Type-I interferon signalling through IFNAR1 plays a deleterious role in the outcome after stroke

Neuroinflammation contributes significantly to the pathophysiology of stroke. Here we test the hypothesis that the type I interferon receptor (IFNARI) plays a critical role in neural injury after stroke by regulating the resultant pro-inflammatory environment. Wild-type and IFNARI(-/-) primary murine neurons and glia were exposed to oxygen glucose deprivation (OGD) and cell viability was assessed. Transient cerebral ischemia/reperfusion injury was induced by mid-cerebral artery occlusion (MCAO) in wild type and IFNAR1(-/-) and IFNAR2(-/-) mice in vivo, and infarct size, and molecular parameters measured. To block IFNARI signalling, wild-type mice were treated with a blocking monoclonal antibody directed to IFNAR1 (MAR-1) and MCAO was performed. Quantitative PCR confirmed MCAO in wild-type mice induced a robust type-I interferon gene regulatory signature. Primary cultured IFNAR1-deficient neurons were found to be protected from cell death when exposed to OGD in contrast to primary cultured IFNARI-deficient glial cells. IFNAR1(-/-) mice demonstrated a decreased infarct size(24.9 +/- 7.1 mm(3) n = 8) compared to wild-type controls (65.1 +/- 4.8 mm3 n = 8). Western blot and immunohistochemistry showed alterations in Akt and Stat-3 phosphorylation profiles in the IFNARI(-/-) brain. MAR-1 injection into WT mice (i.v. 0.5 mg 60 min prior to MCAO) resulted in a 60% decrease in infarct size when compared to the IgG control. IFNAR2(-/-) mice failed to display the neuroprotective phenotype seen in IFNAR1(-/-) mice after MCAO. Our data proposes that central nervous system signalling through IFNARI is a previously unrecognised factor that is critical to neural injury after stroke. (C) 2017 Elsevier Ltd. All rights reserved.