Cited by 1,495Neutrophil, Myeloperoxidase and Oxidative MechanismsAntimicrobial Peptides and ActivitiesBlood disorders and treatments

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PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps

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Li, Pingxin, Li, Ming, Lindberg, Michael R., Kennett, Mary J., Xiong, Na, Wang, Yanming·2010·Journal of Experimental Medicine

DOI 10.1084/jem.20100239PMC PMC2931169

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Abstract

Neutrophils trap and kill bacteria by forming highly decondensed chromatin structures, termed neutrophil extracellular traps (NETs). We previously reported that histone hypercitrullination catalyzed by peptidylarginine deiminase 4 (PAD4) correlates with chromatin decondensation during NET formation. However, the role of PAD4 in NET-mediated bacterial trapping and killing has not been tested. Here, we use PAD4 knockout mice to show that PAD4 is essential for NET-mediated antibacterial function. Unlike PAD4+/+ neutrophils, PAD4−/− neutrophils cannot form NETs after stimulation with chemokines or incubation with bacteria, and are deficient in bacterial killing by NETs. In a mouse infectious disease model of necrotizing fasciitis, PAD4−/− mice are more susceptible to bacterial infection than PAD4+/+ mice due to a lack of NET formation. Moreover, we found that citrullination decreased the bacterial killing activity of histones and nucleosomes, which suggests that PAD4 mainly plays a role in chromatin decondensation to form NETs instead of increasing histone-mediated bacterial killing. Our results define a role for histone hypercitrullination in innate immunity during bacterial infection.

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Authors: Li, P., Li, M., Lindberg, M. R., Kennett, M. J., Xiong, N., & Wang, Y.
Affiliations: Pennsylvania State University (US)
Corresponding author: Wang, Yanming
ORCID: Li, Ming
Lindberg, Michael R.
Xiong, Na
Wang, Yanming
Venue: Journal of Experimental Medicine
Publisher: Rockefeller University Press
Published: 2010-08-23
Volume: 207
Issue: 9
Pages: 1853-1862
ISSN: 0022-1007 (ISSN-L)
1540-9538
DOI: 10.1084/jem.20100239
PMC: PMC2931169
OpenAlex: W2135849676
Cited by: 1,495
References: 31
Citations by year: 2026: 104 · 2025: 121 · 2024: 122 · 2023: 121 · 2022: 134 · 2021: 123 · 2020: 125 · 2019: 118 · 2018: 94 · 2017: 92 · 2016: 81 · 2015: 68 · 2014: 60 · 2013: 61 · 2012: 51
FWCI: 17.98
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: The Journal of Experimental Medicine (publishedVersion)
PubMed Central (publishedVersion, cc-by-nc-sa)
PubMed (publishedVersion)
Funders: National Institutes of Health
National Cancer Institute (R01CA136856)
Topics: Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
Life Sciences › Immunology and Microbiology › Microbiology › Antimicrobial Peptides and Activities
Health Sciences › Medicine › Hematology › Blood disorders and treatments
Keywords: PAD4, neutrophil extracellular traps, neutrophils, chromatin decondensation, bacterial killing, necrotizing fasciitis, nucleosome
MeSH terms: Protein-Arginine Deiminase Type 4, Animals, Cell Differentiation, Dysentery, Bacillary, Extracellular Space, Histones, Hydrolases, Immunity, Innate, Neutrophils, Shigella flexneri, Mice, Knockout, Mice

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PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps

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