 also exerts cell-metabolism-modifying effects in these organelles during the translocation process [ 73 ].…”

Section: Stroke and Bbb Disruptionmentioning

confidence: 99%

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

Nishibori

Wang

Ousaka

et al. 2020

Cells

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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.

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HMGB1 Translocation in Neurons after Ischemic Insult: Subcellular Localization in Mitochondria and Peroxisomes

Cited by 20 publications

References 33 publications

High‐mobility group box‐1 and inter‐alpha inhibitor proteins: In vitro binding and co‐localization in cerebral cortex after hypoxic‐ischemic injury

High‐mobility group box‐1 and inter‐alpha inhibitor proteins: In vitro binding and co‐localization in cerebral cortex after hypoxic‐ischemic injury

Immunological Significance of HMGB1 Post-Translational Modification and Redox Biology

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

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