Release of chromatin protein HMGB1 by necrotic cells triggers inflammation
Abstract
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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Six DAMPs have been mechanistically linked to perception of RCD as immunogenic: CALR, ATP, HMGB1, type I IFN, cancer cell-derived nucleic acids, and ANXA1.
“So far, six DAMPs have been mechanistically linked to the perception of RCD as immunogenic: (1) calreticulin (CALR) [865, 866], (2) ATP [867–869], (3) high-mobility group box 1 (HMGB1) [870–872], (4) type I IFN [854, 873, 874], (5) cancer cell-derived nucleic acids [864, 875], and (6) annexin A1 (ANXA1) [876].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [871]
HMGB1 can be released during secondary necrosis following apoptosis, not only from the nucleus during primary necrosis.
“Although it was initially thought that HMGB1 is released only from the nucleus during primary necrosis, recent data indicate that HMGB1 can be released during secondary necrosis following apoptosis 27,48–50.”
From Immunogenic and tolerogenic cell death (2009) · cites this paper as [48]
Prototypical DAMPs derived from necrotic cells include high-mobility group box 1 (HMGB1), heat shock proteins (HSPs), ATP, and uric acid.
“Prototypical DAMPs derived from necrotic cells include the chromatin-associated protein high-mobility group box 1 (HMGb1)10, heat shock proteins (HSPs)11, and purine metabolites, such as ATP12 and uric acid13 (TABLE 1).”
From Sterile inflammation: sensing and reacting to damage (2010) · cites this paper as [10]
Treatment of mice with HMGB1-specific antibodies during acetaminophen-induced liver necrosis ameliorated inflammatory cell recruitment.
“In one study, treatment of mice with HMGb1-specific antibodies during acetaminophen-induced liver necrosis ameliorated inflammatory cell recruitment10.”
From Sterile inflammation: sensing and reacting to damage (2010) · cites this paper as [10]
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- Authors
- Scaffidi, P., Misteli, T., & Bianchi, M. E.
- Affiliations
- National Institutes of Health (US)
- Vita-Salute San Raffaele University (IT)
- Corresponding author
- Bianchi, Marco E.
- Venue
- Nature
- Published
- 2002-07-11
- Volume
- 418
- Issue
- 6894
- Pages
- 191-195
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2004266769
- Cited by
- 4,221
- References
- 26
- Citations by year
- 2026: 104 · 2025: 106 · 2024: 129 · 2023: 158 · 2022: 168 · 2021: 233 · 2020: 204 · 2019: 196 · 2018: 211 · 2017: 205 · 2016: 228 · 2015: 253 · 2014: 276 · 2013: 261 · 2012: 230
- FWCI
- 47.06
- Type
- journal article
- Language
- en
- Update notices
- erratum (2010-09-30)
- Open access
- closed
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- 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 › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- HMGB1, necrosis, apoptosis, inflammation, chromatin, histone acetylation, RAGE, extracellular HMGB1 release, secondary necrosis, phagocytosis, damage-associated molecular patterns
- MeSH terms
- Acetylation, Animals, Cell Survival, Chromatin, HeLa Cells, Humans, Inflammation, Necrosis, Protein Binding, Apoptosis, Gene Deletion, HMGB1 Protein, Rats
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