Journal
IMMUNITY
Volume 29, Issue 1, Pages 21-32Publisher
CELL PRESS
DOI: 10.1016/j.immuni.2008.05.013
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Funding
- NEI NIH HHS [P30 EY002687-319004, EY02687, R01 EY006765-22, R01 EY006765, R01 EY015570-04, F32 EY006765, P30 EY002687, R01 EY015570, EY015570, EY06765] Funding Source: Medline
- NIAID NIH HHS [R01 AI044828-11, R01 AI040646, R01 AI044828, AI44848, R01 AI040646-13] Funding Source: Medline
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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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