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The clearance of dead cells by efferocytosis

Abstract

Multiple modes of cell death have been identified, each with a unique function and each induced in a setting-dependent manner. As billions of cells die during mammalian embryogenesis and daily in adult organisms, clearing dead cells and associated cellular debris is important in physiology. In this Review, we present an overview of the phagocytosis of dead and dying cells, a process known as efferocytosis. Efferocytosis is performed by macrophages and to a lesser extent by other ‘professional’ phagocytes (such as monocytes and dendritic cells) and ‘non-professional’ phagocytes, such as epithelial cells. Recent discoveries have shed light on this process and how it functions to maintain tissue homeostasis, tissue repair and organismal health. Here, we outline the mechanisms of efferocytosis, from the recognition of dying cells through to phagocytic engulfment and homeostatic resolution, and highlight the pathophysiological consequences that can arise when this process is abrogated.

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Fig. 1: Efferocytosis is critical for tissue homeostasis.
Fig. 2: Cell-surface signals regulating efferocytosis.
Fig. 3: Phagocyte processing of a dying cell.

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Acknowledgements

This work was supported by grants from the US National Institutes of Health (AI40646 and CA231620 to D.R.G.; AI138492 and CA231423 to B.L.H.), American Lebanese Syrian Associated Charities and the John H. Sununu Endowed Fellowship to B.L.H. and an EMBO Long-Term Fellowship (ALTF 1526 -2016) to E.B.R.

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The authors contributed equally to all aspects of the article.

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Correspondence to Bradlee L. Heckmann or Douglas R. Green.

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D.R.G. is on the scientific advisory board of Inzen. The other authors declare no competing interests.

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Nature Reviews Molecular Cell Biology thanks Edward Thorp, Martin Herrman and the other, anonymous, reviewer for their contribution to the peer review of this work.

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Glossary

Efferocytosis

Engulfment and clearance of dead and dying cells, usually (although not exclusively) by myeloid cells such as macrophages.

Entosis

A process by which a living cell invades or is engulfed by another. This process differs from the clearance of apoptotic cells by phagocytosis as the internalized cell is still alive.

Inflammasome

Any molecular complex capable of activating caspase 1.

Immune tolerance

Lack or inhibition of an adaptive immune response to specific antigens.

Flippase

A membrane protein that transports phosphatidylserine from the outer leaflet to the inner leaflet of the plasma membrane.

Scramblase

A membrane protein that, on activation, equilibrates (‘scrambles’) the distribution of phospholipids between the inner and outer leaflets of the plasma membrane.

MLKL

Mixed-lineage kinase domain-like protein (MLKL) is the executioner in necroptosis, disrupting the plasma membrane following its phosphorylation.

Gasdermins

Proteins that, on activation, create pores in the plasma membrane; gasdermin D and gasdermin E function in pyroptosis.

Guanine nucleotide exchange factor

(GEF). An enzyme that activates monomeric GTPases, including RAS, RAC and RHO. GEFs stimulate the release of GDP to allow binding of GTP.

Dynamin

A member of the protein GTPase family, mainly involved in the scission of newly formed vesicles from a membrane and their fusion with another membrane.

Microtubule-associated protein 1A/1B light chain 3 (LC3)-associated phagocytosis

(LAP). A non-apoptotic function of several proteins of the autophagy pathway, resulting in lipidation of LC3 family proteins on the phagosome membrane, enhancing fusion of the phagosome with lysosomes.

SNARE complex

Soluble N-ethylmaleimide-sensitive fusion protein attachment protein (SNAP) receptor complex involved in fusion of the vesicular membrane to other membranes.

Phagolysosome

The intracellular vesicle that results from the fusion of the phagosome with lysosomes.

Cathepsins

A class of proteases mostly present in lysosomes.

LC3 family

The ATG8 protein family, including microtubule-associated protein 1A/1B light chain 3 (LC3) proteins, γ-aminobutyric acid receptor-associated protein (GABARAP), GEC1 and GATE-16.

Chromophore

A substance or molecule that absorbs light, critical for animal and human vision (for example, retinal).

Langerhans cells

Specialized dendritic cells residing in the epidermis of the skin.

Graft-versus-host disease

Disease resulting from the introduction and action of allogeneic T lymphocytes, which can occur following transplant of bone marrow from which T cells have not been removed.

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Boada-Romero, E., Martinez, J., Heckmann, B.L. et al. The clearance of dead cells by efferocytosis. Nat Rev Mol Cell Biol 21, 398–414 (2020). https://doi.org/10.1038/s41580-020-0232-1

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