Neutrophil extracellular traps exacerbate neurological deficits after traumatic brain injury.

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.

journal_name

Sci Adv

journal_title

Science advances

authors

Vaibhav K,Braun M,Alverson K,Khodadadi H,Kutiyanawalla A,Ward A,Banerjee C,Sparks T,Malik A,Rashid MH,Khan MB,Waters MF,Hess DC,Arbab AS,Vender JR,Hoda N,Baban B,Dhandapani KM

doi

10.1126/sciadv.aax8847

subject

Has Abstract

pub_date

2020-05-29 00:00:00

pages

eaax8847

issue

22

issn

2375-2548

pii

aax8847

journal_volume

6

pub_type

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