NET formation can occur independently of RIPK3 and MLKL signaling

Eur J Immunol. 2016 Jan;46(1):178-84. doi: 10.1002/eji.201545615. Epub 2015 Dec 2.


The importance of neutrophil extracellular traps (NETs) in innate immunity is well established but the molecular mechanisms responsible for their formation are still a matter of scientific dispute. Here, we aim to characterize a possible role of the receptor-interacting protein kinase 3 (RIPK3) and the mixed lineage kinase domain-like (MLKL) signaling pathway, which are known to cause necroptosis, in NET formation. Using genetic and pharmacological approaches, we investigated whether this programmed form of necrosis is a prerequisite for NET formation. NETs have been defined as extracellular DNA scaffolds associated with the neutrophil granule protein elastase that are capable of killing bacteria. Neither Ripk3-deficient mouse neutrophils nor human neutrophils in which MLKL had been pharmacologically inactivated, exhibited abnormalities in NET formation upon physiological activation or exposure to low concentrations of PMA. These data indicate that NET formation occurs independently of both RIPK3 and MLKL signaling.

Keywords: MLKL; NET formation; NETosis; Necroptosis; Neutrophils; RIPK.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Extracellular Traps / immunology*
  • Humans
  • Immunity, Innate / immunology
  • Immunoblotting
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microscopy, Confocal
  • Necrosis / immunology
  • Protein Kinases / immunology*
  • Receptor-Interacting Protein Serine-Threonine Kinases / immunology*
  • Signal Transduction / immunology*


  • MLKL protein, human
  • MLKL protein, mouse
  • Protein Kinases
  • RIPK3 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk3 protein, mouse