An Immunogenic Peptide in the A-box of HMGB1 Protein Reverses Apoptosis-induced Tolerance through RAGE Receptor

LeBlanc, Philippe M.; Doggett, Teresa A.; Choi, Jayoung; Hancock, Mark A.; Durocher, Yves; Frank, Filipp; Nagar, Bhushan; Ferguson, T.; Saleh, Maya

doi:10.1074/jbc.m113.541474

Cited by 61 publications

(65 citation statements)

References 38 publications

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“…The HMGB1-mediated pyroptosis may then enable the proinflammatory molecules synthesized in the endosomes and cytoplasm to be released extracellularly. The second exciting novel HMGB1-RAGE report by LeBlanc et al (48) describes an additional RAGE-binding epitope in HMGB1 located in the box A domain (binding region sequence 23-50) (48). This observation suggests the possibility that HMGB1 may mediate different biological functions when interacting with RAGE depending on which of the two RAGEbinding epiotopes is involved.…”

Section: Hmgb1 Receptorsmentioning

confidence: 95%

High Mobility Group Box Protein 1 (HMGB1): The Prototypical Endogenous Danger Molecule

Yang

Wang

Chavan

et al. 2015

Mol Med

285

240

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Section: Hmgb1 Receptorsmentioning

confidence: 95%

High Mobility Group Box Protein 1 (HMGB1): The Prototypical Endogenous Danger Molecule

Yang

Wang

Chavan

et al. 2015

Mol Med

285

240

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“…In line with this, a second binding epitope of HMGB1 to RAGE has been proposed recently. 58 So far, only 1 binding site for HMGB1 on RAGE has been identified, but this was never analyzed with different HMGB1 redox forms. [59][60][61] Whereas 1 of the 2 potential binding sites can be bound similarly by the different HMBG1 redox variants, the other site probably discriminates between the different redox states.…”

Section: Discussionmentioning

confidence: 99%

Disulfide HMGB1 derived from platelets coordinates venous thrombosis in mice

Stark

Philippi

Stockhausen

et al. 2016

Blood

237

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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“…Inhibition of caspapse 1 activity can diminish HMGB1 release and the inflammatory response during pyroptosis (Kamo et al, 2013; Lu et al, 2012b). In addition, a recent study indicated that HMGB1 at the sites of aa67, aa158, and aa169 can be directly cleaved by caspase 1, but not other caspases (-2, -3, -5, -7, -9 or -11) (Leblanc et al, 2014). Different from full length HMGB1, A box with anti-inflammatory activity, the caspase-1 generated A-box fragment (especially residues 23–50) binding to RAGE can rescue apoptosis-induced immune tolerance in a sepsis model (Leblanc et al, 2014).…”

Section: Hmgb1 Releasementioning

confidence: 99%

HMGB1 in health and disease

Kang

Chen

Zhang

et al. 2014

Molecular Aspects of Medicine

802

828

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Complex genetic and physiological variations as well as environmental factors that drive emergence of chromosomal instability, development of unscheduled cell death, skewed differentiation, and altered metabolism are central to the pathogenesis of human diseases and disorders. Understanding the molecular bases for these processes is important for the development of new diagnostic biomarkers, and for identifying new therapeutic targets. In 1973, a group of non-histone nuclear proteins with high electrophoretic mobility was discovered and termed High-Mobility Group (HMG) proteins. The HMG proteins include three superfamilies termed HMGB, HMGN, and HMGA. High-mobility group box 1 (HMGB1), the most abundant and well-studied HMG protein, senses and coordinates the cellular stress response and plays a critical role not only inside of the cell as a DNA chaperone, chromosome guardian, autophagy sustainer, and protector from apoptotic cell death, but also outside the cell as the prototypic damage associated molecular pattern molecule (DAMP). This DAMP, in conjunction with other factors, thus has cytokine, chemokine, and growth factor activity, orchestrating the inflammatory and immune response. All of these characteristics make HMGB1 a critical molecular target in multiple human diseases including infectious diseases, ischemia, immune disorders, neurodegenerative diseases, metabolic disorders, and cancer. Indeed, a number of emergent strategies have been used to inhibit HMGB1 expression, release, and activity in vitro and in vivo. These include antibodies, peptide inhbitiors, RNAi, anti-coagulants, endogenous hormones, various chemical compounds, HMGB1-receptor and signaling pathway inhibition, artificial DNAs, physical strategies including vagus nerve stimulation and other surgical approaches. Future work further investigating the details of HMGB1 localizationtion, structure, post-translational modification, and identifccation of additional partners will undoubtedly uncover additional secrets regarding HMGB1’s multiple functions.

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An Immunogenic Peptide in the A-box of HMGB1 Protein Reverses Apoptosis-induced Tolerance through RAGE Receptor

Cited by 61 publications

References 38 publications

High Mobility Group Box Protein 1 (HMGB1): The Prototypical Endogenous Danger Molecule

High Mobility Group Box Protein 1 (HMGB1): The Prototypical Endogenous Danger Molecule

Disulfide HMGB1 derived from platelets coordinates venous thrombosis in mice

HMGB1 in health and disease

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