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      Review: The role of HMGB1 in spinal cord injury

      review-article
      ,
      Frontiers in Immunology
      Frontiers Media S.A.
      HMGB1, spinal cord injury, inflammation, neuron, mechanism

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          Abstract

          High mobility group box 1 (HMGB1) has dual functions as a nonhistone nucleoprotein and an extracellular inflammatory cytokine. In the resting state, HMGB1 is mainly located in the nucleus and regulates key nuclear activities. After spinal cord injury, HMGB1 is rapidly expressed by neurons, microglia and ependymal cells, and it is either actively or passively released into the extracellular matrix and blood circulation; furthermore, it also participates in the pathophysiological process of spinal cord injury. HMGB1 can regulate the activation of M1 microglia, exacerbate the inflammatory response, and regulate the expression of inflammatory factors through Rage and TLR2/4, resulting in neuronal death. However, some studies have shown that HMGB1 is beneficial for the survival, regeneration and differentiation of neurons and that it promotes the recovery of motor function. This article reviews the specific timing of secretion and translocation, the release mechanism and the role of HMGB1 in spinal cord injury. Furthermore, the role and mechanism of HMGB1 in spinal cord injury and, the challenges that still need to be addressed are identified, and this work will provide a basis for future studies.

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          Most cited references153

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          HMG-1 as a late mediator of endotoxin lethality in mice.

          Endotoxin, a constituent of Gram-negative bacteria, stimulates macrophages to release large quantities of tumor necrosis factor (TNF) and interleukin-1 (IL-1), which can precipitate tissue injury and lethal shock (endotoxemia). Antagonists of TNF and IL-1 have shown limited efficacy in clinical trials, possibly because these cytokines are early mediators in pathogenesis. Here a potential late mediator of lethality is identified and characterized in a mouse model. High mobility group-1 (HMG-1) protein was found to be released by cultured macrophages more than 8 hours after stimulation with endotoxin, TNF, or IL-1. Mice showed increased serum levels of HMG-1 from 8 to 32 hours after endotoxin exposure. Delayed administration of antibodies to HMG-1 attenuated endotoxin lethality in mice, and administration of HMG-1 itself was lethal. Septic patients who succumbed to infection had increased serum HMG-1 levels, suggesting that this protein warrants investigation as a therapeutic target.
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            Release of chromatin protein HMGB1 by necrotic cells triggers inflammation.

            High mobility group 1 (HMGB1) protein is both a nuclear factor and a secreted protein. In the cell nucleus it acts as an architectural chromatin-binding factor that bends DNA and promotes protein assembly on specific DNA targets. Outside the cell, it binds with high affinity to RAGE (the receptor for advanced glycation end products) and is a potent mediator of inflammation. HMGB1 is secreted by activated monocytes and macrophages, and is passively released by necrotic or damaged cells. Here we report that Hmgb1(-/-) necrotic cells have a greatly reduced ability to promote inflammation, which proves that the release of HMGB1 can signal the demise of a cell to its neighbours. Apoptotic cells do not release HMGB1 even after undergoing secondary necrosis and partial autolysis, and thus fail to promote inflammation even if not cleared promptly by phagocytic cells. In apoptotic cells, HMGB1 is bound firmly to chromatin because of generalized underacetylation of histone and is released in the extracellular medium (promoting inflammation) if chromatin deacetylation is prevented. Thus, cells undergoing apoptosis are programmed to withhold the signal that is broadcast by cells that have been damaged or killed by trauma.
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              Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion.

              High Mobility Group 1 protein (HMGB1) is a chromatin component that, when leaked out by necrotic cells, triggers inflammation. HMGB1 can also be secreted by activated monocytes and macrophages, and functions as a late mediator of inflammation. Secretion of a nuclear protein requires a tightly controlled relocation program. We show here that in all cells HMGB1 shuttles actively between the nucleus and cytoplasm. Monocytes and macrophages acetylate HMGB1 extensively upon activation with lipopolysaccharide; moreover, forced hyperacetylation of HMGB1 in resting macrophages causes its relocalization to the cytosol. Cytosolic HMGB1 is then concentrated by default into secretory lysosomes, and secreted when monocytic cells receive an appropriate second signal.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                12 January 2023
                2022
                : 13
                : 1094925
                Affiliations
                [1] Department of Spine Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University , Guangzhou, China
                Author notes

                Edited by: Bo Li, Department of Orthopedics, Sun Yat-sen University, China

                Reviewed by: Junqing Huang, Jinan University, China; Xiaoli Wu, Tianjin University, China

                *Correspondence: Kebing Chen, chkbing@ 123456mail.sysu.edu.cn

                This article was submitted to Multiple Sclerosis and Neuroimmunology, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2022.1094925
                9877301
                36713448
                039db0de-f1f9-4f73-baf2-e5ecb3ace035
                Copyright © 2023 Mo and Chen

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 10 November 2022
                : 19 December 2022
                Page count
                Figures: 1, Tables: 1, Equations: 0, References: 153, Pages: 13, Words: 6060
                Funding
                This work was supported by the National Natural Science Foundation of China (82072513 to KC), Science and Technology Programme of Guangzhou (202102080182 to KC).
                Categories
                Immunology
                Review

                Immunology
                hmgb1,spinal cord injury,inflammation,neuron,mechanism
                Immunology
                hmgb1, spinal cord injury, inflammation, neuron, mechanism

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