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

Abstract

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.

Pulmonary Staphylococcus aureus infection regulates breast cancer cell metastasis via neutrophil extracellular traps (NETs) formation

“…It is well known that target autophagy is just an indirect way of regulating NETs formation. DNase has been widely employed in controlling inflammatory diseases via NETs degradation directly 41 . In our study, blocking NETs by DNase treatment significantly suppressed bacterial pneumonia‐mediated metastasis enhancement but has no effects on other subjects, which demonstrated that the NETs formation by bacterial infection was the key event related to cancer metastasis enhancement (Figure 6).…”

CXCR4hi effector neutrophils in sickle cell anemia: potential role for elevated circulating serotonin (5-HT) in CXCR4hi neutrophil polarization

“…It should be noted that, in addition to our observation of a likely influence of platelet activation on neutrophil phenotype, it is also probable that neutrophil polarization to the CXCR4 hi phenotype may also influence platelet activation. Activated neutrophils are known to release several soluble platelet-activating mediators 34 , and, while we did not evaluate NET generation by the CXCR4 hi neutrophils, stimulation of neutrophil CXCR4 expression with a low dose of lipopolysaccharide has been associated with the release of NETs, which in turn have documented platelet activating and thromboinflammatory effects 35,36 .…”

Neutrophil Extracellular Traps (NETs): Opportunities for Targeted Therapy

“…Furthermore, as established recently, NETs can contain suppressor molecules (e.g., PD-L1) and have a negative effect on the activity of cytotoxic lymphocytes ( Fig. 2, II ) [ 49 ]. A specific role in the study of NETs should be assigned to work on the treatment of cancer pathologies with the help of re-programmed T cells with induced cytolytic activity.…”