NET formation is a default epigenetic program controlled by PAD4 in apoptotic neutrophils

Author:

Zhu Yanfang Peipei12ORCID,Speir Mary34,Tan ZheHao1ORCID,Lee Jamie Casey1ORCID,Nowell Cameron J.5ORCID,Chen Alyce A.34ORCID,Amatullah Hajera67,Salinger Ari J.8,Huang Carolyn J.34ORCID,Wu Gio1ORCID,Peng Weiqi1,Askari Kasra9ORCID,Griffis Eric10ORCID,Ghassemian Majid11ORCID,Santini Jennifer12,Gerlic Motti13ORCID,Kiosses William B.14ORCID,Catz Sergio D.9ORCID,Hoffman Hal M.1,Greco Kimberly F.15,Weller Edie315,Thompson Paul R.8ORCID,Wong Lai Ping1617,Sadreyev Ruslan1718ORCID,Jeffrey Kate L.67ORCID,Croker Ben A.134ORCID

Affiliation:

1. Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA.

2. Immunology Center of Georgia, Augusta University, Augusta, GA 30912, USA.

3. Division of Hematology/Oncology, Boston Children’s Hospital, Boston, MA 02115, USA.

4. Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.

5. Monash Institute of Pharmaceutical Sciences, Parkville, Victoria 3052, Australia.

6. Department of Medicine, Division of Gastroenterology and the Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston MA 02114, USA.

7. Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

8. Program in Chemical Biology and Department of Biochemistry and Molecular Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.

9. Scripps Research Institute, La Jolla, CA 92037, USA.

10. Nikon Imaging Center, University of California San Diego, La Jolla, CA 92093, USA.

11. Biomolecular and Proteomics Mass Spectrometry Facility, University of California San Diego, La Jolla, CA 92093, USA.

12. UCSD School of Medicine Microscopy Core, University of California San Diego, La Jolla 92093, CA, USA.

13. Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.

14. La Jolla Institute for Immunology, La Jolla, CA 92037, USA.

15. Biostatistics and Research Design Center, Institutional Centers for Clinical and Translational Research, Boston Children’s Hospital, Boston, 02115, USA.

16. Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.

17. Department of Genetics, Harvard Medical School, Boston, MA 02114, USA.

18. Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

Abstract

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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