β2 glycoprotein I participates in phagocytosis of apoptotic neurons and in vascular injury in experimental brain stroke
Open Access
- 14 January 2021
- journal article
- research article
- Published by SAGE Publications in Journal of Cerebral Blood Flow & Metabolism
- Vol. 41 (8), 2038-2053
- https://doi.org/10.1177/0271678x20984551
Abstract
Beta-2 Glycoprotein I (β2-GPI) is the main target of anti-phospholipid antibodies (aPL) in the autoimmune anti-phospholipid syndrome, characterized by increased risk of stroke. We here investigated the antibody independent role of β2-GPI after ischemia/reperfusion, modeled in vivo by transient middle cerebral artery occlusion (tMCAo) in male C57Bl/6J mice; in vitro by subjecting immortalized human brain microvascular endothelial cells (ihBMEC) to 16 h hypoxia and 4 h re-oxygenation. ApoH (coding for β2-GPI) was upregulated selectively in the liver at 48 h after tMCAo. At the same time β2-GPI circulating levels increased. β2-GPI was detectable in brain parenchyma and endothelium at all time points after tMCAo. Parenchymal β2-GPI recognized apoptotic neurons (positive for annexin V, C3 and TUNEL) cleared by CD68+ brain macrophages. Hypoxic ihBMEC showed increased release of IL-6, over-expression of thrombomodulin and IL-1α after re-oxygenation with β2-GPI alone. β2-GPI interacted with mannose-binding lectin in mouse plasma and ihBMEC medium, potentially involved in formation of thrombi. We show for the first time that brain ischemia triggers the hepatic production of β2-GPI. β2-GPI is present in the ischemic endothelium, enhancing vascular inflammation, and extravasates binding stressed neurons before their clearance by phagocytosis. Thus β2-GPI may be a new mediator of brain injury following ischemic stroke.Keywords
This publication has 60 references indexed in Scilit:
- Fiji: an open-source platform for biological-image analysisNature Methods, 2012
- Essential role of interleukin-6 in post-stroke angiogenesisBrain, 2012
- Interleukin-6, a Major Cytokine in the Central Nervous SystemInternational Journal of Biological Sciences, 2012
- Temporal pattern of expression and colocalization of microglia/macrophage phenotype markers following brain ischemic injury in miceJournal of Neuroinflammation, 2011
- Multiple Preconditioning Paradigms Converge on Interferon Regulatory Factor-Dependent Signaling to Promote Tolerance to Ischemic Brain InjuryJournal of Neuroscience, 2011
- Novel assays of thrombogenic pathogenicity in the antiphospholipid syndrome based on the detection of molecular oxidative modification of the major autoantigen β 2 ‐glycoprotein IArthritis & Rheumatism, 2011
- Autoantibodies Directed Against Domain I of Beta2-Glycoprotein ICurrent Rheumatology Reports, 2010
- Genetically-Defined Deficiency of Mannose-Binding Lectin Is Associated with Protection after Experimental Stroke in Mice and Outcome in Human StrokePLOS ONE, 2010
- International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS)Journal of Thrombosis and Haemostasis, 2006
- Involvement of p38 MAPK in the up‐regulation of tissue factor on endothelial cells by antiphospholipid antibodiesArthritis & Rheumatism, 2005