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PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps
Open accessAbstract
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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“Next, we determined the importance of peptidylarginine deiminase type 4 (PAD4), the enzyme responsible for histone modifications required for decondensing neutrophil DNA before expulsion (25).”
From Cancer cells induce metastasis-supporting neutrophil extracellular DNA traps (2016) · cites this paper as [25]
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Self-citation
Metadata
- Authors
- Li, P., Li, M., Lindberg, M. R., Kennett, M. J., Xiong, N., & Wang, Y.
- Affiliations
- Pennsylvania State University (US)
- Corresponding author
- 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
- 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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