title: NET formation can occur independently of RIPK3 and MLKL signaling.
abstract: 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.
authors.affiliation: Institute of Pharmacology, University of Bern, Bern, Switzerland.
authors.forename: Poorya
authors.initials: P
authors.lastname: Amini
authors.affiliation: Institute of Pharmacology, University of Bern, Bern, Switzerland.
authors.forename: Darko
authors.initials: D
authors.lastname: Stojkov
authors.affiliation: Institute of Pharmacology, University of Bern, Bern, Switzerland.
authors.forename: Xiaoliang
authors.initials: X
authors.lastname: Wang
authors.affiliation: Institute of Pharmacology, University of Bern, Bern, Switzerland.
authors.forename: Simone
authors.initials: S
authors.lastname: Wicki
authors.affiliation: Institute of Pharmacology, University of Bern, Bern, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kaufmann
authors.affiliation: Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
authors.forename: Wendy Wei-Lynn
authors.initials: WW
authors.lastname: Wong
authors.affiliation: Institute of Pharmacology, University of Bern, Bern, Switzerland.
authors.forename: Hans-Uwe
authors.initials: HU
authors.lastname: Simon
authors.affiliation: Institute of Pharmacology, University of Bern, Bern, Switzerland.
authors.forename: Shida
authors.initials: S
authors.lastname: Yousefi
mesh_terms: D000818:Animals; D065206:Extracellular Traps / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D015151:Immunoblotting; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D009336:Necrosis / Q000276:immunology; D011494:Protein Kinases / Q000276:immunology*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*
chemical_list: C570693:MLKL protein, human; C570694:MLKL protein, mouse; D011494:Protein Kinases; C119705:RIPK3 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse
keywords: MLKL; NET formation; NETosis; Necroptosis; Neutrophils; RIPK