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The scavenging chemokine receptor ACKR2 has a significant impact on acute mortality rate and early lesion development after traumatic brain injury
Citation
Woodcock, TM and Frugier, T and Nguyen, TT and Semple, BD and Bye, N and Massara, M and Savino, B and Besio, R and Sobacchi, C and Locati, M and Morganti-Kossmann, MC, The scavenging chemokine receptor ACKR2 has a significant impact on acute mortality rate and early lesion development after traumatic brain injury, PLoS one, 12, (11) Article e0188305. ISSN 1932-6203 (2017) [Refereed Article]
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Copyright Statement
Copyright 2017 Woodcock et al. Licensed under Creative Commons Attribution 4.0 International (CC BY 4.0) https://creativecommons.org/licenses/by/4.0/
DOI: doi:10.1371/journal.pone.0188305
Abstract
The atypical chemokine receptor ACKR2 promotes resolution of acute inflammation by
operating as a scavenger receptor for inflammatory CC chemokines in several experimental
models of inflammatory disorders, however its role in the brain remains unclear. Based on
our previous reports of increased expression of inflammatory chemokines and their corresponding
receptors following traumatic brain injury (TBI), we hypothesised that ACKR2
modulates neuroinflammation following brain trauma and that its deletion exacerbates cellular
inflammation and chemokine production. We demonstrate increased CCL2 and ACKR2
mRNA expression in post-mortem human brain, whereby ACKR2 mRNA levels correlated
with later times post-TBI. This data is consistent with the transient upregulation of ACKR2
observed in mouse brain after closed head injury (CHI). As compared to WT animals,
ACKR2-/-mice showed a higher mortality rate after CHI, while the neurological outcome in
surviving mice was similar. At day 1 post-injury, ACKR2-/- mice displayed aggravated lesion
volume and no differences in CCL2 expression and macrophage recruitment relative to WT
mice. Reciprocal regulation of ACKR2 and CCL2 expression was explored in cultured astrocytes,
which are recognized as the major source of CCL2 and also express ACKR2. ACKR2
mRNA increased as early as 2 hours after an inflammatory challenge in WT astrocytes. As
expected, CCL2 expression also dramatically increased at 4 hours in WT astrocytes but
was significantly lower in ACKR2-/- astrocytes, possibly indicating a co-regulation of CCL2
and ACKR2 in these cells. Conversely, in vivo, CCL2 mRNA/protein levels were increased
similarly in ACKR2-/- and WT brains at 4 and 12 hours after CHI, in line with the lack of differences
in cerebral macrophage recruitment and neurological recovery. In conclusion,
ACKR2 is induced after TBI and has a significant impact on mortality and lesion development
acutely following CHI, while its role in chemokine expression, macrophage activation,
brain pathology, and neurological recovery at later time-points is minor. Concordant to evidence
in multiple sclerosis experimental models, our data corroborate a distinct role for
ACKR2 in cerebral inflammatory processes compared to its reported functions in peripheral
tissues.
Item Details
Item Type: | Refereed Article |
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Keywords: | traumatic brain injury, neuroinflammation, chemokine receptor ACKR2 |
Research Division: | Biomedical and Clinical Sciences |
Research Group: | Neurosciences |
Research Field: | Central nervous system |
Objective Division: | Health |
Objective Group: | Clinical health |
Objective Field: | Clinical health not elsewhere classified |
UTAS Author: | Bye, N (Dr Nicole Bye) |
ID Code: | 123973 |
Year Published: | 2017 |
Web of Science® Times Cited: | 9 |
Deposited By: | Pharmacy |
Deposited On: | 2018-02-05 |
Last Modified: | 2018-03-22 |
Downloads: | 86 View Download Statistics |
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