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

Moses Zhang, Catherine E Downes, Connie Wong, Kate M Brody, Pedro L. Guio-Agulair, Jodee Gould, Robert Ates, Paul J. Hertzog, Juliet M. Taylor, Peter J. Crack

Research output: Contribution to journalArticleResearchpeer-review

2 Citations (Scopus)

Abstract

Neuroinflammation contributes significantly to the pathophysiology of stroke. Here we test the hypothesis that the type I interferon receptor (IFNAR1) plays a critical role in neural injury after stroke by regulating the resultant pro-inflammatory environment. Wild-type and IFNAR1-/- 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 IFNAR1 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 IFNAR1-deficient glial cells. IFNAR1-/- mice demonstrated a decreased infarct size (24.9 ± 7.1 mm3 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 IFNAR1-/- 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 IFNAR1 is a previously unrecognised factor that is critical to neural injury after stroke.

Original languageEnglish
Pages (from-to)472-480
Number of pages9
JournalNeurochemistry International
Volume108
DOIs
Publication statusPublished - 1 Sep 2017

Cite this

Zhang, Moses ; Downes, Catherine E ; Wong, Connie ; Brody, Kate M ; Guio-Agulair, Pedro L. ; Gould, Jodee ; Ates, Robert ; Hertzog, Paul J. ; Taylor, Juliet M. ; Crack, Peter J. / Type-I interferon signalling through IFNAR1 plays a deleterious role in the outcome after stroke. In: Neurochemistry International. 2017 ; Vol. 108. pp. 472-480.
@article{ddccb0a07e104a259091502a4d59970e,
title = "Type-I interferon signalling through IFNAR1 plays a deleterious role in the outcome after stroke",
abstract = "Neuroinflammation contributes significantly to the pathophysiology of stroke. Here we test the hypothesis that the type I interferon receptor (IFNAR1) plays a critical role in neural injury after stroke by regulating the resultant pro-inflammatory environment. Wild-type and IFNAR1-/- 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 IFNAR1 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 IFNAR1-deficient glial cells. IFNAR1-/- mice demonstrated a decreased infarct size (24.9 ± 7.1 mm3 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 IFNAR1-/- 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 IFNAR1 is a previously unrecognised factor that is critical to neural injury after stroke.",
author = "Moses Zhang and Downes, {Catherine E} and Connie Wong and Brody, {Kate M} and Guio-Agulair, {Pedro L.} and Jodee Gould and Robert Ates and Hertzog, {Paul J.} and Taylor, {Juliet M.} and Crack, {Peter J.}",
year = "2017",
month = "9",
day = "1",
doi = "10.1016/j.neuint.2017.06.009",
language = "English",
volume = "108",
pages = "472--480",
journal = "Neurochemistry International",
issn = "0197-0186",
publisher = "Elsevier",

}

Zhang, M, Downes, CE, Wong, C, Brody, KM, Guio-Agulair, PL, Gould, J, Ates, R, Hertzog, PJ, Taylor, JM & Crack, PJ 2017, 'Type-I interferon signalling through IFNAR1 plays a deleterious role in the outcome after stroke', Neurochemistry International, vol. 108, pp. 472-480. https://doi.org/10.1016/j.neuint.2017.06.009

Type-I interferon signalling through IFNAR1 plays a deleterious role in the outcome after stroke. / Zhang, Moses; Downes, Catherine E; Wong, Connie; Brody, Kate M; Guio-Agulair, Pedro L.; Gould, Jodee; Ates, Robert; Hertzog, Paul J.; Taylor, Juliet M.; Crack, Peter J.

In: Neurochemistry International, Vol. 108, 01.09.2017, p. 472-480.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Type-I interferon signalling through IFNAR1 plays a deleterious role in the outcome after stroke

AU - Zhang, Moses

AU - Downes, Catherine E

AU - Wong, Connie

AU - Brody, Kate M

AU - Guio-Agulair, Pedro L.

AU - Gould, Jodee

AU - Ates, Robert

AU - Hertzog, Paul J.

AU - Taylor, Juliet M.

AU - Crack, Peter J.

PY - 2017/9/1

Y1 - 2017/9/1

N2 - Neuroinflammation contributes significantly to the pathophysiology of stroke. Here we test the hypothesis that the type I interferon receptor (IFNAR1) plays a critical role in neural injury after stroke by regulating the resultant pro-inflammatory environment. Wild-type and IFNAR1-/- 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 IFNAR1 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 IFNAR1-deficient glial cells. IFNAR1-/- mice demonstrated a decreased infarct size (24.9 ± 7.1 mm3 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 IFNAR1-/- 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 IFNAR1 is a previously unrecognised factor that is critical to neural injury after stroke.

AB - Neuroinflammation contributes significantly to the pathophysiology of stroke. Here we test the hypothesis that the type I interferon receptor (IFNAR1) plays a critical role in neural injury after stroke by regulating the resultant pro-inflammatory environment. Wild-type and IFNAR1-/- 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 IFNAR1 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 IFNAR1-deficient glial cells. IFNAR1-/- mice demonstrated a decreased infarct size (24.9 ± 7.1 mm3 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 IFNAR1-/- 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 IFNAR1 is a previously unrecognised factor that is critical to neural injury after stroke.

UR - http://www.scopus.com/inward/record.url?scp=85021811038&partnerID=8YFLogxK

U2 - 10.1016/j.neuint.2017.06.009

DO - 10.1016/j.neuint.2017.06.009

M3 - Article

VL - 108

SP - 472

EP - 480

JO - Neurochemistry International

JF - Neurochemistry International

SN - 0197-0186

ER -