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  1. Article ; Online: Disulfide and Fully Reduced HMGB1 Induce Different Macrophage Polarization and Migration Patterns.

    Salo, Henna / Qu, Heshuang / Mitsiou, Dimitra / Aucott, Hannah / Han, Jinming / Zhang, Xing-Mei / Aulin, Cecilia / Erlandsson Harris, Helena

    Biomolecules

    2021  Volume 11, Issue 6

    Abstract: Macrophage plasticity enables cells to obtain different functions over a broad proinflammatory and repairing spectrum. In different conditions, macrophages can be induced by high-mobility group box 1 (HMGB1), a nuclear DNA-binding protein that activates ... ...

    Abstract Macrophage plasticity enables cells to obtain different functions over a broad proinflammatory and repairing spectrum. In different conditions, macrophages can be induced by high-mobility group box 1 (HMGB1), a nuclear DNA-binding protein that activates innate immunity, to polarize towards a pro- (M1) or anti-inflammatory (M2) phenotype. In this study, we investigated the phenotypes of murine bone-marrow-derived macrophages (BMDMs) induced by different HMGB1 redox isoforms in depth. Our results demonstrate that disulfide HMGB1 (dsHMGB1) induces a unique macrophage phenotype that secretes pro-inflammatory cytokines, rather than inducing metabolic changes leading to nitric oxide production. Fully reduced HMGB1 (frHMGB1) did not induce macrophage polarization. The migrating function of BMDMs was measured by scratch assay after the stimulation with dsHMGB1 and frHMGB1. Both dsHMGB1 and frHMGB1 induced cell migration. We found that dsHMGB1 mediates cytokine secretion and cellular motility, mainly through toll-like receptor 4 (TLR4). Importantly, our data shows that dsHMGB1 and frHMGB1 induce distinct BMDM polarization phenotypes, and that dsHMGB1 induces a unique phenotype differing from the classical proinflammatory macrophage phenotype.
    MeSH term(s) Animals ; Cell Movement/drug effects ; Disulfides/chemistry ; Female ; HMGB1 Protein/chemistry ; HMGB1 Protein/pharmacology ; Macrophages/metabolism ; Mice ; Oxidation-Reduction ; Toll-Like Receptor 4/metabolism
    Chemical Substances Disulfides ; HMGB1 Protein ; HMGB1 protein, mouse ; Tlr4 protein, mouse ; Toll-Like Receptor 4
    Language English
    Publishing date 2021-05-28
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2701262-1
    ISSN 2218-273X ; 2218-273X
    ISSN (online) 2218-273X
    ISSN 2218-273X
    DOI 10.3390/biom11060800
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Ligation of free HMGB1 to TLR2 in the absence of ligand is negatively regulated by the C-terminal tail domain.

    Aucott, Hannah / Sowinska, Agnieszka / Harris, Helena Erlandsson / Lundback, Peter

    Molecular medicine (Cambridge, Mass.)

    2018  Volume 24, Issue 1, Page(s) 19

    Abstract: Background: High mobility group box 1 (HMGB1) protein is a central endogenous inflammatory mediator contributing to the pathogenesis of several inflammatory disorders. HMGB1 interacts with toll-like receptors (TLRs) but contradictory evidence regarding ... ...

    Abstract Background: High mobility group box 1 (HMGB1) protein is a central endogenous inflammatory mediator contributing to the pathogenesis of several inflammatory disorders. HMGB1 interacts with toll-like receptors (TLRs) but contradictory evidence regarding its identity as a TLR2 ligand persists. The aim of this study was to investigate if highly purified HMGB1 interacts with TLR2 and if so, to determine the functional outcome.
    Methods: Full length or C-terminal truncated (Δ30) HMGB1 was purified from E.coli. Binding to TLR2-Fc was investigated by direct-ELISA. For the functional studies, proteins alone or in complex with peptidoglycan (PGN) were added to human embryonic kidney (HEK) cells transfected with functional TLR2, TLR 1/2 or TLR 2/6 dimers, macrophages, whole blood or peripheral blood mononuclear cells (PBMCs). Cytokine levels were determined by ELISA.
    Results: In vitro binding experiments revealed that Δ30 HMGB1, lacking the acidic tail domain, but not full length HMGB1 binds dose dependently to TLR2. Control experiments confirmed that the interaction was specific to TLR2 and could be inhibited by enzymatic digestion. Δ30 HMGB1 alone was unable to induce cytokine production via TLR2. However, full length HMGB1 and Δ30 HMGB1 formed complexes with PGN, a known TLR2 ligand, and synergistically potentiated the inflammatory response in PBMCs.
    Conclusions: We have demonstrated that TLR2 is a receptor for HMGB1 and this binding is negatively regulated by the C-terminal tail. HMGB1 did not induce functional activation of TLR2 while both full length HMGB1 and Δ30 HMGB1 potentiated the inflammatory activities of the TLR2 ligand PGN. We hypothesize that Δ30 HMGB1 generated in vivo by enzymatic cleavage could act as an enhancer of TLR2-mediated inflammatory activities.
    MeSH term(s) Animals ; Cell Line ; Cytokines/metabolism ; HMGB1 Protein/metabolism ; Humans ; Leukocytes, Mononuclear/metabolism ; Ligands ; Mice ; Protein Domains ; Toll-Like Receptor 2/metabolism
    Chemical Substances Cytokines ; HMGB1 Protein ; Ligands ; Toll-Like Receptor 2
    Language English
    Publishing date 2018-05-04
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1283676-x
    ISSN 1528-3658 ; 1076-1551
    ISSN (online) 1528-3658
    ISSN 1076-1551
    DOI 10.1186/s10020-018-0021-x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 4456: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
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  3. Article ; Online: Neuroinflammation in Response to Intracerebral Injections of Different HMGB1 Redox Isoforms.

    Aucott, Hannah / Lundberg, Johan / Salo, Henna / Klevenvall, Lena / Damberg, Peter / Ottosson, Lars / Andersson, Ulf / Holmin, Staffan / Erlandsson Harris, Helena

    Journal of innate immunity

    2018  Volume 10, Issue 3, Page(s) 215–227

    Abstract: Background: Neuroinflammation triggered by infection or trauma is the cause of central nervous system dysfunction. High-mobility group box 1 protein (HMGB1), released from stressed and dying brain cells, is a potent neuroinflammatory mediator. The ... ...

    Abstract Background: Neuroinflammation triggered by infection or trauma is the cause of central nervous system dysfunction. High-mobility group box 1 protein (HMGB1), released from stressed and dying brain cells, is a potent neuroinflammatory mediator. The proinflammatory functions of HMGB1 are tightly regulated by post-translational redox modifications, and we here investigated detailed neuroinflammatory responses induced by the individual redox isoforms.
    Methods: Male Dark Agouti rats received a stereotactic injection of saline, lipopolysaccharide, disulfide HMGB1, or fully reduced HMGB1, and were accessed for blood-brain barrier modifications using magnetic resonance imaging (MRI) and inflammatory responses by immunohistochemistry.
    Results and conclusions: Significant blood-brain barrier disruption appeared 24 h after injection of lipopolysaccharide, disulfide HMGB1, or fully reduced HMGB1 compared to controls, as assessed in post-gadolinium T1-weighted MRI images and confirmed by increased uptake of FITC-conjugated dextran. Immunohistochemistry revealed that both HMGB1 isoforms also induced a local production of IL-1β. Additionally, disulfide HMGB1 increased major histocompatibility complex class II expression and apoptosis. Together, the results demonstrate that extracellular, cerebral HMGB1 causes significant blood-brain barrier disruption in a redox-independent manner and activates several components of neuroinflammation. Blocking HMGB1 might potentially improve clinical outcome in conditions such as stroke and traumatic brain injury.
    MeSH term(s) Animals ; Apoptosis/genetics ; Blood-Brain Barrier/drug effects ; Blood-Brain Barrier/metabolism ; Blood-Brain Barrier/pathology ; Dextrans/metabolism ; Encephalitis/chemically induced ; Encephalitis/metabolism ; Encephalitis/pathology ; Fluorescein-5-isothiocyanate/analogs & derivatives ; Fluorescein-5-isothiocyanate/metabolism ; HMGB1 Protein/administration & dosage ; HMGB1 Protein/metabolism ; HMGB1 Protein/pharmacology ; Histocompatibility Antigens Class II/metabolism ; Immunohistochemistry ; Interleukin-1beta/metabolism ; Magnetic Resonance Imaging ; Male ; Oxidation-Reduction ; Protein Isoforms ; Rats
    Chemical Substances Dextrans ; HMGB1 Protein ; Histocompatibility Antigens Class II ; Interleukin-1beta ; Protein Isoforms ; fluorescein isothiocyanate dextran ; Fluorescein-5-isothiocyanate (I223NX31W9)
    Language English
    Publishing date 2018-02-23
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2454158-8
    ISSN 1662-8128 ; 1662-811X
    ISSN (online) 1662-8128
    ISSN 1662-811X
    DOI 10.1159/000487056
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 6727: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
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  4. Article: Neuroinflammation in Response to Intracerebral Injections of Different HMGB1 Redox Isoforms

    Aucott, Hannah / Lundberg, Johan / Salo, Henna / Klevenvall, Lena / Damberg, Peter / Ottosson, Lars / Andersson, Ulf / Holmin, Staffan / Erlandsson Harris, Helena

    Journal of Innate Immunity

    2018  Volume 10, Issue 3, Page(s) 215–227

    Abstract: Background: Neuroinflammation triggered by infection or trauma is the cause of central nervous system dysfunction. High-mobility group box 1 protein (HMGB1), released from stressed and dying brain cells, is a potent neuroinflammatory mediator. The ... ...

    Institution Department of Medicine Solna, Rheumatology Unit, Centre for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
    Department of Neuroradiology, Karolinska University Hospital, Stockholm, Sweden
    Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden
    Abstract Background: Neuroinflammation triggered by infection or trauma is the cause of central nervous system dysfunction. High-mobility group box 1 protein (HMGB1), released from stressed and dying brain cells, is a potent neuroinflammatory mediator. The proinflammatory functions of HMGB1 are tightly regulated by post-translational redox modifications, and we here investigated detailed neuroinflammatory responses induced by the individual redox isoforms. Methods: Male Dark Agouti rats received a stereotactic injection of saline, lipopolysaccharide, disulfide HMGB1, or fully reduced HMGB1, and were accessed for blood-brain barrier modifications using magnetic resonance imaging (MRI) and inflammatory responses by immunohistochemistry. Results and Conclusions: Significant blood-brain barrier disruption appeared 24 h after injection of lipopolysaccharide, disulfide HMGB1, or fully reduced HMGB1 compared to controls, as assessed in post-gadolinium T1-weighted MRI images and confirmed by increased uptake of FITC-conjugated dextran. Immunohistochemistry revealed that both HMGB1 isoforms also induced a local production of IL-1β. Additionally, disulfide HMGB1 increased major histocompatibility complex class II expression and apoptosis. Together, the results demonstrate that extracellular, cerebral HMGB1 causes significant blood-brain barrier disruption in a redox-independent manner and activates several components of neuroinflammation. Blocking HMGB1 might potentially improve clinical outcome in conditions such as stroke and traumatic brain injury.
    Keywords HMGB1 ; Brain ; Redox ; Neuroinflammation ; Blood-brain barrier
    Language English
    Publishing date 2018-02-23
    Publisher S. Karger AG
    Publishing place Basel, Switzerland
    Document type Article
    Note Research Article ; This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).
    ZDB-ID 2454158-8
    ISSN 1662-8128 ; 1662-811X
    ISSN (online) 1662-8128
    ISSN 1662-811X
    DOI 10.1159/000487056
    Database Karger publisher's database

    Full text online

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 6727: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
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    ab Jg. 2022: Lesesaal (EG)

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