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Apoptotic cell clearance: basic biology and therapeutic potential

Nature Reviews Immunology volume 14, pages 166–180 (2014)Cite this article

Subjects

Key Points

  • Apoptotic cells are rapidly removed by tissue-resident professional phagocytes and/or by neighbouring non-professional phagocytes under homeostatic conditions.

  • The prompt clearance of apoptotic cells involves molecular steps that include the recruitment of phagocytes towards apoptotic cells through 'find-me' signals and the recognition of 'eat-me' signals on apoptotic cells that trigger engulfment.

  • Apoptotic cell clearance under physiological conditions is generally anti-inflammatory and immunologically silent.

  • Defects in apoptotic cell removal are associated with the initiation and progression of a number of pathological conditions, including inflammation and autoimmunity.

  • The process of apoptotic cell clearance can be manipulated potentially by pharmacological means to treat a variety of human diseases.

Abstract

The prompt removal of apoptotic cells by phagocytes is important for maintaining tissue homeostasis. The molecular and cellular events that underpin apoptotic cell recognition and uptake, and the subsequent biological responses, are increasingly better defined. The detection and disposal of apoptotic cells generally promote an anti-inflammatory response at the tissue level, as well as immunological tolerance. Consequently, defects in apoptotic cell clearance have been linked with various inflammatory diseases and autoimmunity. Conversely, under certain conditions, such as the killing of tumour cells by specific cell-death inducers, the recognition of apoptotic tumour cells can promote an immunogenic response and antitumour immunity. Here, we review the current understanding of the complex process of apoptotic cell clearance in physiology and pathology, and discuss how this knowledge could be harnessed for new therapeutic strategies.

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Figure 1: Phases of apoptotic cell clearance.
Figure 2: Potential approaches for targeting the apoptotic cell clearance process for therapeutic benefits.

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Acknowledgements

The authors acknowledge funding from the Australian National Health and Medical Research Council (1013584) for I.K.H.P., Wellcome Trust, UK (WT094415) for C.D.L., the Medical Research Council, UK (G0601481 and MR/K013386/1) for A.G.R. and the US National Institutes of Health (GM107848, GM64709, MH096484, and HD074981) for K.S.R.

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Author notes

  1. Ivan K. H. Poon and Christopher D. Lucas: These authors contributed equally to this work.

Authors and Affiliations

  1. Center for Cell Clearance and the Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, 22908, Virginia, USA

    Ivan K. H. Poon & Kodi S. Ravichandran

  2. Department of Biochemistry, La Trobe Institute for Molecular Science, La Trobe University, 3086, Victoria, Australia

    Ivan K. H. Poon

  3. MRC Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, EH16 4TJ, UK

    Christopher D. Lucas & Adriano G. Rossi

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Correspondence to Adriano G. Rossi or Kodi S. Ravichandran.

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Glossary

Professional phagocytes

Professional phagocytes such as macrophages and immature dendritic cells can efficiently detect and engulf pathogens and dying cells.

Non-professional phagocytes

Non-professional phagocytes, such as fibroblasts, epithelial cells and endothelial cells, can engulf a variety of particles, including their dying brethren, but their primary function is not phagocytosis.

Plasma membrane blebs

Globular protrusions seen at the plasma membrane. Membrane blebs are dynamic and can occur during cell migration, cytokinesis and apoptosis.

Apoptotic bodies

Subcellular fragments released from apoptotic cells that are approximately 1–5μm in size. Apoptotic bodies are non-uniform membrane-bound particles that contain portions of cytoplasm and fragmented organelles.

Focal adhesions

Macromolecular complexes that function as structural links between the cell and the extracellular matrix. Components of focal adhesion are also important for regulating intracellular signalling.

Adherens junctions

Intercellular macromolecular complexes that mediate cell–cell adhesion. Cadherin and catenin are key components of adherens junctions.

Cross-presentation

A process that describes the ability of antigen-presenting cells to display a peptide fragment from exogenous antigen, through MHC class I molecules, to CD8+ T cells.

Organelle fragmentation

A process during apoptosis that aids the disassembly of organelles into smaller portions. Organelle fragmentation is driven by caspase-mediated cleavage of certain proteins and actomyosin contraction.

Apoptotic cell-derived microparticles

Another category of subcellular fragments released from apoptotic cells that are approximately 0.1–1μm in size. Apoptotic cell-derived microparticles and apoptotic bodies represent a spectrum of membrane-bound apoptotic vesicles characterized mainly by size and density.

Germinal centre

A lymphoid structure that arises within follicles after immunization with, or exposure to, a T cell-dependent antigen. It is specialized for facilitating the development of high-affinity, long-lived plasma cells and memory B cells.

Aminophospholipid asymmetry of the plasma membrane

The distribution of aminophospholipids (such as phosphatidylserine, phosphatidylethanolamine and phosphatidylcholine) between the outer and inner leaflet of the plasma membrane is often asymmetrical and may differ depending on the cell type, activation status and viability. This asymmetry is actively maintained by ATP-dependent processes and compromised by activation of phospholipid scramblases.

Endoplasmic reticulum stress

(ER stress). A response by the ER that results in the disruption of protein folding and in the accumulation of unfolded proteins in the ER.

Photodynamic therapy

A treatment that uses a combination of a specific wavelength of light and a photosensitizing agent to induce the production of reactive oxygen species and cause lethal damage to the cells.

Pathogen-associated molecular patterns

(PAMPs). Molecular signatures that are found in pathogens but not in mammalian cells. Examples include terminally mannosylated and polymannosylated compounds (which bind the mannose receptor) and various microbial components, such as bacterial lipopolysaccharide, hypomethylated DNA, flagellin and double-stranded RNA (all of which bind Toll-like receptors).

Damage-associated molecular patterns

(DAMPs). As a result of cellular stress, cellular damage and non-physiological cell death, DAMPs are released from the degraded stroma (for example, hyaluronate), from the nucleus (for example, high-mobility group box 1 protein), from the cytosol (for example, ATP, uric acid, S100 calcium-binding proteins and heat-shock proteins) and from mitochondria (formylated peptides and mitochondrial DNA). Such DAMPs are thought to elicit both local and systemic inflammatory responses.

Chronic obstructive pulmonary disease

(COPD). A group of diseases characterized by the pathological limitation of airflow in the airway, including chronic bronchitis and emphysema. COPD is most often caused by tobacco smoking but can also be caused by other airborne irritants, such as coal dust, and occasionally by genetic abnormalities, such as α1-antitrypsin deficiency.

Pulmonary fibrosis

A heterogenous group of disorders characterized by diffuse abnormalities of the pulmonary interstitium, with increased and variable inflammation, and fibrosis. Frequently of unknown aetiology, pulmonary fibrosis can also be related to autoimmune disease and secondary to medications.

Cystic fibrosis

An autosomal recessive genetic condition secondary to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR; a chloride channel). This leads to a multisystem disorder with lung, gastrointestinal, endocrine and fertility complications. Chronic infection of the lungs ensues, leading to significant morbidity and mortality.

Efferocytosis

The phagocytic clearance of apoptotic cells.

Intima

The innermost layer of an artery, which consists of loose connective tissue and is covered by a monolayer of endothelium. Atherosclerotic plaques form within the intima.

C1q

A complement protein and a component of the classical complement pathway. C1q is involved in diverse functions including immune function, autoimmunity and facilitates apoptotic cell clearance.

Statins

A family of inhibitors targeting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, an enzyme that catalyses the conversion of HMG-CoA to L-mevalonate. These molecules are mainly used as cholesterol-lowering drugs, but they also have immunoregulatory and anti-inflammatory properties. L-mevalonate and its metabolites are implicated in cholesterol synthesis and other intracellular pathways.

Foam cell

A macrophage in the arterial wall that ingests oxidized low-density lipoprotein and assumes a foamy appearance. These cells secrete various substances contributing to plaque growth and inflammation.

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Poon, I., Lucas, C., Rossi, A. et al. Apoptotic cell clearance: basic biology and therapeutic potential. Nat Rev Immunol 14, 166–180 (2014). https://doi.org/10.1038/nri3607

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