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NET formation is a default epigenetic program controlled by PAD4 in apoptotic neutrophils.
Yanfang Peipei Zhu1,2, Mary Speir3,4, ZheHao Tan1
1Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA.
Science Advances
|December 20, 2023
Summary
Neutrophil extracellular traps (NETs) are involved in pathogen defense and disease. This study reveals that gasdermin E (GSDME) mediates histone citrullination during neutrophil apoptosis, a key step for NET formation.
Area of Science:
- Immunology
- Cell Biology
- Pathology
Background:
- Neutrophil extracellular traps (NETs) play a dual role in immunity and disease.
- NETosis, characterized by citrullinated histones, was previously thought to be independent of apoptosis.
- Peptidylarginine deiminase 4 (PAD4) generates citrullinated histones.
Purpose of the Study:
- To investigate the relationship between apoptosis and NETosis.
- To elucidate the role of gasdermin E (GSDME) in NET formation during neutrophil apoptosis.
Main Methods:
- Studied apoptosis in bone marrow neutrophils.
- Investigated histone H3 citrullination (H3Cit) localization and redistribution.
- Assessed the impact of GSDME loss on neutrophil apoptosis and NETosis.
Main Results:
- Mitochondrial and death receptor pathways induce GSDME-dependent calcium mobilization and membrane permeabilization.
- This process leads to H3Cit, DNA extrusion, and cytoplast formation in apoptotic neutrophils.
- GSDME is essential for nuclear and plasma membrane disruption, priming neutrophils for NETosis.
Conclusions:
- Apoptotic signaling engages PAD4 in neutrophils, priming them for NETosis.
- GSDME-mediated membrane disruption is critical for initiating NETosis in apoptotic neutrophils.
- This redefines the terminal differentiation of neutrophils as a GSDME-dependent process.
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