Back to 2026 Abstracts
Impact of NETosis on Pathophysiologic Nerve Regeneration
Wesley S. Warner, BA
1, Sama Noroozi Gilandehi, MD
1, Madeline Rose, BA
1, Jie Zhang, PhD
1, Stewart Yeoh, PhD
1; Mark A. Mahan, MD
2(1)University of Utah, Salt Lake City, UT, (2)Department of Neurosurgery, University of Utah, Salt Lake City, UT
Introduction: Immunological response to nerve injury is critical for nerve regeneration and recovery. However, pathologic inflammatory events likely participate in the formation of neuromas and failed nerve regeneration. NETosis is a form of neutrophil cell death deployed for pathogen engulfment, but may have pathologic consequences when aberrantly activated, such as after trauma. Recent investigation in central nervous system trauma has demonstrated that maladaptive NETosis activation is associated with impaired vascular remodeling, amplification of the inflammatory response, increased fibrotic deposition, and impaired neurologic recovery. By contrast, there is limited interrogation of NETosis in peripheral nervous system trauma.
Methods: One-hundred and fifty-two adolescent male mice (n=7/group) underwent rapid-stretch injury of different biomechanically determined grades: sham injured (surgical exposure alone), elastic (<15% persistent length deformation), inelastic (permanent length change), and rupture. NETosis formation was modulated by: 1) perineural DNAse I administration to degrade NETs 2) PAD4 knockout which prevents NETosis formation. Sciatic nerves were harvested at 6 hours, day 2, 7, 14, and 48 post-injury. Behavioral tests evaluated motor and sensory function. Microstructure and cellular composition were evaluated by immunostaining and fluorescence activated cell sorting.
Results: The extent of NETosis correlated with the severity of nerve injury (p<.01). Blocking NETosis with PAD4 KO animals demonstrated a shift in inflammatory cell phenotype and attenuation of inflammatory cell recruitment, in the acute timeframe after injury (day 7, p<.01). At the terminal endpoint, PAD4 KO animals demonstrated substantial amelioration of pathology, with evidence of improved axonal regeneration (p<.05), myelination, and reduced fibrosis. Similarly, degradation of NETs with DNase I treatment reduced neuroma formation, typical pathology, and demonstrated improved axonal regeneration (p<.05). Behavioral results demonstrated moderate improvement in sensory recovery, whereby statistical difference is no longer observed compared to baseline by day 14 post-injury (p=.16).
Conclusion: NETosis may be a treatable event in peripheral nerve trauma. Reduction of NETosis improves regeneration and decreases fibrotic deposition. Further evaluation of NETosis in humans is necessary for future clinical translation.
Back to 2026 Abstracts
