Fernando, Dinesh
- Department of Forest Biomaterials and Technology, Swedish University of Agricultural Sciences
Research article2024Peer reviewedOpen access
Pharmacological blocking of neutrophil extracellular traps attenuates immunothrombosis and neuroinflammation in cerebral cavernous malformation
Onyeogaziri, Favour C.; Smith, Ross; Arce, Maximiliano; Huang, Hua; Erzar, Iza; Rorsman, Charlotte; Malinverno, Matteo; Orsenigo, Fabrizio; Sundell, Veronica; Fernando, Dinesh; Daniel, Geoffrey; Niemela, Mika; Laakso, Aki; Jahromi, Behnam Rezai; Olsson, Anna-Karin; Magnusson, Peetra U.
Abstract
Cerebral cavernous malformation (CCM) is a neurovascular disease with symptoms such as strokes, hemorrhages and neurological deficits. With surgery being the only treatment strategy, understanding the molecular mechanisms of CCM is crucial in finding alternative therapeutic options for CCM. Neutrophil extracellular traps (NETs) were recently reported in CCM, and NETs were shown to have positive or negative effects in different disease contexts. In this study, we investigated the roles of NETs in CCM by pharmacologically inhibiting NET formation using Cl-amidine (a peptidyl arginine deiminase inhibitor). We show here that Cl-amidine treatment reduced lesion burden, coagulation and endothelial-to-mesenchymal transition. Furthermore, NETs promoted the activation of microglia and fibroblasts, leading to increased neuroinflammation and a chronic wound microenvironment in CCM. The inhibition of NET formation caused endothelial quiescence and promoted a healthier microenvironment. Our study suggests the inhibition of NETs as a potential therapeutic strategy in CCM.Onyeogaziri et al. show that the formation of neutrophil extracellular traps contributes to a chronic wound state in cerebral cavernous malformation, while inhibition of these traps with CI-amidine establishes a healthier microenvironment and promotes endothelial cell quiescence, suggesting use of CI-amidine as a potential therapeutic strategy.
Published in
Nature cardiovascular research
2024, volume: 3, number: 12, pages: 1549–1567
Publisher: SPRINGERNATURE
SLU Authors
Daniel, Geoffrey
- Department of Forest Biomaterials and Technology, Swedish University of Agricultural Sciences
- Department of Forest Biomaterials and Technology, Swedish University of Agricultural Sciences
UKÄ Subject classification
Cardiac and Cardiovascular Systems
Pharmacology and Toxicology
Publication identifier
- DOI: https://doi.org/10.1038/s44161-024-00577-y
Permanent link to this page (URI)
https://res.slu.se/id/publ/139882