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Drugging the efferocytosis process: concepts and opportunities

Nature Reviews Drug Discovery volume 21, pages 601–620 (2022)Cite this article

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Abstract

The daily removal of billions of apoptotic cells in the human body via the process of efferocytosis is essential for homeostasis. To allow for this continuous efferocytosis, rapid phenotypic changes occur in the phagocytes enabling them to engulf and digest the apoptotic cargo. In addition, efferocytosis is actively anti-inflammatory and promotes resolution. Owing to its ubiquitous nature and the sheer volume of cell turnover, efferocytosis is a point of vulnerability. Aberrations in efferocytosis are associated with numerous inflammatory pathologies, including atherosclerosis, cancer and infections. The recent exciting discoveries defining the molecular machinery involved in efferocytosis have opened many avenues for therapeutic intervention, with several agents now in clinical trials.

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Fig. 1: Steps in efferocytosis and therapeutic opportunities.
Fig. 2: Opportunities to target efferocytosis steps in specific pathologies.
Fig. 3: The metabolic dynamics of efferocytosis.

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Acknowledgements

The authors thank the members of the Ravichandran laboratory for numerous discussions. This work was supported by Fonds Wetenschappelijk Onderzoek (FWO) Odysseus grant G0F5716N, EOS DECODE 30837538, Special Research Fund UGent (iBOF BOF20/IBF/037), European Research Council (ERC) (grant agreement no. 835243) and grants from the National Heart, Lung, and Blood Institute (NHLBI) (P01HL120840), National Institute of Allergy and Infectious Diseases (NIAID) (R01AI159551) and National Institute of General Medical Sciences (NIGMS) (R35GM122542). P.M. is supported by a FWO Postdoctoral Fellowship (1227220N).

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Authors and Affiliations

  1. Unit for Cell Clearance in Health and Disease, VIB Center for Inflammation Research, Ghent, Belgium

    Parul Mehrotra

  2. Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium

    Kodi S. Ravichandran

  3. The Center for Cell Clearance, University of Virginia, Charlottesville, VA, USA

    Kodi S. Ravichandran

  4. Division of Immunobiology, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA

    Kodi S. Ravichandran

Authors
  1. Parul Mehrotra
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  2. Kodi S. Ravichandran
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Contributions

The authors contributed equally to the discussion, writing, preparation, and editing of this manuscript.

Corresponding author

Correspondence to Kodi S. Ravichandran.

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Glossary

Apoptosis

A process of cell death triggered by either extrinsic or intrisic cues that ultimately result in activation of executioner caspases and caspase-dependent cleavage of cellular substrates, leading to an ordered cellular demise.

Necroptosis

A regulated form of lytic cell death, requiring the function of receptor interacting protein 1/3 and their substrate, MLKL, oligomerization-induced plasma membrane pore formation and eventual loss of membrane integrity.

Pyroptosis

Inflammatory caspase-driven lytic cell death, usually triggered by pathogenic insults. This involves inflammasome assembly, which via caspase 1 induces Gasdermin D activation. Gasdermin D proteins form pores in the plasma membrane, leading to membrane rupture and lytic cell death accompanied by the release of IL-1β and IL-18.

Ferroptosis

A form of caspase-independent lytic cell death induced by excess free intracellular iron inducing lipid peroxidation, causing plasma membrane pore formation and osmotic cell rupture.

Fc receptor-mediated phagocytosis

The process in which a cell-surface immune cell receptor recognizes and binds to the Fc fragment of antibodies, allowing for phagocytosis of the antibody-coated particles.

Solute carrier (SLC) family

A superfamily of membrane transporters that carry a wide number of substrates across the plasma membrane, and membranes of intracellular organelles.

Chemokines

Secreted proteins that act as chemoattractants and induce immune cell migration.

Pannexin channels

Heptameric plasma membrane channels that are activated in apoptotic cells by caspase 3 cleavage (or other modes in live cells) allowing the release of metabolites, including ATP.

Purinergic receptor P2Y

A G-protein-coupled receptor that is activated by extracellular adenine and uridine nucleotides, and UDP-glucose. The P2Y family consists of eight receptors that can engage in intracellular signalling via adenylate cyclase or phospholipase C.

Liver-X receptors (LXRs) α/β

Transcription factors belonging to the nuclear receptor family. The receptors are activated by the presence of oxysterols and form heterodimers with retinoic acid receptors to initiate transcriptional changes.

PPARγ

A transcription factor belonging to the members of the nuclear receptor family, involved in regulating cellular metabolism and immune cell behaviour, and anti-inflammatory responses.

Foam cells

Macrophages carrying high lipid and cholesterol burden seen in atherosclerotic plaques, due to enhanced lipoprotein uptake.

ADAM family proteases

(A disintegrin and metalloprotease (ADAM) family of proteins). A family of transmembrane proteins with strong proteolytic activity. The substrates for ADAM proteases are very often the extracellular domains of transmembrane proteins.

Specialized pro-resolvin mediators

(SPMs). A class of immunologically active lipid derivates that limit acute inflammatory responses and aid in inflammation resolution. The family includes lipoxins, E-series and D-series resolvins, protectins and maresins.

Senotherapies

Therapies aimed at killing senescent cells and diminishing the effects of the senescence-associated secretory phenotype that is a key driver of sterile inflammation during ageing.

Pore-induced intracellular traps

The cellular debris emanating from a pyroptotic cell that entrap the intracellular bacteria as they are released during pyroptosis of the host cell.

ARDS

(Acute respiratory distress syndrome). A form of severe respiratory trauma and failure characterized by inflammation and oedema in the alveolar spaces.

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Mehrotra, P., Ravichandran, K.S. Drugging the efferocytosis process: concepts and opportunities. Nat Rev Drug Discov 21, 601–620 (2022). https://doi.org/10.1038/s41573-022-00470-y

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