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PMID: 18631454 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Induction of immunological tolerance by apoptotic cells requires caspase-dependent oxidation of high-mobility group box-1 protein.

Immunity ·Vol. 29 ·No. 1 ·2008-07-18 ·Pages 21-32

Kazama H, Ricci JE, Herndon JM, Hoppe G, Green DR, Ferguson TA

Abstract

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.

MeSH Terms
Animals Apoptosis/immunology Caspases/immunology Dendritic Cells/immunology HMGB1 Protein/immunology,metabolism HeLa Cells Humans Immune Tolerance/immunology Immunoblotting Mice Mice, Inbred C57BL Mitochondria/immunology,metabolism Oxidation-Reduction Reactive Oxygen Species/immunology,metabolism
Chemicals
HMGB1 Protein Reactive Oxygen Species Caspases
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Kazama Hirotaka
Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St Louis, MO 631101, USA.
Ricci Jean-Ehrland
Herndon John M
Hoppe George
Green Douglas R
Ferguson Thomas A
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Article Info
Journal
Immunity
Abbr.
Immunity
ISSN
1097-4180
DOI
10.1016/j.immuni.2008.05.013
Published
2008-07-18
Pages
21-32
Language
English
Region
United States
NLM ID
9432918
PMCID
PMC2704496
Subset
IM
Grants
NEI NIH HHS · F32 EY006765 · United States
NEI NIH HHS · R01 EY015570-04 · United States
NIAID NIH HHS · R01 AI044828-11 · United States
NEI NIH HHS · R01 EY006765 · United States
NEI NIH HHS · R01 EY006765-22 · United States
NEI NIH HHS · EY02687 · United States
NEI NIH HHS · P30 EY002687-319004 · United States
NIAID NIH HHS · R01 AI040646-13 · United States
NIAID NIH HHS · AI44848 · United States
NIAID NIH HHS · R01 AI044828 · United States
NIAID NIH HHS · R01 AI040646 · United States
NEI NIH HHS · P30 EY002687 · United States
NEI NIH HHS · R01 EY015570 · United States
NEI NIH HHS · EY015570 · United States
NEI NIH HHS · EY06765 · United States
Corrections
CommentIn
PMID: 18631448
External Links
PubMed source DOI: 10.1016/j.immuni.2008.05.013 PMC Full Text View journal details
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