The DOI matches its Crossref record; 60 of the 60 references it cites were found in a registry or an index.
Induction of Immunological Tolerance by Apoptotic Cells Requires Caspase-Dependent Oxidation of High-Mobility Group Box-1 Protein
Open accessAbstract
The mammalian immune system discriminates between modes of cell death; necrosis often results in inflammation and adaptive immunity, whereas apoptosis tends to be anti-inflammatory and promote immune tolerance. We have examined apoptosis for the features responsible for tolerance; specifically, we looked at the roles of caspases and mitochondria. Our results show that caspase activation targeted the mitochondria to produce reactive oxygen species (ROS), which were critical to tolerance induction by apoptotic cells. ROS oxidized the potential danger signal high-mobility group box-1 protein (HMGB1) released from dying cells and thereby neutralized its stimulatory activity. Apoptotic cells failed to induce tolerance and instead stimulated immune responses by scavenging or by mutating a mitochondrial caspase target protein when ROS activity was prohibited. Similarly, blocking sites of oxidation in HMGB1 prevented tolerance induction by apoptotic cells. These results suggest that caspase-orchestrated mitochondrial events determine the impact of apoptotic cells on the immune response.
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“Potential immunogenic signals emanating from dying cells include proteins that appear at the surface of stressed and dying cells (such as calreticulin and heat shock proteins, HSPs), lipid moieties that flip from the inner plasma membrane leaflet to the outer leaflet (such as phosphatidylserine) 38,60, proteins that are released into the supernatant of cells (such as HMGB1) 51, as well as nucleic”
From Immunogenic and tolerogenic cell death (2009) · cites this paper as [51]
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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 [921]
In the citing paper
“The inhibition of caspases affects the exposure of find-me signals 40, eat-me signals 40 (Box 4), and the secretion of DAMPs51 from dying cells, as well as the exposure of CRT on anthracyclin-treated cancer cells60.”
From Immunogenic and tolerogenic cell death (2009) · cites this paper as [51]
In the citing paper
“Thus, HMGB1 may act on the receptor for advanced glycated endproducts (RAGEs) and possibly the toll-like receptors (TLRs) including TLR2 and TLR4 51,52, although the latter are controversial 53.”
From Immunogenic and tolerogenic cell death (2009) · cites this paper as [51]
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Citations
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Metadata
- Authors
- Kazama, H., Ricci, J.-E., Herndon, J. M., Hoppe, G., Green, D. R., & Ferguson, T. A.
- Affiliations
- Washington University in St. Louis (US)
- Université Côte d'Azur (FR)
- Cleveland Clinic (US)
- St. Jude Children's Research Hospital (US)
- Corresponding author
- Ferguson, Thomas A.
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2008-07
- Volume
- 29
- Issue
- 1
- Pages
- 21-32
- ISSN
- 1074-7613 (ISSN-L)
- PMC
- PMC2704496
- OpenAlex
- W2084623259
- Cited by
- 627
- References
- 60
- Citations by year
- 2026: 24 · 2025: 23 · 2024: 33 · 2023: 35 · 2022: 24 · 2021: 38 · 2020: 32 · 2019: 26 · 2018: 33 · 2017: 31 · 2016: 20 · 2015: 44 · 2014: 47 · 2013: 43 · 2012: 34
- FWCI
- 19.04
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Research to Prevent Blindness (EY02687)
- National Institutes of Health (AI44848, EY02687, EY06765)
- National Eye Institute (EY 02687, P30EY002687, EY 015570, F32EY006765, EY06765, R01EY015570, R01EY006765)
- National Institute of Allergy and Infectious Diseases (AI44848, R01AI044828, R01AI040646)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Keywords
- immune tolerance, apoptotic cells, caspases, HMGB1, high mobility group box 1 protein, reactive oxygen species, oxidative modification, damage-associated molecular patterns, necrosis, tolerance induction
- MeSH terms
- Animals, Dendritic Cells, HeLa Cells, Humans, Immune Tolerance, Mice, Inbred C57BL, Mitochondria, Oxidation-Reduction, Immunoblotting, Apoptosis, Reactive Oxygen Species, Caspases, HMGB1 Protein, Mice
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