Neutrophil extracellular trap cell death requires both autophagy and superoxide generation.
Neutrophil extracellular traps (NETs) are extracellular chromatin structures that can trap and degrade microbes. They arise from neutrophils that have activated a cell death program called NET cell death, or NETosis. Activation of NETosis has been shown to involve NADPH oxidase activity, disintegration of the nuclear envelope and most granule membranes, decondensation of nuclear chromatin and formation of NETs. We report that in phorbol myristate acetate (PMA)-stimulated neutrophils, intracellular chromatin decondensation and NET formation follow autophagy and superoxide production, both of which are required to mediate PMA-induced NETosis and occur independently of each other. Neutrophils from patients with chronic granulomatous disease, which lack NADPH oxidase activity, still exhibit PMA-induced autophagy. Conversely, PMA-induced NADPH oxidase activity is not affected by pharmacological inhibition of autophagy. Interestingly, inhibition of either autophagy or NADPH oxidase prevents intracellular chromatin decondensation, which is essential for NETosis and NET formation, and results in cell death characterized by hallmarks of apoptosis. These results indicate that apoptosis might function as a backup program for NETosis when autophagy or NADPH oxidase activity is prevented.
IRC - Laboratory of Biochemistry, Department of Medicine, KU Leuven Campus Kortrijk, Kortrijk, Belgium.
Quinten
Q
Remijsen
Tom
T
Vanden Berghe
Ellen
E
Wirawan
Bob
B
Asselbergh
Eef
E
Parthoens
Riet
R
De Rycke
Sam
S
Noppen
Michel
M
Delforge
Jean
J
Willems
Peter
P
Vandenabeele
D017209:Apoptosis; D001343:Autophagy; D042002:Chromatin Assembly and Disassembly; D006105:Granulomatous Disease, Chronic / Q000378:metabolism; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D008562:Membrane Glycoproteins; D013481:Superoxides; D009247:NADH, NADPH Oxidoreductases; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D013755:Tetradecanoylphorbol Acetate