Rohrbach, Amanda S.Slade, Daniel J.Thompson, Paul RMowen, Kerri A.2022-08-232022-08-232012-11-292015-05-22Front Immunol. 2012 Nov 29;3:360. doi: 10.3389/fimmu.2012.00360. eCollection 2012. <a href="http://dx.doi.org/10.3389/fimmu.2012.00360">Link to article on publisher's site</a>1664-3224 (Linking)10.3389/fimmu.2012.00360https://hdl.handle.net/20.500.14038/50033<p>At the time of publication, Paul Thompson was not yet affiliated with UMass Medical School.</p>Peptidylarginine deiminases, or PADs, convert arginine residues to the non-ribosomally encoded amino acid citrulline in a variety of protein substrates. PAD4 is expressed in granulocytes and is essential for the formation of neutrophil extracellular traps (NETs) via PAD4-mediated histone citrullination. Citrullination of histones is thought to promote NET formation by inducing chromatin decondensation and facilitating the expulsion of chromosomal DNA that is coated with antimicrobial molecules. Numerous stimuli have been reported to lead to PAD4 activation and NET formation. However, how this signaling process proceeds and how PAD4 becomes activated in cells is largely unknown. Herein, we describe the various stimuli and signaling pathways that have been implicated in PAD4 activation and NET formation, including the role of reactive oxygen species generation. To provide a foundation for the above discussion, we first describe PAD4 structure and function, and how these studies led to the development of PAD-specific inhibitors. A comprehensive survey of the receptors and signaling pathways that regulate PAD4 activation will be important for our understanding of innate immunity, and the identification of signaling intermediates in PAD4 activation may also lead to the generation of pharmaceuticals to target NET-related pathogenesis.en-USCopyright: © 2012 Rohrbach, Slade, Thompson and Mowen. This is an open-access article distributed under the terms of theCreative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.http://creativecommons.org/licenses/by/3.0/NETPAD4citrullinationdeiminationneutrophilBiochemistryEnzymes and CoenzymesImmunology and Infectious DiseaseMedicinal-Pharmaceutical ChemistryTherapeuticsJournal Articlehttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1041&amp;context=thompson&amp;unstamped=1https://escholarship.umassmed.edu/thompson/427135709thompson/42