title: Induction of immunological tolerance by apoptotic cells requires caspase-dependent oxidation of high-mobility group box-1 protein.
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.
authors.affiliation: Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St Louis, MO 631101, USA.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Kazama
authors.forename: Jean-Ehrland
authors.initials: JE
authors.lastname: Ricci
authors.forename: John M
authors.initials: JM
authors.lastname: Herndon
authors.forename: George
authors.initials: G
authors.lastname: Hoppe
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Green
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Ferguson
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D020169:Caspases / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D024243:HMGB1 Protein / Q000276:immunology* / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D015151:Immunoblotting; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000276:immunology / Q000378:metabolism*; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000276:immunology / Q000378:metabolism
chemical_list: D024243:HMGB1 Protein; D017382:Reactive Oxygen Species; D020169:Caspases