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Cell Death Differ. 2016 Jun;23(6):962-78. doi: 10.1038/cdd.2016.11. Epub 2016 Feb 26.

Phosphatidylserine is a global immunosuppressive signal in efferocytosis, infectious disease, and cancer.

Author information

1
Department of Microbiology, Biochemistry and Molecular Genetics, Cancer Center, Rutgers New Jersey Medical School, 205 South Orange Ave, Newark, NJ 07103, USA.
2
Department of Internal Medicine 3-Rheumatology and Immunology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), University Hospital Erlangen, 91054 Erlangen, Germany.
3
Peregrine Pharmaceuticals, 14282 Franklin Avenue, Tustin, CA 92780, USA.
4
Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
5
Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Rio de Janeiro, Brazil.
6
Division of Surgical Oncology, Department of Surgery, Hamon Center for Therapeutic Oncology Research, Dallas, TX 75390-8593, USA.
7
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390-8593, USA.
8
Medical Research Council Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, UK.
9
Simmons Cancer Center and the Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390 USA.

Abstract

Apoptosis is an evolutionarily conserved and tightly regulated cell death modality. It serves important roles in physiology by sculpting complex tissues during embryogenesis and by removing effete cells that have reached advanced age or whose genomes have been irreparably damaged. Apoptosis culminates in the rapid and decisive removal of cell corpses by efferocytosis, a term used to distinguish the engulfment of apoptotic cells from other phagocytic processes. Over the past decades, the molecular and cell biological events associated with efferocytosis have been rigorously studied, and many eat-me signals and receptors have been identified. The externalization of phosphatidylserine (PS) is arguably the most emblematic eat-me signal that is in turn bound by a large number of serum proteins and opsonins that facilitate efferocytosis. Under physiological conditions, externalized PS functions as a dominant and evolutionarily conserved immunosuppressive signal that promotes tolerance and prevents local and systemic immune activation. Pathologically, the innate immunosuppressive effect of externalized PS has been hijacked by numerous viruses, microorganisms, and parasites to facilitate infection, and in many cases, establish infection latency. PS is also profoundly dysregulated in the tumor microenvironment and antagonizes the development of tumor immunity. In this review, we discuss the biology of PS with respect to its role as a global immunosuppressive signal and how PS is exploited to drive diverse pathological processes such as infection and cancer. Finally, we outline the rationale that agents targeting PS could have significant value in cancer and infectious disease therapeutics.

PMID:
26915293
PMCID:
PMC4987730
DOI:
10.1038/cdd.2016.11
[Indexed for MEDLINE]
Free PMC Article

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