Phosphatidylserine externalization, "necroptotic bodies" release, and phagocytosis during necroptosis

PLoS Biol. 2017 Jun 26;15(6):e2002711. doi: 10.1371/journal.pbio.2002711. eCollection 2017 Jun.


Necroptosis is a regulated, nonapoptotic form of cell death initiated by receptor-interacting protein kinase-3 (RIPK3) and mixed lineage kinase domain-like (MLKL) proteins. It is considered to be a form of regulated necrosis, and, by lacking the "find me" and "eat me" signals that are a feature of apoptosis, necroptosis is considered to be inflammatory. One such "eat me" signal observed during apoptosis is the exposure of phosphatidylserine (PS) on the outer plasma membrane. Here, we demonstrate that necroptotic cells also expose PS after phosphorylated mixed lineage kinase-like (pMLKL) translocation to the membrane. Necroptotic cells that expose PS release extracellular vesicles containing proteins and pMLKL to their surroundings. Furthermore, inhibition of pMLKL after PS exposure can reverse the process of necroptosis and restore cell viability. Finally, externalization of PS by necroptotic cells drives recognition and phagocytosis, and this may limit the inflammatory response to this nonapoptotic form of cell death. The exposure of PS to the outer membrane and to extracellular vesicles is therefore a feature of necroptotic cell death and may serve to provide an immunologically-silent window by generating specific "find me" and "eat me" signals.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Membrane / drug effects
  • Cell Membrane / immunology
  • Cell Membrane / metabolism*
  • Cell Membrane / ultrastructure
  • Cell Membrane Permeability / drug effects
  • Cell Survival / drug effects
  • Cells, Cultured
  • Extracellular Vesicles / drug effects
  • Extracellular Vesicles / immunology
  • Extracellular Vesicles / metabolism
  • Extracellular Vesicles / ultrastructure
  • Humans
  • Macrophages / cytology
  • Macrophages / immunology
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Necrosis / immunology
  • Necrosis / metabolism*
  • Necrosis / pathology
  • Necrosis / prevention & control
  • Phagocytosis* / drug effects
  • Phosphatidylserines / metabolism*
  • Phosphorylation / drug effects
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinases / chemistry
  • Protein Kinases / metabolism*
  • Protein Processing, Post-Translational* / drug effects
  • Protein Transport / drug effects
  • Surface Properties / drug effects


  • Phosphatidylserines
  • Protein Kinase Inhibitors
  • MLKL protein, human
  • MLKL protein, mouse
  • Protein Kinases