The DOI matches its Crossref record; 29 of the 29 references it cites were found in a registry or an index.
Mutually exclusive redox forms of HMGB1 promote cell recruitment or proinflammatory cytokine release
Open accessAbstract
Tissue damage causes inflammation, by recruiting leukocytes and activating them to release proinflammatory mediators. We show that high-mobility group box 1 protein (HMGB1) orchestrates both processes by switching among mutually exclusive redox states. Reduced cysteines make HMGB1 a chemoattractant, whereas a disulfide bond makes it a proinflammatory cytokine and further cysteine oxidation to sulfonates by reactive oxygen species abrogates both activities. We show that leukocyte recruitment and activation can be separated. A nonoxidizable HMGB1 mutant in which serines replace all cysteines (3S-HMGB1) does not promote cytokine production, but is more effective than wild-type HMGB1 in recruiting leukocytes in vivo. BoxA, a HMGB1 inhibitor, interferes with leukocyte recruitment but not with activation. We detected the different redox forms of HMGB1 ex vivo within injured muscle. HMGB1 is completely reduced at first and disulfide-bonded later. Thus, HMGB1 orchestrates both key events in sterile inflammation, leukocyte recruitment and their induction to secrete inflammatory cytokines, by adopting mutually exclusive redox states.
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“That said, it should be noted that biological activities of HMGB1 may flip from pro-inflammatory to anti-inflammatory depending on multiple variables including its oxidation state [917–923].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [918]
In the citing paper
“The disulfide form mediates the proinflammatory effects of HMGB1 by signaling through TLR4, whereas the reduced form mediates the chemotactic properties of HMGB1 by forming a complex with the chemokine CXCL12 and signaling through CXCR4.”
From Danger Signals and Inflammasomes: Stress-Evoked Sterile Inflammation in Mood Disorders (2017) · cites this paper as Venereau et al, 2012
In the citing paper
“HMGB1 can function either as a chemotactic or proinflammatory mediator depending on the redox state of three critical cysteines (Venereau et al, 2012).”
From Danger Signals and Inflammasomes: Stress-Evoked Sterile Inflammation in Mood Disorders (2017) · cites this paper as Venereau et al, 2012
In the citing paper
“The disulfide form mediates the proinflammatory effects of HMGB1 by signaling through TLR4, whereas the reduced form mediates the chemotactic properties of HMGB1 by forming a complex with the chemokine CXCL12 and signaling through CXCR4.”
From Danger Signals and Inflammasomes: Stress-Evoked Sterile Inflammation in Mood Disorders (2017) · cites this paper as Venereau et al, 2012
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Cites
1 retracted
Yang, H., Lundbäck, P., Ottosson, L., Erlandsson-Harris, H., Venereau, E., Bianchi, M. E., Al-Abed, Y., Andersson, U., Tracey, K. J., & Antoine, D. J. (2012) · Molecular Medicine · doi:10.2119/molmed.2011.00389 · Cited by 407
Self-citationRetractedDAMPs, PAMPs and alarmins: all we need to know about danger
Bianchi, M. E. (2007) · Journal of Leukocyte Biology · doi:10.1189/jlb.0306164 · Cited by 2,794 · cited 1×
“High-mobility group box 1 (HMGB1) is a nuclear protein that signals tissue damage when released into the extracellular medium, and thus works as a damage-associated molecular pattern (DAMP; Bianchi, 2007).”
BackgroundSelf-citationHMGB1 is a therapeutic target for sterile inflammation and infection
Andersson, U., & Tracey, K. J. (2011) · Annual Review of Immunology · doi:10.1146/annurev-immunol-030409-101323 · Cited by 1,437 · cited 1×
“Notably, immune cells secrete HMGB1 when activated by infection or tissue damage (Andersson and Tracey, 2011); mesothelioma and other cancer cells secrete HMGB1 constitutively (Jube et al., 2012).”
BackgroundSelf-citationAndersson, U., Wang, H., Palmblad, K., Aveberger, A.-C., Bloom, O., Erlandsson-Harris, H., Janson, A., Kokkola, R., Zhang, M., Yang, H., et al. (2000) · The Journal of Experimental Medicine · doi:10.1084/jem.192.4.565 · Cited by 1,401
Self-citationGardella, S., Andrei, C., Ferrera, D., Lotti, L. V., Torrisi, M. R., Bianchi, M. E., & Rubartelli, A. (2002) · EMBO Reports · doi:10.1093/embo-reports/kvf198 · Cited by 926 · cited 1×
“HMGB1 is released passively into the extracellular medium during necrosis and is secreted actively by monocytes and macrophages after stimulation with LPS and ATP (Gardella et al., 2002).”
BackgroundSelf-citationYang, H., Hreggvidsdottir, H. S., Palmblad, K., Wang, H., Ochani, M., Li, J., Lü, B., Chavan, S. S., Rosas‐Ballina, M., Al‐Abed, Y., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1003893107 · Cited by 812
Self-citationSchiraldi, M., Raucci, A., Martínez‐Muñoz, L., Livoti, E., Celona, B., Vénéreau, E., Apuzzo, T., Marchis, F. D., Pedotti, M., Bachi, A., et al. (2012) · The Journal of Experimental Medicine · doi:10.1084/jem.20111739 · Cited by 676
Self-citationHigh-Mobility Group Box-1 in Ischemia-Reperfusion Injury of the Heart
Andrassy, M., Volz, H. C., Igwe, J. C., Funke, B., Eichberger, S. N., Kaya, Z., Buss, S. J., Autschbach, F., Pleger, S. T., Lukić, I. K., et al. (2008) · Circulation · doi:10.1161/circulationaha.108.769331 · Cited by 635 · cited 1×
“…effects of BoxA in models of hepatitis (Sitia et al., 2007), peritonitis (Orlova et al., 2007), ischemia/reperfusion of the heart and the brain (Andrassy et al., 2008; Muhammad et al., 2008), and other ailments, may be entirely attributable to the reduced recruitment of inflammatory cells in…”
BackgroundSelf-citationKazama, H., Ricci, J.-E., Herndon, J. M., Hoppe, G., Green, D. R., & Ferguson, T. A. (2008) · Immunity · doi:10.1016/j.immuni.2008.05.013 · Cited by 627 · cited 1×
“High ROS levels produced during apoptosis cause terminal oxidation of HMGB1, redirecting its ability to activate acquired immune responses toward tolerance (Kazama et al., 2008).”
BackgroundBianchi, M. E. (2009) · Journal of Leukocyte Biology · doi:10.1189/jlb.1008585 · Cited by 419 · cited 2×
“, 2000), several studies could not reproduce these results, leading us to conclude that HMGB1 can only act in synergy with other inflammatory mediators (Bianchi, 2009).”
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Galluzzi, L., Vitale, I., Aaronson, S. A., Abrams, J. M., Adam, D., Agostinis, P., Alnemri, E. S., Altucci, L., Amelio, I., Andrews, D. W., et al. (2018) · Cell Death & Differentiation · doi:10.1038/s41418-017-0012-4 · Cited by 6,680
Immunogenic cell death and DAMPs in cancer therapy
Krysko, D. V., Garg, A. D., Kaczmarek, A., Krysko, O., Agostinis, P., & Vandenabeele, P. (2012) · Nature Reviews Cancer · doi:10.1038/nrc3380 · Cited by 3,223
“These authors showed that a recombinant N-terminal fragment of CRT (39-272) is a potent inducer of activation and maturation of B cells and macrophages and can trigger Ig class switching in B cells without T cell help in vitro and in vivo72.”
BackgroundNecroptosis and its role in inflammation
Pasparakis, M., & Vandenabeele, P. (2015) · Nature · doi:10.1038/nature14191 · Cited by 2,148
ROS and the DNA damage response in cancer
Srinivas, U. S., Tan, B. W. Q., Vellayappan, B. A., & Jeyasekharan, A. D. (2019) · Redox Biology · doi:10.1016/j.redox.2018.101084 · Cited by 2,144
Necroptosis: The Release of Damage-Associated Molecular Patterns and Its Physiological Relevance
Kaczmarek, A., Vandenabeele, P., & Krysko, D. V. (2013) · Immunity · doi:10.1016/j.immuni.2013.02.003 · Cited by 1,411
Metadata
- Authors
- Venereau, E., Casalgrandi, M., Schiraldi, M., Antoine, D. J., Cattaneo, A., De Marchis, F., Liu, J., Antonelli, A., Preti, A., Raeli, L., Shams, S. S., Yang, H., Varani, L., Andersson, U., Tracey, K. J., Bachi, A., Uguccioni, M., & Bianchi, M. E.
- Affiliations
- Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milan, Italy 1
- HMGBiotech Srl, 20133 Milan, Italy 2
- Institute for Research in Biomedicine (CH)
- University of Liverpool (GB)
- IRCCS Ospedale San Raffaele (IT)
- Vita-Salute San Raffaele University (IT)
- Feinstein Institute for Medical Research (US)
- Karolinska University Hospital (SE)
- Corresponding author
- Bianchi, Marco E.
- ORCID
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2012-08-06
- Volume
- 209
- Issue
- 9
- Pages
- 1519-1528
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC3428943
- OpenAlex
- W2141438911
- Semantic Scholar
- 17d0978fd742005f41f9a10b50083eec9ce6ff3d
- Cited by
- 720
- References
- 29
- Citations by year
- 2026: 48 · 2025: 38 · 2024: 54 · 2023: 46 · 2022: 38 · 2021: 44 · 2020: 56 · 2019: 40 · 2018: 60 · 2017: 58 · 2016: 52 · 2015: 64 · 2014: 66 · 2013: 46 · 2012: 10
- FWCI
- 38.20
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- reroDoc Digital Library (submittedVersion)
- Funders
- European Commission (281608, 280873)
- National Institute of General Medical Sciences (R01GM062508)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Keywords
- HMGB1, high mobility group box 1, redox regulation, cysteine oxidation, disulfide bonds, leukocyte recruitment, sterile inflammation, tissue damage, muscle damage, reactive oxygen species, chemoattractants, leukocyte activation
- MeSH terms
- Animals, Antibodies, Monoclonal, Cell Movement, Chemotactic Factors, Cysteine, Disulfides, Inflammation, Leukocytes, Male, Mice, Inbred C57BL, Mutation, Recombinant Proteins, Cytokines, Reactive Oxygen Species, Muscle, Skeletal, HMGB1 Protein, Mice, Rats
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