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

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....

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Published inThe Journal of experimental medicine Vol. 207; no. 9; pp. 1853 - 1862
Main Authors Li, Pingxin, Li, Ming, Lindberg, Michael R., Kennett, Mary J., Xiong, Na, Wang, Yanming
Format Journal Article
LanguageEnglish
Published United States The Rockefeller University Press 30.08.2010
Subjects
Animals
Brief Definitive Report
Cell Differentiation
Dysentery, Bacillary - immunology
Extracellular Space - immunology
Extracellular Space - metabolism
Histones - metabolism
Hydrolases - deficiency
Hydrolases - immunology
Hydrolases - metabolism
Immunity, Innate
Mice
Mice, Knockout
Neutrophils - cytology
Neutrophils - immunology
Neutrophils - metabolism
Shigella flexneri - immunology
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Summary: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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ISSN:0022-1007
1540-9538
1540-9538
DOI:10.1084/jem.20100239