Martinod Kimberly, Witsch Thilo, Erpenbeck Luise, Savchenko Alexander, Hayashi Hideki, Cherpokova Deya, Gallant Maureen, Mauler Maximilian, Cifuni Stephen M, Wagner Denisa D
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115.
Department of Pediatrics, Harvard Medical School, Boston, MA 02115.
J Exp Med. 2017 Feb;214(2):439-458. doi: 10.1084/jem.20160530. Epub 2016 Dec 28.
Aging 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.
衰老会促进炎症反应，这一过程会导致纤维化和器官功能衰退。由肽基精氨酸脱氨酶4（PAD4）协调的中性粒细胞胞外诱捕网（NETs [NETosis]）的释放，在急性炎症模型中会损害器官。我们确定NETosis在老年小鼠中更为普遍，并研究了PAD4/NETs在与年龄相关的器官纤维化中的作用。与野生型（WT）小鼠相比，老年PAD4小鼠的心脏和肺部纤维化有所减轻。左心室间质胶原沉积增加以及收缩和舒张功能下降仅出现在WT小鼠中，而不出现在PAD4小鼠中。在心脏纤维化的实验模型中，心脏压力过载在WT心肌中诱导了NETosis和显著的血小板募集，但在PAD4心肌中未出现。给予脱氧核糖核酸酶1（DNase 1）以评估细胞外染色质的作用。PAD4缺乏或DNase 1同样能保护心脏免受纤维化影响。我们提出NETs在心脏纤维化中发挥作用，并得出结论：PAD4调节与年龄相关的器官纤维化和功能障碍。
