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

Pingxin Li, Ming Li, Michael R. Lindberg, Mary J. Kennett, Na Xiong, Yanming Wang

Research output: Contribution to journalArticle

622 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1853-1862
Number of pages10
JournalJournal of Experimental Medicine
Volume207
Issue number9
DOIs
StatePublished - Aug 30 2010

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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