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Front. Immunol. | doi: 10.3389/fimmu.2019.02535

Recombinant Thrombomodulin Suppresses Histone-Induced Neutrophil Extracellular Trap Formation

 Binita Shrestha1, 2,  Takashi Ito2*, Tomoka Nagasato2, Mika Yamamoto2 and Ikuro Maruyama2
  • 1University of Michigan, United States
  • 2Kagoshima University, Japan

Histones, the major protein components of chromatin, are released into the extracellular space during sepsis, trauma, and ischemia-reperfusion injury, and subsequently mediate organ failure. Extracellular histones can promote endothelial damage and platelet aggregation, which can be suppressed by administration of recombinant thrombomodulin (rTM). The present study aimed to clarify whether histones can activate neutrophils to induce NET formation and whether rTM can prevent histone-induced NET formation. NET formation was analyzed in vitro by stimulating human neutrophils with histones in the absence or presence of rTM. NET formation was further analyzed in vivo by intravenous infusion of histones into rats with or without rTM. Histones induced NET release in a dose-dependent manner in vitro and NET release was induced as early as 1 h after stimulation. Histone-induced NET release was independent of NADPH oxidase. rTM suppressed histone-induced NET release in vitro as well as in vivo. The suppression might be mediated by rTM binding to histones, as suggested by analysis using a quartz crystal microbalance system. The present findings suggest that histones can activate neutrophils to form NETs and that rTM can inhibit histone-induced NET formation.

Keywords: histone, Thrombomodulin, Thrombosis, NETs (neutrophil extracellular traps, chondroitin sulfate

Received: 01 Aug 2019; Accepted: 11 Oct 2019.

Copyright: © 2019 Shrestha, Ito, Nagasato, Yamamoto and Maruyama. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Takashi Ito, Kagoshima University, Kagoshima, 890-8580, Kagoshima, Japan,