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Cells
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HMGB1 in Health and Disease
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HMGB1 in Health and Disease

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Immunology".

Deadline for manuscript submissions: closed (15 March 2020) | Viewed by 38995

Special Issue Editor

Prof. Dr. Atsufumi Kawabata

E-Mail Website
Guest Editor
Laboratory of Pharmacology and Pathophysiology/Faculty of Pharmacy, Kindai University, Higashi-Osaka 577-8502, Japan
Interests: high-mobility group box 1 (HMGB1); T-type calcium channel; hydrogen sulfide; proteinase-activated receptor (PAR); neuroinflammation; pain
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

High mobility group box 1 (HMGB1) functions as a DNA chaperone in the nucleus, and its translocation to the cytoplasm promotes autophagy. HMGB1 is passively released to the extracellular space from dying cells and actively secreted by immune cells, platelets, endothelial cells, etc. in response to infection, inflammatory stimuli, and so on. Extracellular HMGB1 acts as a damage-associated molecular pattern (DAMP) molecule mainly through interaction with pattern-recognition receptors (PRRs), leading to tissue repair or healing, but also aggravation of inflammation or tissue damage. HMGB1 is not only associated with acute inflammatory symptoms, including disseminated intravascular coagulation (DIC), but also with autoimmune disorders, deep venous thrombosis, cancer, etc. Notably, HMGB1 also participates in neuroinflammation, neurodegeneration, and neuronal hyperexcitability and is considered a key molecule in a neuroimmune crosstalk. Thus, HMGB1 is present in the peripheral tissue and CNS plays a wide range of roles in health and disease.

The aim of this Special Issue of Cells is to provide an update of our understandings of the roles played by HMGB1 present in the nucleus, cytoplasm, and extracellular milieu in health and disease. Both original research articles and reviews are welcome.

Prof. Atsufumi Kawabata
Guest Editor

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Keywords

  • high mobility group box 1 (HMGB1)
  • alarmin
  • damage-associated molecular patterns (DAMPs)
  • pattern-recognition receptors (PRRs)
  • neuroinflammation
  • neuroimmune crosstalk

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Published Papers (6 papers)

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Research

Jump to: Review

20 pages, 6856 KiB  
Article
Cystitis-Related Bladder Pain Involves ATP-Dependent HMGB1 Release from Macrophages and Its Downstream H2S/Cav3.2 Signaling in Mice
by Shiori Hiramoto, Maho Tsubota, Kaoru Yamaguchi, Kyoko Okazaki, Aya Sakaegi, Yuki Toriyama, Junichi Tanaka, Fumiko Sekiguchi, Hiroyasu Ishikura, Hidenori Wake, Masahiro Nishibori, Huy Du Nguyen, Takuya Okada, Naoki Toyooka and Atsufumi Kawabata
Cells 2020, 9(8), 1748; https://doi.org/10.3390/cells9081748 - 22 Jul 2020
Cited by 30 | Viewed by 3731
Abstract
Cystitis-related bladder pain involves RAGE activation by HMGB1, and increased Cav3.2 T-type Ca2+ channel activity by H2S, generated by upregulated cystathionine-γ-lyase (CSE) in mice treated with cyclophosphamide (CPA). We, thus, investigated possible crosstalk between the HMGB1/RAGE and CSE/H [...] Read more.
Cystitis-related bladder pain involves RAGE activation by HMGB1, and increased Cav3.2 T-type Ca2+ channel activity by H2S, generated by upregulated cystathionine-γ-lyase (CSE) in mice treated with cyclophosphamide (CPA). We, thus, investigated possible crosstalk between the HMGB1/RAGE and CSE/H2S/Cav3.2 pathways in the bladder pain development. Bladder pain (nociceptive behavior/referred hyperalgesia) and immuno-reactive CSE expression in the bladder were determined in CPA-treated female mice. Cell signaling was analyzed in urothelial T24 and macrophage-like RAW264.7 cells. The CPA-induced bladder pain was abolished by pharmacological inhibition of T-type Ca2+ channels or CSE, and genetic deletion of Cav3.2. The CPA-induced CSE upregulation, as well as bladder pain was prevented by HMGB1 inactivation, inhibition of HMGB1 release from macrophages, antagonists of RAGE or P2X4/P2X7 receptors, and N-acetylcysteine, an antioxidant. Acrolein, a metabolite of CPA, triggered ATP release from T24 cells. Adenosine triphosphate (ATP) stimulated cell migration via P2X7/P2X4, and caused HMGB1 release via P2X7 in RAW264.7 cells, which was dependent on p38MAPK/NF-κB signaling and reactive oxygen species (ROS) accumulation. Together, our data suggest that CPA, once metabolized to acrolein, causes urothelial ATP-mediated, redox-dependent HMGB1 release from macrophages, which in turn causes RAGE-mediated CSE upregulation and subsequent H2S-targeted Cav3.2-dependent nociceptor excitation, resulting in bladder pain. Full article
(This article belongs to the Special Issue HMGB1 in Health and Disease)
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24 pages, 5010 KiB  
Article
Regulation of Neurogenesis in Mouse Brain by HMGB1
by Xiang Zhao, Ari Rouhiainen, Zhilin Li, Su Guo and Heikki Rauvala
Cells 2020, 9(7), 1714; https://doi.org/10.3390/cells9071714 - 17 Jul 2020
Cited by 18 | Viewed by 6989
Abstract
The High Mobility Group Box 1 (HMGB1) is the most abundant nuclear nonhistone protein that is involved in transcription regulation. In addition, HMGB1 has previously been found as an extracellularly acting protein enhancing neurite outgrowth in cultured neurons. Although HMGB1 is widely expressed [...] Read more.
The High Mobility Group Box 1 (HMGB1) is the most abundant nuclear nonhistone protein that is involved in transcription regulation. In addition, HMGB1 has previously been found as an extracellularly acting protein enhancing neurite outgrowth in cultured neurons. Although HMGB1 is widely expressed in the developing central nervous system of vertebrates and invertebrates, its function in the developing mouse brain is poorly understood. Here, we have analyzed developmental defects of the HMGB1 null mouse forebrain, and further examined our findings in ex vivo brain cell cultures. We find that HMGB1 is required for the proliferation and differentiation of neuronal stem cells/progenitor cells. Enhanced apoptosis is also found in the neuronal cells lacking HMGB1. Moreover, HMGB1 depletion disrupts Wnt/β-catenin signaling and the expression of transcription factors in the developing cortex, including Foxg1, Tbr2, Emx2, and Lhx6. Finally, HMGB1 null mice display aberrant expression of CXCL12/CXCR4 and reduced RAGE signaling. In conclusion, HMGB1 plays a critical role in mammalian neurogenesis and brain development. Full article
(This article belongs to the Special Issue HMGB1 in Health and Disease)
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16 pages, 1563 KiB  
Article
Corticosterone Induces HMGB1 Release in Primary Cultured Rat Cortical Astrocytes: Involvement of Pannexin-1 and P2X7 Receptor-Dependent Mechanisms
by Kazue Hisaoka-Nakashima, Honami Azuma, Fumina Ishikawa, Yoki Nakamura, Dengli Wang, Keyue Liu, Hidenori Wake, Masahiro Nishibori, Yoshihiro Nakata and Norimitsu Morioka
Cells 2020, 9(5), 1068; https://doi.org/10.3390/cells9051068 - 25 Apr 2020
Cited by 21 | Viewed by 3872
Abstract
A major risk factor for major depressive disorder (MDD) is stress. Stress leads to the release of high-mobility group box-1 (HMGB1), which in turn leads to neuroinflammation, a potential pathophysiological basis of MDD. The mechanism underlying stress-induced HMGB1 release is not known, but [...] Read more.
A major risk factor for major depressive disorder (MDD) is stress. Stress leads to the release of high-mobility group box-1 (HMGB1), which in turn leads to neuroinflammation, a potential pathophysiological basis of MDD. The mechanism underlying stress-induced HMGB1 release is not known, but stress-associated glucocorticoids could be involved. To test this, rat primary cultured cortical astrocytes, the most abundant cell type in the central nervous system (CNS), were treated with corticosterone and HMGB1 release was assessed by Western blotting and ELISA. Significant HMGB1 was released with treatment with either corticosterone or dexamethasone, a synthetic glucocorticoid. HMGB1 translocated from the nucleus to the cytoplasm following corticosterone treatment. HMGB1 release was significantly attenuated with glucocorticoid receptor blocking. In addition, inhibition of pannexin-1, and P2X7 receptors led to a significant decrease in corticosterone-induced HMGB1 release. Taken together, corticosterone stimulates astrocytic glucocorticoid receptors and triggers cytoplasmic translocation and extracellular release of nuclear HMGB1 through a mechanism involving pannexin-1 and P2X7 receptors. Thus, under conditions of stress, glucocorticoids induce astrocytic HMGB1 release, leading to a neuroinflammatory state that could mediate neurological disorders such as MDD. Full article
(This article belongs to the Special Issue HMGB1 in Health and Disease)
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13 pages, 24859 KiB  
Article
HMGB1 Translocation in Neurons after Ischemic Insult: Subcellular Localization in Mitochondria and Peroxisomes
by Dengli Wang, Keyue Liu, Yusuke Fukuyasu, Kiyoshi Teshigawara, Li Fu, Hidenori Wake, Aiji Ohtsuka and Masahiro Nishibori
Cells 2020, 9(3), 643; https://doi.org/10.3390/cells9030643 - 6 Mar 2020
Cited by 18 | Viewed by 4399
Abstract
High mobility group box-1 (HMGB1), a nonhistone chromatin DNA-binding protein, is released from neurons into the extracellular space under ischemic, hemorrhagic, and traumatic insults. However, the details of the time-dependent translocation of HMGB1 and the subcellular localization of HMGB1 through the release process [...] Read more.
High mobility group box-1 (HMGB1), a nonhistone chromatin DNA-binding protein, is released from neurons into the extracellular space under ischemic, hemorrhagic, and traumatic insults. However, the details of the time-dependent translocation of HMGB1 and the subcellular localization of HMGB1 through the release process in neurons remain unclear. In the present study, we examined the subcellular localization of HMGB1 during translocation of HMGB1 in the cytosolic compartment using a middle cerebral artery occlusion and reperfusion model in rats. Double immunofluorescence microscopy revealed that HMGB1 immunoreactivities were colocalized with MTCO1(mitochondrially encoded cytochrome c oxidase I), a marker of mitochondria, and catalase, a marker of peroxisomes, but not with Rab5/Rab7 (RAS-related GTP-binding protein), LC3A/B (microtubule-associated protein 1 light chain 3), KDEL (KDEL amino acid sequence), and LAMP1 (Lysosomal Associated Membrane Protein 1), which are endosome, phagosome, endoplasmic reticulum, and lysosome markers, respectively. Immunoelectron microscopy confirmed that immune-gold particles for HMGB1 were present inside the mitochondria and peroxisomes. Moreover, HMGB1 was found to be colocalized with Drp1 (Dynamin-related protein 1), which is involved in mitochondrial fission. These results revealed the specific subcellular localization of HMGB1 during its release process under ischemic conditions. Full article
(This article belongs to the Special Issue HMGB1 in Health and Disease)
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Review

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31 pages, 2764 KiB  
Review
High Mobility Group Box 1 in Human Cancer
by Bernardo L. Rapoport, Helen C. Steel, Annette J. Theron, Liezl Heyman, Teresa Smit, Yastira Ramdas and Ronald Anderson
Cells 2020, 9(7), 1664; https://doi.org/10.3390/cells9071664 - 10 Jul 2020
Cited by 46 | Viewed by 4854
Abstract
High mobility group box 1 (HMGB1) is an extremely versatile protein that is located predominantly in the nucleus of quiescent eukaryotic cells, where it is critically involved in maintaining genomic structure and function. During cellular stress, however, this multifaceted, cytokine-like protein undergoes posttranslational [...] Read more.
High mobility group box 1 (HMGB1) is an extremely versatile protein that is located predominantly in the nucleus of quiescent eukaryotic cells, where it is critically involved in maintaining genomic structure and function. During cellular stress, however, this multifaceted, cytokine-like protein undergoes posttranslational modifications that promote its translocation to the cytosol, from where it is released extracellularly, either actively or passively, according to cell type and stressor. In the extracellular milieu, HMGB1 triggers innate inflammatory responses that may be beneficial or harmful, depending on the magnitude and duration of release of this pro-inflammatory protein at sites of tissue injury. Heightened awareness of the potentially harmful activities of HMGB1, together with a considerable body of innovative, recent research, have revealed that excessive production of HMGB1, resulting from misdirected, chronic inflammatory responses, appears to contribute to all the stages of tumorigenesis. In the setting of established cancers, the production of HMGB1 by tumor cells per se may also exacerbate inflammation-related immunosuppression. These pro-inflammatory mechanisms of HMGB1-orchestrated tumorigenesis, as well as the prognostic potential of detection of elevated expression of this protein in the tumor microenvironment, represent the major thrusts of this review. Full article
(This article belongs to the Special Issue HMGB1 in Health and Disease)
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26 pages, 1572 KiB  
Review
Impact of HMGB1, RAGE, and TLR4 in Alzheimer’s Disease (AD): From Risk Factors to Therapeutic Targeting
by Yam Nath Paudel, Efthalia Angelopoulou, Christina Piperi, Iekhsan Othman, Khurram Aamir and Mohd. Farooq Shaikh
Cells 2020, 9(2), 383; https://doi.org/10.3390/cells9020383 - 7 Feb 2020
Cited by 150 | Viewed by 14260
Abstract
Alzheimer’s disease (AD) is a devastating neurodegenerative disorder and a leading cause of dementia, with accumulation of amyloid-beta (Aβ) and neurofibrillary tangles (NFTs) as defining pathological features. AD presents a serious global health concern with no cure to date, reflecting the complexity of [...] Read more.
Alzheimer’s disease (AD) is a devastating neurodegenerative disorder and a leading cause of dementia, with accumulation of amyloid-beta (Aβ) and neurofibrillary tangles (NFTs) as defining pathological features. AD presents a serious global health concern with no cure to date, reflecting the complexity of its pathogenesis. Recent evidence indicates that neuroinflammation serves as the link between amyloid deposition, Tau pathology, and neurodegeneration. The high mobility group box 1 (HMGB1) protein, an initiator and activator of neuroinflammatory responses, has been involved in the pathogenesis of neurodegenerative diseases, including AD. HMGB1 is a typical damage-associated molecular pattern (DAMP) protein that exerts its biological activity mainly through binding to the receptor for advanced glycation end products (RAGE) and toll-like receptor 4 (TLR4). RAGE and TLR4 are key components of the innate immune system that both bind to HMGB1. Targeting of HMGB1, RAGE, and TLR4 in experimental AD models has demonstrated beneficial effects in halting AD progression by suppressing neuroinflammation, reducing Aβ load and production, improving spatial learning, and inhibiting microglial stimulation. Herein, we discuss the contribution of HMGB1 and its receptor signaling in neuroinflammation and AD pathogenesis, providing evidence of its beneficial effects upon therapeutic targeting. Full article
(This article belongs to the Special Issue HMGB1 in Health and Disease)
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