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Review
. 2014 Mar 1;20(7):1075-85.
doi: 10.1089/ars.2013.5179. Epub 2013 Mar 19.

Redox modulation of HMGB1-related signaling

Christina Janko  1 , Milos Filipović, Luis E Munoz, Christine Schorn, Georg Schett, Ivana Ivanović-Burmazović, Martin Herrmann
Affiliations
Review

Redox modulation of HMGB1-related signaling

Christina Janko et al. Antioxid Redox Signal. .

Abstract

Significance: In the cells' nuclei, high-mobility group box protein 1 (HMGB1) is a nonhistone chromatin-binding protein involved in the regulation of transcription. Extracellularly, HMGB1 acts as a danger molecule with properties of a proinflammatory cytokine. It can be actively secreted from myeloid cells or passively leak from any type of injured, necrotic cell. Increased serum levels of active HMGB1 are often found in pathogenic inflammatory conditions and correlate with worse prognoses in cancer, sepsis, and autoimmunity VSports手机版. By damaging cells, superoxide and peroxynitrite promote leakage of HMGB1. .

Recent advances: The activity of HMGB1 strongly depends on its redox state: Inflammatory-active HMGB1 requires an intramolecular disulfide bond (Cys23 and Cys45) and a reduced Cys106. Oxidation of the latter blocks its stimulatory activity and promotes immune tolerance. V体育安卓版.

Critical issues: Reactive oxygen and nitrogen species create an oxidative environment and can be detoxified by superoxide dismutase (SOD), catalase, and peroxidases. Modifications of the oxidative environment influence HMGB1 activity V体育ios版. .

Future directions: In this review, we hypothesize that manipulations of an oxidative environment by SOD mimics or by hydrogen sulfide are prone to decrease tissue damage. Both the concomitant decreased HMGB1 release and its redox chemical modifications ameliorate inflammation and tissue damage VSports最新版本. .

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Figures

<b>FIG. 1.</b>
FIG. 1.
Structure of HMGB1. High-mobility group box protein 1 (HMGB1) consists of 215 amino acids organized into two HMG boxes, which are the DNA-binding domains, and an acidic C-terminus.
<b>FIG. 2.</b>
FIG. 2.
HMGB1-associated molecules and interactions with cell surface receptors. Beside HMGB1 signalling per se employing receptor for advanced glycation endproducts (RAGE) and Toll-like receptor 4 (TLR4), HMGB1 forms complexes with immunostimulatory molecules as the TLR4 ligand lipopolysaccharide (LPS), the TLR2 ligands Pam3CSK4 and nucleosomes, the IL-1R ligand IL-1β, the CXCR4 ligand CXCL12, as well as the TLR ligands RNA and DNA. HMGB1 has also been described to bind to CD24 and thrombospondin, eliciting negative regulatory signals.
<b>FIG. 3.</b>
FIG. 3.
Passive release of HMGB1 from dying and dead cells. In viable cells, HMGB1 acts as nonhistone, architectural chromatin-binding factor. During apoptosis under-acetylation of histones leads to chromatin condensation, and HMGB1 is irreversibly attached to the chromatin. If apoptotic cells are not cleared in time by phagocytes, they undergo secondary necrosis, and HMGB1–nucleosome complexes can leak through the disrupted plasma membrane. Primary necrotic cells release free HMGB1.
<b>FIG. 4.</b>
FIG. 4.
Development of reactive oxygen species (ROS) and reactive nitrogen species (RNS). Leakage of electrons from the mitochondrial electron transport chain (ETC), NAD(P)H oxidase, and xanthine oxidase, and uncoupling of nitric oxide (NO) synthases lead to the development of O2•−. Peroxynitrite can be produced from NO and O2•−. ROS can be detoxified by catalase, peroxidase, and superoxide dismutase. Free ROS/RNS cause oxidative damage of DNA, proteins, and lipids, resulting in the loss of the mitochondrial membrane potential (Δψm), in apoptosis or necrosis.
<b>FIG. 5.</b>
FIG. 5.
Oxidative states of HMGB1. In inflammatory conditions, Cys23 and Cys45 form an intramolecular disulfide bond, whereas Cys106 remains in the reduced state (HMGB1 is semioxidized). Oxidation of HMGB1 by ROS/RNS abolishes its proinflammatory features.
<b>FIG. 6.</b>
FIG. 6.
Double-edged role of ROS/RNS in HMGB1 release and resolution of inflammation. On one hand, ROS/RNS induce cell death leading to the leakage of proinflammatory HMGB1, which further enforces cell death in the environment. On the other hand, the oxidation of HMGB1 by ROS/RNS into its inactive form acts as a feedback mechanism to control its proinflammatory activity.
<b>FIG. 7.</b>
FIG. 7.
Functions and receptors of HMGB1 are dependent on its redox state. HMGB1 with C23 and C45 in a disulfide bond signals via TLR4, eliciting the release of proinflammatory cytokines. Complete reduction of cysteines to thiols abrogates the cytokine-stimulating activity; it induces autophagy via RAGE. Thiol HMGB1-complexed CXCL12 serves as a chemoattractant and induces cell migration. The actions of disulfide and thiol HMGB1 are mutually exclusive. Terminal oxidation of cysteines to sulfonates completely abolishes HMGB1 activity and contributes to the resolution of inflammation.
<b>FIG. 8.</b>
FIG. 8.
Hypothetical depiction of the possible roles of hydrogen sulfide (H2S) and superoxide dismutase mimics (SODm) on structural modifications of HMGB1. The active form of HMGB1 (semioxidized), where Cys106 is reduced while Cys23 and 45 form disulfides, can be further modified depending on the extent of oxidative stress to form oxidized HMGB1, where Cys106 is in the form of sulfenic (RSOH), sulfinic (RSO2H), or sulfonic (RSO3H) acid. Only sulfenic acid can be reversed. Small amounts of H2S could react with it to form sulfhydrylated HMGB1, while in the excess of H2S, further breakage of the Cys23–45 disulfide bond can be achieved. On the other side, by reacting with NO, SODm dismutate it to nitrosonium (NO+) and nitroxyl (NO−/HNO) and induce formation of S-nitros(yl)ated HMGB1 or HMGB1 dimers. The extent to which this modifications influence the HMGB1 remains to be elucidated.
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