IMMUNE TOLERANCE INDUCTION BY APOPTOTIC CELLS REQUIRES CASPASE-DEPENDENT OXIDATION OF HMGB1

By H. Kazama, J. Ricci, J. Herndon, G. Hoppe, Douglas R. Green, T. Ferguson. Immunity, 2008

630 citations recorded by the source corpus.

SUMMARY The mammalian immune system discriminates between modes of cell death, with necrosis often resulting in inflammation and adaptive immunity, while apoptosis tends to be anti-inflammatory, promoting immune tolerance. In many systems immune tolerance can be established through cross presentation of antigens derived from apoptotic cells via the MHC class I pathway to CD8+ T cells. We have examined the features of apoptosis responsible for tolerance to cell-mediated immune responses in vivo, specifically the roles of caspases and the mitochondria. Our results show that caspase activation targets the mitochondria to produce ROS, which are critical to tolerance induction by apoptotic cells. ROS oxidizes the potential danger signal HMGB1 released from dying cells, thereby neutralizing its stimulatory activity and promoting tolerance. Apoptotic cells failed to induce tolerance and instead stimulated immune responses when caspase-dependent ROS activity was prohibited by scavenging or by mutation of a mitochondrial caspase target, p75 NDUSF1. 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.

Subfields: Clinical Biochemistry, Immunology

View Paper: https://www.semanticscholar.org/paper/b32427d96300bbe7af5c84accb18216985319b29

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In Clinical Biochemistry

1. Kevin J. Tracey
2. D. Tang
3. R. Kang
4. Michael Lotze
5. H. J. Zeh
6. U. Andersson
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In Immunology

1. Guido Kroemer
2. L. Galluzzi
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4. L. Zitvogel
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7. D. Tang
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Citations in the corpus

• Mitochondria and cell death: outer membrane permeabilization and beyond (2010, background): “Furthermore, modulation of mitochondrial dysfunction during apoptosis by the expression of non-cleavable NDUFS1 alters how the immune system responds to a dying cel”
• Endogenous HMGB1 regulates autophagy (2010, background): “Blocking sites of oxidation in HMGB1 prevents the induction of tolerance by apoptotic cells (Kazama et al., 2008).”
• Apoptotic Caspases Suppress mtDNA-Induced STING-Mediated Type I IFN Production (2014, neutral): “Although apoptotic caspases have been previously reported to inactivate the DAMPs HMGB1 (Kazama et al., 2008) and IL33 (Cayrol and Girard, 2009; Lüthi et al.”
• Mechanism of action of conventional and targeted anticancer therapies: reinstating immunosurveillance. (2013, background): “Perhaps depending on posttranslational modifications including redox-dependent changes (Kazama et al., 2008; Venereau et al., 2012), extracellular HMGB1 can interact with several distinct pattern recognition receptors, including advanced glycosylation end product-specific receptor (AGER) and…”
• PAMPs and DAMPs: Signal 0s that Spur Autophagy and Immunity (2012, background): “This requires both TLR and Atg5 signaling in DCs (134–137).”
• Mutually exclusive redox forms of HMGB1 promote cell recruitment or proinflammatory cytokine release (2012, background): “High ROS levels produced during apoptosis cause terminal oxidation of HMGB1, redirecting its ability to activate acquired immune responses toward tolerance (Kazama et al., 2008).”