Martinod, KimberlyWitsch, ThiloErpenbeck, LuiseSavchenko, AlexanderHayashi, HidekiCherpokova, DeyaGallant, MaureenMauler, MaximilianCifuni, Stephen M.Wagner, Denisa2017-11-212017Martinod, Kimberly, Thilo Witsch, Luise Erpenbeck, Alexander Savchenko, Hideki Hayashi, Deya Cherpokova, Maureen Gallant, Maximilian Mauler, Stephen M. Cifuni, and Denisa D. Wagner. 2017. “Peptidylarginine deiminase 4 promotes age-related organ fibrosis.” The Journal of Experimental Medicine 214 (2): 439-458. doi:10.1084/jem.20160530. http://dx.doi.org/10.1084/jem.20160530.http://nrs.harvard.edu/urn-3:HUL.InstRepos:34375234Aging promotes inflammation, a process contributing to fibrosis and decline in organ function. The release of neutrophil extracellular traps (NETs [NETosis]), orchestrated by peptidylarginine deiminase 4 (PAD4), damages organs in acute inflammatory models. We determined that NETosis is more prevalent in aged mice and investigated the role of PAD4/NETs in age-related organ fibrosis. Reduction in fibrosis was seen in the hearts and lungs of aged PAD4−/− mice compared with wild-type (WT) mice. An increase in left ventricular interstitial collagen deposition and a decline in systolic and diastolic function were present only in WT mice, and not in PAD4−/− mice. In an experimental model of cardiac fibrosis, cardiac pressure overload induced NETosis and significant platelet recruitment in WT but not PAD4−/− myocardium. DNase 1 was given to assess the effects of extracellular chromatin. PAD4 deficiency or DNase 1 similarly protected hearts from fibrosis. We propose a role for NETs in cardiac fibrosis and conclude that PAD4 regulates age-related organ fibrosis and dysfunction.en-USArticleJournal Article2017-11-2110.1084/jem.20160530