Neutrophil extracellular traps exacerbate neurological deficits after traumatic brain injury

Kumar Vaibhav, Molly Braun, Katelyn Alverson, Hesam Khodadadi, Ammar Kutiyanawalla, Ayobami Ward, Christopher Banerjee, Tyler Sparks, Aneeq Malik, Mohammad H. Rashid, Mohammad H. Rashid, Mohammad Badruzzaman Khan, Michael F. Waters, David C. Hess, Ali S. Arbab, John R. Vender, Nasrul Hoda, Nasrul Hoda, Nasrul Hoda, Babak BabanBabak Baban, Babak Baban, Krishnan M. Dhandapani

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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, 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.

Original languageEnglish (US)
Article numberEAAX8847
JournalScience Advances
Volume6
Issue number22
DOIs
StatePublished - May 2020

ASJC Scopus subject areas

  • General

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