Dead but Not Deadly

Science Signaling  22 Jul 2008:
Vol. 1, Issue 29, pp. ec269
DOI: 10.1126/scisignal.129ec269

The presence of cells dying by the process of necrosis is a signal for activation of the adaptive immune system and a stimulus for an inflammatory response to protect the organism from the threat that is damaging the dying cells. However, billions of cells in the human immune system die every day by apoptosis, a more orderly physiological form of cell death, and these dying cells are actually anti-inflammatory and promote tolerance of antigens by the immune system. Kazama et al. show that one key difference that influences the immunogenicity of the dying cells is the disruption of mitochondrial function in apoptotic cells and consequent generation of reactive oxygen species (ROS). The authors used an assay of immunogenicity in which mice exposed to dying cells were subsequently exposed to antigens. Treatment of apoptotic cells with the reducing agent dithiothreitol (DTT) prevented their promotion of tolerance, and exposure of necrotic cells to the oxidant hydrogen peroxide made them promote tolerance rather than inflammation. The authors focused on high-mobility group box-1 (HMGB1), a protein that binds chromatin and acts as a transcription factor but also functions as an inflammatory cytokine. Release of HMGB1 had been proposed to be a marker of necrotic death, but Kazama et al. saw release of the protein from both apoptotic and necrotic cells. What differed was the oxidation state of HMGB1. Supernatants from apoptotic cells could promote tolerance, but this effect was prevented if ROS species were neutralized with a scavenger or if oxidation of HMGB1 was prevented by mutation of cysteine residues that likely mediate its response to oxidation. Recombinant human HMGB1 could also eliminate the tolerogenic effect of apoptotic cells if the HMGB1 was first treated with DTT, but not if the HMGB1 was first oxidized with hydrogen peroxide. Peter provides commentary and notes that the studies open the way for exploration of how dendritic cells specifically recognize oxidized HMGB1 and what signaling pathways are activated--work that may allow these new concepts to be exploited to modulate immunological activation in patients.

H. Kazama, J.-E. Ricci, J. M. Herndon, G. Hoppe, D. R. Green, T. A. Ferguson, Induction of immunological tolerance by apoptotic cells requires caspase-dependent oxidation of high-mobility group box-1 protein. Immunity 29, 21-32 (2008). [PubMed]

M. E. Peter, ROS eliminate danger. Immunity 29, 1-2 (2008). [PubMed]