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A blast from the past: clearance of apoptotic cells regulates immune responses

Key Points

  • Apoptosis, a programmed and physiological form of cell death, is known to shape the immune system by regulating populations of effector lymphocytes. However, the binding and ingestion of dying cells by monocytes/macrophages and dendritic cells can also influence immune responses markedly by inducing or suppressing inflammation. Therefore, dead cells, which are a reflection of an organism's immediate past, can control its immunological future.

  • Dying cells are recognized by phagocytes as being non-self, altered-self or non-motile self, using innate-immune recognition, scavenger receptors or immunoglobulin-superfamily molecules, respectively.

  • Cell clearance by apoptosis has anti-inflammatory properties, by suppressing the release of pro-inflammatory cytokines by monocytes/macrophages and by the direct release of immunosuppressive cytokines, such as interleukin-10 and transforming growth factor-β1, by apoptotic cells.

  • Dendritic-cell maturation and presentation of antigen are suppressed by the uptake of apoptotic cells, which leads to the promotion of tolerance.

  • Defects in the clearance of apoptotic cells are associated with spontaneous/persistent tissue inflammation and autoimmunity to cell contents.

  • Strategies to promote the safe, anti-inflammatory and immunosuppressive clearance of dying cells are discussed.

  • There is a need to understand the mechanisms that, under certain circumstances, paradoxically allow apoptotic cells to stimulate the release of pro-inflammatory cytokines, such as tumour-necrosis factor, by macrophages and that allow dendritic cells to present antigen derived from apoptotic cells.

Abstract

Apoptosis, which is a programmed and physiological form of cell death, is known to shape the immune system by regulating populations of effector lymphocytes. However, the binding and ingestion of dying cells by monocytes/macrophages and dendritic cells can also influence immune responses markedly by enhancing or suppressing inflammation. Therefore, dead cells, which are a reflection of an organism's immediate past, can control its immunological future.

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Figure 1: Three classes of mechanism for the recognition of apoptotic cells by phagocytes.
Figure 2: Virtual colour-scanning electron micrograph of phagocyte sampling of the surface of an apoptotic cell.
Figure 3: Two classes of mechanism for apoptotic-cell suppression of phagocyte pro-inflammatory responses.
Figure 4: Simple model of the modulation of dendritic-cell maturation by ingestion of apoptotic cells.

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Acknowledgements

We have received long-term support from the Wellcome Trust and the Medical Research Council. Many colleagues have been instrumental in developing the ideas that are presented here, not least those whose work could not be cited owing to space constraints. C. Gilchrist typed the manuscript.

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Correspondence to John Savill.

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DATABASES

LocusLink

αVβ3 integrin

ABC1

ARP2/3 complex

Axl

β2-GPI

β2-integrin

C1q

C4

calreticulin

caspase-1

CD11B

CD11C

CD14

CD18

CD31

CD36

CD44

CD68

CD86

CD91

CD95

CD95L

CDC42

CR3

CR4

CRKII

CRP

DNase I

DOCK180

Gas6

GM-CSF

ICAM3

IFN-γ

IL-1β

IL-8

IL-10

IL-12

IL-18

LOX1

MBL

Mer

MFGE8

myeloperoxidase

p130CAS

paxillin

proteinase-3

PtdSerR

PYK2

RAC1

RHOA

S19

SAP

SRA

TGF-β1

TNF

TSP1

Tyro3

WASp

OMIM

SLE

WAS

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Savill, J., Dransfield, I., Gregory, C. et al. A blast from the past: clearance of apoptotic cells regulates immune responses. Nat Rev Immunol 2, 965–975 (2002). https://doi.org/10.1038/nri957

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