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  • Review Article
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Efferocytosis in health and disease

Abstract

The clearance of apoptotic cells by professional and non-professional phagocytes — a process termed ‘efferocytosis’ — is essential for the maintenance of tissue homeostasis. Accordingly, defective efferocytosis underlies a growing list of chronic inflammatory diseases. Although much has been learnt about the mechanisms of apoptotic cell recognition and uptake, several key areas remain incompletely understood. This Review focuses on new discoveries related to how phagocytes process the metabolic cargo they receive during apoptotic cell uptake; the links between efferocytosis and the resolution of inflammation in health and disease; and the roles of efferocytosis in host defence. Understanding these aspects of efferocytosis sheds light on key physiological and pathophysiological processes and suggests novel therapeutic strategies for diseases driven by defective efferocytosis and impaired inflammation resolution.

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Fig. 1: Mechanisms for handling AC-derived metabolic cargo in macrophage efferocytes.
Fig. 2: Mechanisms of impaired efferocytosis in disease.
Fig. 3: The role of efferocytosis in infection and host defence.

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Acknowledgements

A.C.D. is supported by funding from American Heart Association grant 17FTF33660643. A.Y. is supported by funding from US National Institutes of Health (NIH) grant K99HL145131. The laboratory of I.T. is supported by funding from NIH grants R35HL145228, R01HL127464 and P01HL087123. The authors thank past and present members of the Tabas laboratory who participated in research related to this Review.

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Glossary

Low-density lipoprotein receptor-deficient mice

(LDLR-deficient mice). A mouse model of atherosclerosis in which hypercholesterolaemia is induced by a targeted deletion of the gene encoding LDLR, which functions to clear LDL from the circulation. Ldlr−/− mice fed a high-fat, high-cholesterol diet have a very high level of plasma LDL and develop aortic lesions that are morphologically similar to human atherosclerotic plaques.

Western diet

A commonly used rodent diet that contains a higher fat, sucrose and cholesterol content than standard chow diet, akin to the fast food diet encountered in the Western hemisphere. Ingestion of this diet by Ldlr−/− mice results in weight gain, high glucose levels and elevated levels of circulating cholesterol and triglycerides that drive the development of atherosclerotic plaques.

Foam cells

Macrophages that localize at sites of early atherosclerotic lesion development and that subsequently ingest apolipoprotein B-containing lipoproteins in the subendothelium. They are called foam cells because lipoprotein uptake and metabolism by these macrophages leads to the accumulation of cholesterol ester droplets in the cytoplasm, which gives the cells a ‘foamy’ appearance.

Peroxisome proliferator-activated receptor-γ

(PPARγ). A member of a group of nuclear receptor proteins involved in altering lipid and glucose metabolism and inflammation. Their ligands include free fatty acids and eicosanoids.

Fatty acid oxidation

An important metabolic process used to derive energy through the mobilization and oxidation of fatty acids, mainly in the mitochondrial matrix. Fatty acid oxidation is positively and negatively regulated by 5' AMP-activated protein kinase and mechanistic target of rapamycin, respectively.

Myocardial infarction

An episode of acute cardiac ischaemia that leads to the death of heart muscle cells. It is usually caused by the rupture or erosion of an atherosclerotic plaque leading to occlusive clot formation.

Oxidative phosphorylation

The metabolic pathway that occurs at the inner mitochondrial membrane and uses an electrochemical gradient created by the oxidation of electron carriers to generate ATP.

Glycolysis

A metabolic pathway that generates the cellular high-energy store ATP by oxidizing glucose to pyruvate. In eukaryotic cells, pyruvate is further oxidized to CO2 and H2O in a process known as aerobic respiration, which results in a net yield of 36–38 molecules of ATP per metabolized molecule of glucose.

Secondary necrosis

A process that occurs in apoptotic cells that are not cleared by phagocytes. The integrity of the plasma membrane is lost, and the constituents of the cell are released.

WNT signalling

A signalling pathway that regulates cell fate determination, proliferation, adhesion, migration and polarity during development. In addition to the crucial role of this pathway in embryogenesis, WNT ligands and their downstream signalling molecules have been implicated in tumorigenesis and have causative roles in human colon cancers.

LC3-associated phagocytosis

A non-autophagosomal pathway in which many downstream effector proteins of classic macroautophagy, notably LC3 (the mammalian homologue of yeast Atg8), are used by macrophages to mediate the fusion of lysosomes with phagosomes. It has been shown to facilitate the degradation of internalized apoptotic cells and bacteria by macrophages.

Apolipoprotein E-deficient mice

(Apoe−/− mice). A widely used mouse model that is prone to develop atherosclerosis because the mice have high levels of remnant lipoproteins (a type of atherogenic lipoprotein). This lipoprotein abnormality is caused by the genetic absence of apolipoprotein E, which normally clears remnant lipoproteins from the bloodstream by interacting with hepatocytes.

CD47

A plasma membrane molecule that interacts with several receptors on other cells, including signal-regulatory protein-α (SIRPα), thrombospondin and membrane integrins. The interaction of a cell expressing CD47 with SIRPα on a macrophage prevents cell engulfment by the macrophage. This mechanism prevents the internalization of living cells, but can also prevent the uptake of dead cells if CD47 is inappropriately expressed on dead cells.

Necroptotic cells

Cells undergoing a programmed form of necrotic cell death mediated by receptor-interacting protein kinase 1 (RIPK1), RIPK3 and mixed lineage kinase domain-like protein (MLKL). It can be induced by death receptors and by TIR-domain-containing adaptor protein-inducing interferon-β (TRIF)-dependent Toll-like receptor 3 (TLR3) and TLR4 signalling. Inhibition of caspase 8 activation sensitizes cells to necroptosis.

RHOA

A member of a subfamily of small GTP-binding proteins that have key roles in rearrangement of the cytoskeleton. The nucleotide-bound state of these GTPases is generally regulated by guanine-nucleotide exchange factors, which catalyse GDP–GTP exchange, and GTPase-activating proteins, which facilitate the hydrolysis of the bound GTP. Activation, by extracellular signals through various receptors, results in translocation to the plasma membrane, thereby localizing their activity to discrete sites in the cell.

Statins

A family of inhibitors targeting 3-hydroxy-3-methylglutaryl-CoA reductase (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.

ob/ob mice

A mouse model of metabolic dysregulation and obesity that arises from increased appetite due to a leptin gene mutation that renders these mice functionally leptin deficient.

Cross-presentation

The ability of certain antigen-presenting cells to load peptides that are derived from exogenous antigens onto MHC class I molecules. This property is atypical, because most cells exclusively present peptides from their endogenous proteins on MHC class I molecules. Cross-presentation is essential for the initiation of immune responses to viruses that do not infect antigen-presenting cells.

Palmitoylethanolamide

An endogenous fatty acid amide that has potent anti-inflammatory effects through its effects on peroxisome proliferator-activated receptor-α and G protein-coupled receptor 55.

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Doran, A.C., Yurdagul, A. & Tabas, I. Efferocytosis in health and disease. Nat Rev Immunol 20, 254–267 (2020). https://doi.org/10.1038/s41577-019-0240-6

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