Neutrophil extracellular trap biomarkers in aneurysmal subarachnoid hemorrhage: early decline of DNase 1 activity associated with delayed cerebral ischemia

Philipp Hendrix; Jens Witsch; Valérie Spalart; Hauke Schneider; Joachim Oertel; Jürgen Geisel; Kimberly Martinod; Sina Hemmer

doi:10.3389/fneur.2024.1354224

Neutrophil extracellular trap biomarkers in aneurysmal subarachnoid hemorrhage: early decline of DNase 1 activity associated with delayed cerebral ischemia

Front Neurol. 2024 Apr 19:15:1354224. doi: 10.3389/fneur.2024.1354224. eCollection 2024.

Authors

Philipp Hendrix^#^{1

2}, Jens Witsch^#³, Valérie Spalart⁴, Hauke Schneider⁵, Joachim Oertel¹, Jürgen Geisel⁶, Kimberly Martinod⁴, Sina Hemmer¹

Affiliations

¹ Department of Neurosurgery, Saarland University Medical Center, Homburg, Germany.
² Department of Neurosurgery, Geisinger Medical Center, Danville, PA, United States.
³ Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.
⁴ Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium.
⁵ Department of Neurology, University Hospital Augsburg, Augsburg, Germany.
⁶ Department of Clinical Chemistry and Laboratory Medicine, Saarland University Medical Center, Homburg, Germany.

^# Contributed equally.

Abstract

Introduction: High-mobility group box 1 (HMGB1) protein is a critical mediator of neutrophil extracellular trap (NET) formation (NETosis). Myeloperoxidase (MPO)-DNA complexes, a biomarker of NETs, and HMGB1 have been associated with delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH). Additional mechanistic NET-related biomarkers and their role in the neuroinflammatory cascade surrounding DCI remain to be explored.

Methods: A post-hoc analysis of a prospective, blinded, single-center biomarker observational study was performed. De novo measurements of serum citrullinated histone H3-DNA complexes (H3Cit-DNA), peptidylarginine deiminase 4 (PAD4), cell-free DNA (cf-DNA), and DNase 1 activity were conducted on admission (D0) and day 4 (D4). Delayed cerebral infarction (DCI) was defined as new cerebral infarction on CT head not present on the post-treatment scan.

Results: H3Cit-DNA, PAD4, cf-DNA, and DNase 1 activity were within quantifiable ranges in all serum samples analyzed at D0 and D4. Admission biomarker levels were not associated with DCI development. From D0 to D4, in both the DCI and the non-DCI groups, H3Cit-DNA levels significantly decreased, cf-DNA levels significantly increased, and PAD4 levels remained stable. In contrast, DNase 1 activity significantly decreased from D0 to D4 in the DCI group (p < 0.001) but not in the non-DCI group.

Conclusion: This exploratory analysis demonstrated NET-related biomarkers such as H3Cit-DNA, PAD4, cf-DNA, and DNase 1 activity in all aSAH patients. A decline of systemic DNase 1 activity in the early phase might increase the risk of delayed cerebral ischemia.

Keywords: DNase activity; cell-free DNA; intracranial aneurysm; neutrophil extracellular traps; subarachnoid hemorrhage.

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. Intramural research grants from the Homburger Forschungsförderung (PH and SH) and the Theiss Research Award (PH), and a career development grant (https://doi.org/10.58275/AHA.23CDA1053561.pc.gr.168057) of the American Heart Association (JW).