Abstract
Cell death occurs when a pathogen invades a host organism or the organism is subjected to sterile injury. Thus, cell death is often closely associated with the induction of an immune response. Furthermore, cell death can occur as a consequence of the immune response and precedes the tissue renewal and repair responses that are initiated by innate immune cells during resolution of an immune response. Beyond immunity, cell death is required for development, morphogenesis and homeostasis. How can such a ubiquitous event as cell death trigger such a wide range of context-specific effector responses? Dying cells are sensed by innate immune cells using specialized receptors and phagocytosed through a process termed efferocytosis. Here, we outline a general principle whereby signals within the dead cell as well as the environment are integrated by specific efferocytes to define the appropriate effector response.
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Acknowledgements
C.V.R. and S.G. acknowledge M. K. Basu for analyses and discussions of single-cell RNA-sequencing data. T.D.H. acknowledges M. Chalfant for insightful discussions. This work was supported by grants from the National Institutes of Health (NIH-NIAID R01 AI089824 and NIH-NCI R01 CA212376) and the Kenneth Rainin Foundation. C.V.R is a Howard Hughes Medical Institute Faculty Scholar.
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T.D.H conceived and developed the mathematical representation. C.V.R and S.G. wrote the manuscript.
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Glossary
- Necrosome complex
-
An amyloid signalling complex assembled upon interaction and activation (phosphorylation) of receptor-interacting serine/threonine protein kinase 3 (RIPK3) and RIPK1. The necrosome leads to the phosphorylation of mixed lineage kinase domain-like protein (MLKL) and induction of necroptosis.
- LC3-associated phagocytosis
-
(LAP). A form of phagocytosis during which the canonical autophagy protein LC3 is conjugated to the phagosome to form the LAPosome. LC3 conjugation is crucial for phagosome maturation and acidification, through fusion with lysosomes, and the degradation of cargo.
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Rothlin, C.V., Hille, T.D. & Ghosh, S. Determining the effector response to cell death. Nat Rev Immunol 21, 292–304 (2021). https://doi.org/10.1038/s41577-020-00456-0
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DOI: https://doi.org/10.1038/s41577-020-00456-0
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