title: PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps.
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.
authors: Center for Eukaryotic Gene Regulation, Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA.
authors: Pingxin
authors: P
authors: Li
authors: Ming
authors: M
authors: Li
authors: Michael R
authors: MR
authors: Lindberg
authors: Mary J
authors: MJ
authors: Kennett
authors: Na
authors: N
authors: Xiong
authors: Yanming
authors: Y
authors: Wang
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D004405:Dysentery, Bacillary / Q000276:immunology*; D005110:Extracellular Space / Q000276:immunology / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006867:Hydrolases / Q000172:deficiency / Q000276:immunology* / Q000378:metabolism; D007113:Immunity, Innate; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D000080002:Protein-Arginine Deiminase Type 4; D012763:Shigella flexneri / Q000276:immunology*
chemical_list: D006657:Histones; D006867:Hydrolases; D000080002:Protein-Arginine Deiminase Type 4; C552151:peptidylarginine deiminase 4, mouse