Neutrophil Extracellular Traps Promote the Development of Intracranial Aneurysm Rupture

Abstract

Potential roles for neutrophils in the pathophysiology of intracranial aneurysm have long been suggested by clinical observations. The presence of neutrophil enzymes in the aneurysm wall has been associated with significant increases in rupture risk. However, the mechanisms by which neutrophils may promote aneurysm rupture are not well understood. Neutrophil extracellular traps (NETs) were implicated in many diseases that involve inflammation and tissue remodeling, including atherosclerosis, vasculitis, and abdominal aortic aneurysm. Therefore, we hypothesized that NETs may promote the rupture of intracranial aneurysm, and that removal of NETs can reduce the rate of rupture. We employed both pharmacological and genetic approaches for the disruption of NETs and used a mouse model of intracranial aneurysm to investigate the roles of NETs in the development of intracranial aneurysm rupture. Here, we showed that NETs are detected in human intracranial aneurysms. Both global and granulocyte-specific knockout of peptidyl arginine deiminase 4 (an enzyme essential for NET formation) reduced the rate of aneurysm rupture. Pharmacological blockade of the NET formation by Cl-amidine also reduced the rate of aneurysm rupture. In addition, the resolution of already formed NETs by deoxyribonuclease was effective against aneurysm rupture. Inhibition of NETs formation with Cl-amidine decreased mRNA expression of proinflammatory cytokines (intercellular adhesion molecule 1 (ICAM-1), interleukin 1 beta (IL-1β), monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor alpha (TNF-α)) in cerebral arteries. These data suggest that NETs promote the rupture of intracranial aneurysm. Pharmacological removal of NETs, by inhibition of peptidyl arginine deiminase 4 or resolution of already-formed NETs, may represent a potential therapeutic strategy for preventing aneurysmal rupture.

Contemporary Lifestyle and Neutrophil Extracellular Traps: An Emerging Link in Atherosclerosis Disease

“…The authors suggest that this NET formation may be triggered by endothelial damage, hemodynamic stress and the general context of inflammation that exist in the aneurysm vascular wall, conditions that resemble those found in atherosclerosis. Knowing that high blood pressure has been shown to play an important role in the formation and rupture of intracranial aneurysms, this is another example of the interplay between NETs, hypertension and hypertension-associated conditions [208]. Briefly, under pathological conditions like arterial hypertension there seems to exist an imbalance towards vascular ROS release against the generation of antioxidant molecules, which would ultimately augment vascular damage and endothelial dysfunction.…”

Transcriptome-Based Dissection of Intracranial Aneurysms Unveils an “Immuno-Thermal” Microenvironment and Defines a Pathological Feature-Derived Gene Signature for Risk Estimation

“…Recently, the potential roles of mast cells and neutrophils in IA have also been reported. Mast cells related to intramural microhemorrhage and wall degeneration, as well as neutrophil extracellular traps (NETs) involved in inflammation and tissue remodeling, both contribute to the increased risk of aneurysm rupture ( 45 , 46 ). For NK cells and MDSC, the perception of their roles in IA pathological processes is extremely limited.…”

Identification of the key immune-related genes in aneurysmal subarachnoid hemorrhage

“…Recent studies suggest that NETs are involved in the progression of intracranial aneurysm (Kang et al, 2020 ; Korai et al, 2021 ). The neutrophils infiltrate into the damaged brain tissue following SAH.…”