Netosis and Inflammasomes in Large Vessel Occlusion Thrombi

Authors

Stephanie H. Chen, The Miami Project to Cure Paralysis
Xavier O. Scott, University of Miami Leonard M. Miller School of Medicine
Yoandy Ferrer Marcelo, The Miami Project to Cure Paralysis
Vania W. Almeida, The Miami Project to Cure Paralysis
Patricia L. Blackwelder, University of MiamiFollow
Dileep R. Yavagal, University of Miami Leonard M. Miller School of Medicine
Eric C. Peterson, The Miami Project to Cure Paralysis
Robert M. Starke, The Miami Project to Cure Paralysis
W. Dalton Dietrich, The Miami Project to Cure Paralysis
Robert W. Keane, The Miami Project to Cure Paralysis
Juan Pablo de Rivero Vaccari, The Miami Project to Cure Paralysis

Document Type

Article

Publication Title

Frontiers in Pharmacology

ISSN

1663-9812

Publication Date

1-22-2021

Keywords

ASC, caspase-1, inflammasome, inflammation, NETs, neutrophil extracellular traps, stroke, thrombus

Abstract

The inflammatory response appears to play a critical role in clotting in which neutrophil extracellular traps (NETs) are the major drivers of thrombosis in acute ischemic stroke (AIS). The inflammasome is an innate immune complex involved in the activation of interleukin (IL)-18 and IL-1β through caspase-1, but whether the inflammasome plays a role in NETosis in AIS remains poorly understood. Here we assessed the levels of inflammasome signaling proteins in NETs and their association with clinical and procedural outcomes of mechanical thrombectomy for AIS. Electron microscopy and immunofluorescence indicate the presence of NETs in thrombi of patients with AIS. Moreover, the inflammasome signaling proteins caspase-1 and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) were also present in clots associated with the marker of NETosis citrullinated histone H (CitH3). Analysis of protein levels by a simple plex assay show that caspase-1, ASC and interleukin (IL)-1β were significantly elevated in clots when compared to plasma of AIS patients and healthy controls, while IL-18 levels were lower. Moreover, multivariate analyses show that IL-1β levels in clots contribute to the number of passes to achieve complete recanalization, and that ASC, caspase-1 and IL-18 are significant contributors to time to recanalization. Thus, inflammasome proteins are elevated in NETs present in thrombi of patients with AIS that contribute to poor outcomes following stroke. 3

DOI

10.3389/fphar.2020.607287

Volume

11

Comments

This research received grant funding from the Robert J. Dempsey Cerebrovascular Research Award to SC and JdR, an R01 grant from the NIH/NINDS to RK and JdR (R01NS113969-01) and a James and Ester King Biomedical Research Program grant from the State of Florida (7JK03) to WD. RS research is supported by the NREF, Joe Niekro Foundation, Brain Aneurysm Foundation, Bee Foundation, and by the NIH (R01NS111119-01A1) and (UL1TR002736, KL2TR002737) through the Miami Clinical and Translational Science Institute, from the National Center for Advancing Translational Sciences and the National Institute on Minority Health and Health Disparities. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

NSUWorks Citation

Stephanie H. Chen, Xavier O. Scott, Yoandy Ferrer Marcelo, Vania W. Almeida, Patricia L. Blackwelder, Dileep R. Yavagal, Eric C. Peterson, Robert M. Starke, W. Dalton Dietrich, Robert W. Keane, and Juan Pablo de Rivero Vaccari. 2021. Netosis and Inflammasomes in Large Vessel Occlusion Thrombi .Frontiers in Pharmacology . https://nsuworks.nova.edu/occ_facarticles/1153.