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Cell death by phagocytosis

Abstract

Cells can die as a consequence of being phagocytosed by other cells — a form of cell death that has been called phagotrophy, cell cannibalism, programmed cell removal and primary phagocytosis. However, these are all different manifestations of cell death by phagocytosis (termed ‘phagoptosis’ for short). The engulfed cells die as a result of cytotoxic oxidants, peptides and degradative enzymes within acidic phagolysosomes. Cell death by phagocytosis was discovered by Metchnikov in the 1880s, but was neglected until recently. It is now known to contribute to developmental cell death in nematodes, Drosophila and mammals, and is central to innate and adaptive immunity against pathogens. Cell death by phagocytosis mediates physiological turnover of erythrocytes and other leucocytes, making it the most abundant form of cell death in the mammalian body. Immunity against cancer is also partly mediated by macrophage phagocytosis of cancer cells, but cancer cells can also phagocytose host cells and other cancer cells in order to survive. Recent evidence indicates neurodegeneration and other neuropathologies can be mediated by microglial phagocytosis of stressed neurons. Thus, despite cell death by phagocytosis being poorly recognized, it is one of the oldest, commonest and most important forms of cell death.

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Fig. 1: Cell death by phagocytosis.
Fig. 2: Eat-me signals, don’t-eat-me signals, opsonins and phagocytic receptors.
Fig. 3: Immunity by phagocytosis.
Fig. 4: Cell death by phagocytosis in cancer.
Fig. 5: Cell death by phagocytosis contributes to neurodegeneration.

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Acknowledgements

The author thanks the many different researchers who have contributed to this field. The author thanks A. Tolkovsky, V. Borutaite, J. Neher, M. Fricker and U. Neniskyte, who have contributed to his understanding of cell death by phagocytosis.

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Correspondence to Guy C. Brown.

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Glossary

Cell cannibalism

Cells phagocytosing other cells, which may be dead or alive.

Desialylation

The removal of terminal sialic acid residues from glycoproteins or glycolipids.

Don’t-eat-me signals

Molecules on a cell that inhibit a phagocyte eating that cell.

Eat-me signal

A molecule on a cell that induces a phagocyte to eat that cell.

Efferocytosis

Phagocytosis of a cell dying by apoptosis.

Eryptosis

A mechanism of cell death of erythrocytes.

Entotic cell death

The death of a cell that has invaded into another cell by entosis.

Find-me signals

Molecules released from a cell that encourage a phagocyte to chemotactically migrate to the cell.

Haemophagocytosis

The phagocytosis of blood cells.

NADPH oxidase

A membrane-bound enzyme that uses cytosolic NADPH to reduce oxygen to superoxide that is released into phagosomes to kill engulfed cells.

Nurse cells

Specialized cells that support the growth and stability of neighbouring cells.

Opsonins

Normally extracellular molecules that when bound to a cell induce a phagocyte to eat that cell.

Phagocytic receptors

Receptors that directly bind eat-me signals or opsonins and then induce phagocytosis.

Programmed cell removal

The phagocytic removal of cells that may be dead, dying or alive.

Primary phagocytosis

The same as cell death by phagocytosis.

Scavenger receptors

A diverse set of receptors that mediate phagocytosis or endocytosis.

Secondary phagocytosis

Phagocytosis of a dead or dying cell.

Sialic acid-binding immunoglobulin-type lectin (SIGLEC) receptors

A family of receptors binding sialic acid residues.

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Brown, G.C. Cell death by phagocytosis. Nat Rev Immunol 24, 91–102 (2024). https://doi.org/10.1038/s41577-023-00921-6

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