title: Phosphatidylserine is a global immunosuppressive signal in efferocytosis, infectious disease, and cancer.
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.
authors.affiliation: Department of Microbiology, Biochemistry and Molecular Genetics, Cancer Center, Rutgers New Jersey Medical School, 205 South Orange Ave, Newark, NJ 07103, USA.
authors.forename: R B
authors.initials: RB
authors.lastname: Birge
authors.affiliation: Department of Internal Medicine 3-Rheumatology and Immunology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), University Hospital Erlangen, 91054 Erlangen, Germany.
authors.forename: S
authors.identifier: 0000-0001-5227-8707
authors.initials: S
authors.lastname: Boeltz
authors.affiliation: Department of Microbiology, Biochemistry and Molecular Genetics, Cancer Center, Rutgers New Jersey Medical School, 205 South Orange Ave, Newark, NJ 07103, USA.
authors.forename: S
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Peregrine Pharmaceuticals, 14282 Franklin Avenue, Tustin, CA 92780, USA.
authors.forename: J
authors.initials: J
authors.lastname: Carlson
authors.affiliation: Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: J
authors.identifier: 0000-0002-9707-6284
authors.initials: J
authors.lastname: Wanderley
authors.affiliation: Department of Microbiology, Biochemistry and Molecular Genetics, Cancer Center, Rutgers New Jersey Medical School, 205 South Orange Ave, Newark, NJ 07103, USA.
authors.forename: D
authors.initials: D
authors.lastname: Calianese
authors.affiliation: Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Rio de Janeiro, Brazil.
authors.forename: M
authors.initials: M
authors.lastname: Barcinski
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Hamon Center for Therapeutic Oncology Research, Dallas, TX 75390-8593, USA.|Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390-8593, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Brekken
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Hamon Center for Therapeutic Oncology Research, Dallas, TX 75390-8593, USA.|Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390-8593, USA.
authors.forename: X
authors.initials: X
authors.lastname: Huang
authors.affiliation: Peregrine Pharmaceuticals, 14282 Franklin Avenue, Tustin, CA 92780, USA.
authors.forename: J T
authors.initials: JT
authors.lastname: Hutchins
authors.affiliation: Peregrine Pharmaceuticals, 14282 Franklin Avenue, Tustin, CA 92780, USA.
authors.forename: B
authors.initials: B
authors.lastname: Freimark
authors.affiliation: Peregrine Pharmaceuticals, 14282 Franklin Avenue, Tustin, CA 92780, USA.
authors.forename: C
authors.initials: C
authors.lastname: Empig
authors.affiliation: Medical Research Council Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: J
authors.initials: J
authors.lastname: Mercer
authors.affiliation: Simmons Cancer Center and the Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390 USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Schroit
authors.affiliation: Department of Internal Medicine 3-Rheumatology and Immunology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), University Hospital Erlangen, 91054 Erlangen, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Schett
authors.affiliation: Department of Internal Medicine 3-Rheumatology and Immunology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), University Hospital Erlangen, 91054 Erlangen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Herrmann
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000627:therapeutic use; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D015551:Autoimmunity; D003141:Communicable Diseases / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D010718:Phosphatidylserines / Q000276:immunology / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000906:Antibodies; D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D010718:Phosphatidylserines; D011956:Receptors, Cell Surface; C408123:phosphatidylserine receptor