TY - JOUR
T1 - Neutrophil extracellular traps exacerbate neurological deficits after traumatic brain injury
AU - Vaibhav, Kumar
AU - Braun, Molly
AU - Alverson, Katelyn
AU - Khodadadi, Hesam
AU - Kutiyanawalla, Ammar
AU - Ward, Ayobami
AU - Banerjee, Christopher
AU - Sparks, Tyler
AU - Malik, Aneeq
AU - Rashid, Mohammad H.
AU - Rashid, Mohammad H.
AU - Khan, Mohammad Badruzzaman
AU - Waters, Michael F.
AU - Hess, David C.
AU - Arbab, Ali S.
AU - Vender, John R.
AU - Hoda, Nasrul
AU - Hoda, Nasrul
AU - Hoda, Nasrul
AU - Baban, Babak
AU - Dhandapani, Krishnan M.
N1 - Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).
PY - 2020/5
Y1 - 2020/5
N2 - 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, Tolllike 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.
AB - 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, Tolllike 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.
UR - http://www.scopus.com/inward/record.url?scp=85086356328&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85086356328&partnerID=8YFLogxK
U2 - 10.1126/sciadv.aax8847
DO - 10.1126/sciadv.aax8847
M3 - Article
C2 - 32523980
AN - SCOPUS:85086356328
SN - 2375-2548
VL - 6
SP - eaax8847
JO - Science Advances
JF - Science Advances
IS - 22
M1 - EAAX8847
ER -