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

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

1,450 citations recorded by the source corpus.

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.

Subfields: Genetics, Immunology

View Paper: https://www.semanticscholar.org/paper/720f7aaaee8d6d8e60ab409e989608f4c948f2bb

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In Immunology

1. Guido Kroemer
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Citations in the corpus

• Neutrophil extracellular traps: Is immunity the second function of chromatin? (2012, background): “pyogenes infection model, PAD4­null mice developed larger lesions than their PAD4­expressing siblings (Li et al., 2010), but NET for­ mation remains to be quantified in this model.”
• NETosis: how vital is it? (2013, background): “Mice with PAD4 deficiency displayed impaired NETosis and were highly susceptible to some severe skin infections such as necrotizing fasciitis.(23) However, it is equally important to point out that PAD4 deficiency does not contribute, for example, to lung infections, cause by influenza virus,(24) de”
• Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018 (2018, background): “also been proposed to participate in chromatin dispersion [745], but its actual involvement remains a matter of debate and appears to depend on the initiating stimulus [746, 747].”
• Neutrophils, from marrow to microbes. (2010, background): “…target for C/EBPa, which displaces NFI-A from the miR223 promoter (Fazi et al., 2005), allowing for subsequent granulocytic differentiation, in part by downregulating the cell-cycle regulator E2F1 (Pulikkan et al., 2010), which is also inhibited directly by C/EBPa (D'Alo' et al., 2003).”
• The Multifaceted Functions of Neutrophils (2013, background): “Knockout mice lacking PAD4 (peptidylarginine deiminase 4), the enzyme required for histone deimination, have impaired NETosis and reduced host defense to infection (123).”
• Cancers predispose neutrophils to release extracellular DNA traps that contribute to cancer-associated thrombosis (2012, background): “Moreover, citrullinated histone H3 (H3Cit), a histone modification necessary for NET production (27, 28), was present in the plasma at a late stage of the disease when plasma DNA is high, consistent with a drop in the number of hypercitrullinated neutrophils in peripheral blood (Fig.”
• Neutrophil Extracellular Traps and Its Implications in Inflammation: An Overview (2017, background): “Suicidal NETosis is dependent on ROS for histone citrullination by PAD4, which allows chromatin decondensation (16, 17, 19), finally releasing the DNA as extracellular traps (ETs) (Figure 1) (20, 21).”
• Intravascular neutrophil extracellular traps capture bacteria from the bloodstream during sepsis. (2012, background): “…roles of NETs in host defense, NETs have been observed within tissues such as the skin and lungs, where they contribute to the containment of acute bacterial infections in animal models of cellulitis, necrotizing faciitis, and pneumonia (Beiter et al., 2006; Buchanan et al., 2006; Li et al., 2010).”
• Metabolic reprogramming and epigenetic modifications on the path to cancer (2021, background): “The citrullination of H3 has been reported to open chromatin and promote gene transcription (Fuhrmann and Thompson, 2016), and citrullinated histone H3, which is mediated by PAD4, plays a vital role in the release of neutrophil extracellular traps (NETs) (Li et al., 2010).”
• Ferroptosis in infection, inflammation, and immunity (2021, methodology): “, 2009) and peptidyl arginine deiminase 4 (PADI4, best known as PAD4; Li et al., 2010) is essential for NET formation.”
• Neutrophil extracellular traps (NETs): Double-edged swords of innate immunity (2012, background): “Analysis of neutrophils from mice deficient in PAD4 revealed that they were impaired in their capacity to form NETs in vitro (54, 62).”
• NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis (2013, background): “Further, an important role for PAD4 in NETosis has been proposed, potentially due to its role in histone deimination (18).”