NET formation is a default epigenetic program controlled by PAD4 in apoptotic neutrophils.
Yanfang Peipei ZhuMary SpeirZheHao TanJamie Casey LeeCameron J NowellAlyce A ChenHajera AmatullahAri J SalingerCarolyn J HuangGio WuWeiqi PengKasra AskariEric R GriffisMajid GhassemianJennifer SantiniMordechay GerlicWilliam B KiossesSergio D CatzHal M HoffmanKimberly F GrecoEdie WellerPaul R ThompsonLai Ping WongRuslan I SadreyevKate L JeffreyBen A CrokerPublished in: Science advances (2023)
Neutrophil extracellular traps (NETs) not only counteract bacterial and fungal pathogens but can also promote thrombosis, autoimmunity, and sterile inflammation. The presence of citrullinated histones, generated by the peptidylarginine deiminase 4 (PAD4), is synonymous with NETosis and is considered independent of apoptosis. Mitochondrial- and death receptor-mediated apoptosis promote gasdermin E (GSDME)-dependent calcium mobilization and membrane permeabilization leading to histone H3 citrullination (H3Cit), nuclear DNA extrusion, and cytoplast formation. H3Cit is concentrated at the promoter in bone marrow neutrophils and redistributes in a coordinated process from promoter to intergenic and intronic regions during apoptosis. Loss of GSDME prevents nuclear and plasma membrane disruption of apoptotic neutrophils but prolongs early apoptosis-induced cellular changes to the chromatin and cytoplasmic granules. Apoptotic signaling engages PAD4 in neutrophils, establishing a cellular state that is primed for NETosis, but that occurs only upon membrane disruption by GSDME, thereby redefining the end of life for neutrophils.
Keyphrases
- cell death
- oxidative stress
- cell cycle arrest
- dna methylation
- gene expression
- endoplasmic reticulum stress
- bone marrow
- diabetic rats
- transcription factor
- dna damage
- anti inflammatory
- quality improvement
- single molecule
- gram negative
- genome wide
- high glucose
- cell free
- multidrug resistant
- circulating tumor cells
- celiac disease
- resting state