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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


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Woodcock, TM, Frugier, T, Nguyen, TT, Semple, BD, Bye, N ORCID: 0000-0003-0976-5870, Massara, M, Savino, B, Besio, R, Sobacchi, C, Locati, M and Morganti-Kossmann, MC 2017 , 'The scavenging chemokine receptor ACKR2 has a significant impact on acute mortality rate and early lesion development after traumatic brain injury' , PLoS one, vol. 12, no. 11 , pp. 1-21 , doi: 10.1371/journal.pone.0188305.

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The atypical chemokine receptor ACKR2 promotes resolution of acute inflammation byoperating as a scavenger receptor for inflammatory CC chemokines in several experimentalmodels of inflammatory disorders, however its role in the brain remains unclear. Based onour previous reports of increased expression of inflammatory chemokines and their correspondingreceptors following traumatic brain injury (TBI), we hypothesised that ACKR2modulates neuroinflammation following brain trauma and that its deletion exacerbates cellularinflammation and chemokine production. We demonstrate increased CCL2 and ACKR2mRNA expression in post-mortem human brain, whereby ACKR2 mRNA levels correlatedwith later times post-TBI. This data is consistent with the transient upregulation of ACKR2observed 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 insurviving mice was similar. At day 1 post-injury, ACKR2-/- mice displayed aggravated lesionvolume and no differences in CCL2 expression and macrophage recruitment relative to WTmice. 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. ACKR2mRNA increased as early as 2 hours after an inflammatory challenge in WT astrocytes. Asexpected, CCL2 expression also dramatically increased at 4 hours in WT astrocytes butwas significantly lower in ACKR2-/- astrocytes, possibly indicating a co-regulation of CCL2and ACKR2 in these cells. Conversely, in vivo, CCL2 mRNA/protein levels were increasedsimilarly in ACKR2-/- and WT brains at 4 and 12 hours after CHI, in line with the lack of differencesin cerebral macrophage recruitment and neurological recovery. In conclusion,ACKR2 is induced after TBI and has a significant impact on mortality and lesion developmentacutely following CHI, while its role in chemokine expression, macrophage activation,brain pathology, and neurological recovery at later time-points is minor. Concordant to evidencein multiple sclerosis experimental models, our data corroborate a distinct role forACKR2 in cerebral inflammatory processes compared to its reported functions in peripheraltissues.

Item Type: Article
Authors/Creators: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
Keywords: traumatic brain injury, neuroinflammation, chemokine receptor ACKR2
Journal or Publication Title: PLoS one
Publisher: Public Library of Science
ISSN: 1932-6203
DOI / ID Number: 10.1371/journal.pone.0188305
Copyright Information:

Copyright 2017 Woodcock et al. Licensed under Creative Commons Attribution 4.0 International (CC BY 4.0)

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