Abstract
Focal cerebral ischemia is accompanied by inflammation, which further exacerbates injury. CD73 is an ectoenzyme with 5’-nucleotidase activity, which generates anti-inflammatory adenosine, from precursor AMP. In the CNS, CD73 is located on the choroid plexus cuboidal epithelium and on leptomeninges, two critical entry ports for anti- (M2) and pro-inflammatory (M1) macrophages, respectively. We previously showed that acute brain ischemia (48h) in CD73 -/- mice resulted in larger infarct volumes related to greater influx of M1 macrophages. Netrin-1 (Ntn-1) is secreted protein with leukorepulsive and neurite outgrowth- promoting properties. We hypothesized that macrophage influx is regulated by CD73 through its modulation of Ntn-1 expression after stroke. We examined the Ntn-1 expression in acute (24h) and delayed phases (7days) after induction of brain ischemia in wild type (WT) and CD73 -/- mice after photothrombotic middle cerebral artery occlusion. We demonstrated that Ntn-1 mRNA and protein expression was induced during the acute phase of brain ischemia, and suppressed in the delayed phase in WT compared to CD73 -/- mice. Netrin-1 mRNA expression at the 24 hr time point was higher in WT vs CD73 -/- mice (2.7 ± 0.2 vs 1.4 ± 0.4, respectively, p<0.05). However, 7 days following brain ischemia, Ntn-1 protein expression was suppressed in WT compared to CD73 -/- mice (0.4 ± 0.1 to 0.9 ± 0.2; p<0.03 respectively). In CD73 -/- mice, mRNA for CCR2 and IRF5 , were upregulated at day 7, whereas IRF4 the major polarization transcription factor for anti-inflammatory macrophages, was downregulated. These findings are consistent with the hypothesis that in acute stroke, CD73 acts to suppres influx of pro-inflammatory macrophages through induction of chemorepulsive Ntn-1 protein, but promotes influx of reparative macrophages by suppressing Ntn-1 expression at delayed phase of stroke. Our data are the first to identify a potential link between CD73 and Ntn-1 expressions in the ischemic brain, underscoring CD73 as an important modulator of the immune inflammatory response in stroke.
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