Programmed necrosis in inflammation: Toward identification of the effector molecules

D Wallach, TB Kang, CP Dillon, DR Green - Science, 2016 - science.org
D Wallach, TB Kang, CP Dillon, DR Green
Science, 2016science.org
BACKGROUND Inflammatory lesions often contain dead cells. Cell death in developmental
processes characteristically occurs by apoptosis, a form of programmed cell death in which
dying cells are phagocytized before undergoing membrane damage. In inflammation,
however, cell death is often necrotic, where cellular constituents are released after
membrane rupture. The death of cells in inflammation was until recently thought to result
from other changes in the inflamed tissue. This view has changed, however, owing to …
BACKGROUND
Inflammatory lesions often contain dead cells. Cell death in developmental processes characteristically occurs by apoptosis, a form of programmed cell death in which dying cells are phagocytized before undergoing membrane damage. In inflammation, however, cell death is often necrotic, where cellular constituents are released after membrane rupture. The death of cells in inflammation was until recently thought to result from other changes in the inflamed tissue. This view has changed, however, owing to several findings: that necrotic cell death can be induced by biomolecules known to initiate inflammation [such as the cytokine tumor necrosis factor (TNF) or the pathogen component lipopolysaccharide (LPS)]; that it can be dictated in a programmed manner by distinct sets of signaling mechanisms; and that it yields release of some cellular components capable of facilitating inflammation. It now seems probable that necrotic cell death is not always a consequence of inflammation, but is sometimes rather its trigger. To confirm this notion, we need reliable tools for detection of programmed necrosis in vivo. Because programmed necrosis cannot be distinguished morphologically from accidental cell death, its identification in inflamed tissues must be based on its distinctive molecular details.
ADVANCES
We now have quite detailed knowledge of the mechanisms initiating apoptotic cell death and those initiating two forms of programmed necrosis—necroptosis and pyroptosis. Apoptosis is triggered by proteases of the caspase family. Necroptosis is triggered by specific protein kinases, most crucially receptor-interacting protein kinase–3 (RIPK3). Pyroptosis is triggered by caspases distinct from those mediating apoptosis, and whose activation yields proteolytic activation of the inflammatory cytokines interleukin-1β (IL-1β) and IL-18. All of these molecular initiators of death programs, however, also contribute to the initiation of nondeadly cell functions and are thus not specific markers for death. Two proteins were recently found to act further downstream in the signaling pathways leading to programmed necrosis. One, the pseudokinase mixed lineage kinase domain–like protein (MLKL), is crucial for necroptosis. The other, gasdermin-D (GSDMD), after cleavage by the pyroptosis-mediating caspases, is a major player in their induction of death. Mere expression of activated MLKL, or of the N-terminal proteolytic fragment of GSDMD, can trigger necrotic death. The finding that MLKL and GSDMD play roles in necroptosis and pyroptosis raises hopes that we are approaching the identification of molecules that exclusively serve these forms of death.
OUTLOOK
What are the parameters that can reliably allow us to define a cause-effect relationship between necrotic death and inflammation—and more generally, to define the causal relationships between any disease and its co-occurring pathogenic events? In the case of cell death, this question boils down to the need to identify molecular events that contribute specifically enough to allow their use as definitive molecular probes. The effectors of death—proteins found to mediate deadly changes in the cell—are likely to have that absolute specificity. Whether MLKL and GSDMD are such death effectors has yet to be established. Some studies suggest that MLKL directly permeabilizes membranes, whereas others suggest that it does not. Regarding GSDMD, there is still no knowledge of the mechanisms by which its N-terminal fragment triggers death. Identifying death-effector molecules will be of immense importance to medicine. Such molecules will not only be the best markers for detecting programmed …
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