Neutrophil extracellular traps exacerbate neurological deficits after traumatic brain injury

Kumar Vaibhav, Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA, USA.
Molly Braun, Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA, USA.
Katelyn Alverson, Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA, USA.
Hesam Khodadadi, Department of Oral Biology, Dental College of Georgia, Augusta University, Augusta, GA, USA.
Ammar Kutiyanawalla, Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA, USA.
Ayobami Ward, Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA, USA.
Christopher Banerjee, Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA, USA.
Tyler Sparks, Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA, USA.
Aneeq Malik, Department of Oral Biology, Dental College of Georgia, Augusta University, Augusta, GA, USA.
Mohammad H. Rashid, Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, USA.
Mohammad Badruzzaman Khan, Department of Neurology, Medical College of Georgia, Augusta University, Augusta, GA, USA.
Michael F. Waters, Department of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, USA.
David C. Hess, Department of Neurology, Medical College of Georgia, Augusta University, Augusta, GA, USA.
Ali S. Arbab, Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, USA.
John R. Vender, Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA, USA.
Nasrul Hoda, Department of Neurology, Medical College of Georgia, Augusta University, Augusta, GA, USA.
Babak Baban, Department of Oral Biology, Dental College of Georgia, Augusta University, Augusta, GA, USA.
Krishnan M. Dhandapani, Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA, USA.

Document Type

Article

Abstract

Traumatic brain injury (TBI) is a major cause of mortality and morbidity. Preventative measures reduce injury incidence and/or severity, yet one-third of hospitalized patients with TBI die from secondary pathological processes that develop during supervised care. Neutrophils, which orchestrate innate immune responses, worsen TBI outcomes via undefined mechanisms. We hypothesized that formation of neutrophil extracellular traps (NETs), a purported mechanism of microbial trapping, exacerbates acute neurological injury after TBI. NET formation coincided with cerebral hypoperfusion and tissue hypoxia after experimental TBI, while elevated circulating NETs correlated with reduced serum deoxyribonuclease-1 (DNase-I) activity in patients with TBI. Functionally, Toll-like receptor 4 (TLR4) and the downstream kinase peptidylarginine deiminase 4 (PAD4) mediated NET formation and cerebrovascular dysfunction after TBI. Last, recombinant human DNase-I degraded NETs and improved neurological function. Thus, therapeutically targeting NETs may provide a mechanistically innovative approach to improve TBI outcomes without the associated risks of global neutrophil depletion.

Publication Date

5-1-2020

Publication Title

Science advances

E-ISSN

2375-2548

Volume

6

Issue

22

First Page

eaax8847

PubMed ID

32523980

Digital Object Identifier (DOI)

10.1126/sciadv.aax8847

This document is currently not available here.

Share

COinS