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.