Frontiers in Immunology (May 2020)

Hepatic Surgical Stress Promotes Systemic Immunothrombosis That Results in Distant Organ Injury

  • Hongji Zhang,
  • Hongji Zhang,
  • Julie Goswami,
  • Patrick Varley,
  • Dirk J. van der Windt,
  • Jinghua Ren,
  • Jinghua Ren,
  • Patricia Loughran,
  • Patricia Loughran,
  • Hamza Yazdani,
  • Matthew D. Neal,
  • Richard L. Simmons,
  • Jinxiang Zhang,
  • Allan Tsung,
  • Hai Huang

DOI
https://doi.org/10.3389/fimmu.2020.00987
Journal volume & issue
Vol. 11

Abstract

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Innate immunity can initiate platelet activation during the development of thrombosis through a process, termed immunothrombosis. Neutrophils form neutrophil extracellular traps (NETs) that have been shown to interact directly with platelets and play pro-coagulant roles in a variety of infectious and sterile inflammatory settings. Hepatic surgical stress initiated by ischemia/reperfusion (I/R) injury has wide systemic consequences on distant organs. However, the mechanisms of this remote injury phenomenon are not well-understood. Here, we sought to determine the role of NETs in causing systemic immunothrombosis and distant organ injury following a local inflammatory insult with liver I/R. Postoperative thromboelastographic revealed that the speed of clot formation (alpha-angle) was significantly increased whereas time to clot formation (R-time) were decreased by in patients undergoing liver resection, indicating a hypercoagulable state after surgery. In mice subjected to liver I/R, circulating platelet activation and platelet-neutrophil aggregates were significantly increased. Injured distant organs such as the lung and kidney displayed NETs and platelet-rich micro-thrombi in the microvasculature following liver I/R. The immune-thrombi and organ damage were dramatically decreased when NETs were inhibited by DNase treatment. Depletion of Tlr4 on platelets limited NET-induced activation of platelets but had no effect on NET formation. Furthermore, platelet-specific TLR4 KO mice had significantly reduced distant organ injury with decreased circulating platelet activation, platelet-neutrophil aggregates following liver I/R in comparison to their control counterparts. These data establish that after an acute local inflammatory process, NET-activated platelets can lead to a systemic pro-coagulant state with resultant remote organ injury by immunothrombosis.

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