Abstract
Neutrophil extracellular traps (NETs) comprise decondensed chromatin, histones and neutrophil granular proteins and are involved in the response to infectious as well as non-infectious diseases. The prothrombotic activity of NETs has been reported in various thrombus-related diseases; this activity can be attributed to the fact that the NETs serve as a scaffold for cells and numerous coagulation factors and stimulate fibrin deposition. A crosstalk between NETs and thrombosis has been indicated to play a role in numerous thrombosis-related conditions including stroke. In cerebral ischemia, neutrophils are the first group of cells to infiltrate the damaged brain tissue, where they produce NETs in the brain parenchyma and within blood vessels, thereby aggravating inflammation. Increasing evidences suggest the connection between NETosis and thrombosis as a possible cause of “tPA resistance”, a problem encountered during the treatment of stroke patients. Several damage-associated molecular pattern molecules have been proven to induce NETosis and thrombosis, with high mobility group box 1 (HMGB1) playing a critical role. This review discusses NETosis and thrombosis and their crosstalk in various thrombosis-related diseases, focusing on the role of HMGB1 as a mediator in stroke. We also addresses the function of peptidylarginine deiminase 4 with respect to the interplay with HMGB1 in NET-induced thrombosis.
Highlights
Neutrophils infiltrate damaged brain tissue in the earlier stages of various pathologic conditions of the central nervous system (CNS) and produce proinflammatory cytokines, matrix metalloproteinases (MMPs), nitric oxide (NO), reactive oxygen species (ROS) and other cytotoxic molecules that accelerate brain damage [1,2]
We summarize the role of peptidylarginine deiminase 4 (PAD4), an enzyme that condenses chromatin during the interplay between NETosis and thrombosis, theorizing a reciprocal modulation between high mobility group box 1 (HMGB1) and PAD4
The first report on HMGB1-mediated induction of NETosis demonstrated that recombinant HMGB1 induced neutrophil extracellular traps (NETs) formation through interaction with TLR4 and that it was inhibited by the administration of neutralizing HMGB1 antibodies [32]
Summary
Neutrophils infiltrate damaged brain tissue in the earlier stages of various pathologic conditions of the central nervous system (CNS) and produce proinflammatory cytokines, matrix metalloproteinases (MMPs), nitric oxide (NO), reactive oxygen species (ROS) and other cytotoxic molecules that accelerate brain damage [1,2]. Histological and biochemical examination of those thrombi revealed the localization of neutrophils and citrullinated histone H3 (CitH3, a NETosis marker) in most thrombi [9,10,11] and demonstrated that ex vivo lysis of patient thrombi was more successful when DNase 1 was combined with standard tPA treatment [9]. Based on these reports, it can be suggested that NETs have a prothrombotic effect and confer resistance to fibrinolysis in acute ischemic stroke. We summarize the role of peptidylarginine deiminase 4 (PAD4), an enzyme that condenses chromatin during the interplay between NETosis and thrombosis, theorizing a reciprocal modulation between HMGB1 and PAD4
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
