Real-time Kinetics of High-mobility Group Box 1 (HMGB1) Oxidation in Extracellular Fluids Studied by in Situ Protein NMR Spectroscopy

Zandarashvili, Levani; Sahu, Debashish; Lee, Kwanbok; Lee, Yong Sun; Singh, Pomila; Rajarathnam, Krishna; Iwahara, Junji

doi:10.1074/jbc.m113.449942

Cited by 67 publications

(67 citation statements)

References 46 publications

(55 reference statements)

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“…Thus, fr-HMGB1 may be susceptible to ROS-mediated oxidation and conversion to ds-HMGB1 in vivo. Indeed, fr-HMGB1 has a relatively short half-life (∼17 min) in biological fluids such as serum and saliva [37]. Other studies support this hypothesis and our findings are in agreement with these investigations [6, 16, 32, 38].…”

Section: Discussionsupporting

confidence: 83%

Neuroinflammation in Response to Intracerebral Injections of Different HMGB1 Redox Isoforms

et al. 2018

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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.

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Section: Discussionsupporting

confidence: 83%

Neuroinflammation in Response to Intracerebral Injections of Different HMGB1 Redox Isoforms

et al. 2018

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“…15,35 It has been shown recently that in the extracellular space HMGB1 is oxidized quickly: the half-life for allthiol HMGB1 within the serum is 17 minutes before it is oxidized into disulfide HMGB1 in vitro. 57 In addition, in a model of ischemic stroke mainly all-thiol HMGB1 is found after 2 hours in serum samples, whereas both all-thiol and disulfide HMGB1 are found after 24 hours. 32 Therefore, reduced HMGB1 released from platelets is probably oxidized quickly within the blood stream.…”

Section: Discussionmentioning

confidence: 99%

Disulfide HMGB1 derived from platelets coordinates venous thrombosis in mice

Stark

Philippi

Stockhausen

et al. 2016

Blood

232

240

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Key Points• Sterile inflammation inducing venous thrombosis is coordinated by the damageassociated molecular pattern HMGB1 delivered by platelets.• The effect of HMGB1 depends on the redox form, and disulfide HMGB1 induces NET formation, platelet aggregation, and monocyte activation.Deep venous thrombosis (DVT) is one of the most common cardiovascular diseases, but its pathophysiology remains incompletely understood. Although sterile inflammation has recently been shown to boost coagulation during DVT, the underlying molecular mechanisms are not fully resolved, which could potentially identify new antiinflammatory approaches to prophylaxis and therapy of DVT. Using a mouse model of venous thrombosis induced by flow reduction in the vena cava inferior, we identified blood-derived high-mobility group box 1 protein (HMGB1), a prototypical mediator of sterile inflammation, to be a master regulator of the prothrombotic cascade involving platelets and myeloid leukocytes fostering occlusive DVT formation. Transfer of platelets into Hmgb1 2/2 chimeras showed that this cell type is the major source of HMGB1, exposing reduced HMGB1 on their surface upon activation thereby enhancing the recruitment of monocytes. Activated leukocytes in turn support oxidation of HMGB1 unleashing its prothrombotic activity and promoting platelet aggregation. This potentiates the amount of HMGB1 and further nurtures the accumulation and activation of monocytes through receptor for advanced glycation end products (RAGE) and Toll-like receptor 2, leading to local delivery of monocyte-derived tissue factor and cytokines. Moreover, disulfide HMGB1 facilitates formation of prothrombotic neutrophil extracellular traps (NETs) mediated by RAGE, exposing additional HMGB1 on their extracellular DNA strands. Eventually, a vicious circle of coagulation and inflammation is set in motion leading to obstructive DVT formation. Therefore, platelet-derived disulfide HMGB1 is a central mediator of the sterile inflammatory process in venous thrombosis and could be an attractive target for an anti-inflammatory approach for DVT prophylaxis. (Blood. 2016; 128(20):2435-2449

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“…Disulfide HMGB1 can only act on the receptor toll-like receptor 4 (TLR4) (110) and influences the production of inflammatory cytokines (133)(134)(135). Important work using an NMR-based approach to distinguish the oxidation states and half-lives of HMGB1 in serum, saliva and cell culture media revealed that the half-life of all-thiol HMGB1 is as short as 17-18 minutes in human serum and saliva and the subsequent clearance of the disulfide HMGB1 varies between 65 and 642 minutes, depending on the extracellular fluid (139) (Fig. 3).…”

Section: Extracellular Forms Of Hmgb1mentioning

confidence: 99%

“…3). Disulfide HMGB1 is then further reduced following oxidation of Cys-106 in the B-domain to an inert form (139). …”

Section: Extracellular Forms Of Hmgb1mentioning

confidence: 99%

“…Extracellular HMGB1 undergoes limited proteolysis by serine proteinases that are secreted by stimulated cells. Though the degradation of HMGB1 can produce a 10 amino acid fragment that retains some functional activity in leukocytic cells (105), the kinetics of HMGB1 oxidation and the half-lives of all-thiol and disulfide HMGB1 species in serum, saliva, and cell culture medium is relatively restricted (139).…”

Section: Hmgb1 Releasementioning

confidence: 99%

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The HMGB1-RAGE Inflammatory Pathway: Implications for Brain Injury-Induced Pulmonary Dysfunction

Weber

Allette

Wilkes

et al. 2015

Antioxidants & Redox Signaling

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Real-time Kinetics of High-mobility Group Box 1 (HMGB1) Oxidation in Extracellular Fluids Studied by in Situ Protein NMR Spectroscopy

Cited by 67 publications

References 46 publications

Neuroinflammation in Response to Intracerebral Injections of Different HMGB1 Redox Isoforms

Neuroinflammation in Response to Intracerebral Injections of Different HMGB1 Redox Isoforms

Disulfide HMGB1 derived from platelets coordinates venous thrombosis in mice

The HMGB1-RAGE Inflammatory Pathway: Implications for Brain Injury-Induced Pulmonary Dysfunction

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