Β2 glycoprotein I participates in phagocytosis of apoptotic neurons and in vascular injury in experimental brain stroke. Issue 8 (August 2021)

• Record Type: Journal Article
• Authors: Grossi, Claudia; Artusi, Carolina; Meroni, PierLuigi; Borghi, Maria Orietta; Neglia, Laura; Lonati, Paola Adele; Oggioni, Marco; Tedesco, Francesco; De Simoni, Maria-Grazia; Fumagalli, Stefano
• Is Part Of: Journal of cerebral blood flow & metabolism. Volume 41:Issue 8(2021)
• Page Start: 2038
• Page End: 2053
• Publication Date: 2021-08
• Subjects: Brain ischemia -- β2 glycoprotein I -- complement system -- thromboinflammation -- mannose-binding lectin; Cerebral circulation -- Periodicals; Brain -- Metabolism -- Periodicals; Brain -- Blood-vessels -- Periodicals; Cerebrovascular disease -- Periodicals; 612.824
• DOI: 10.1177/0271678X20984551
• Languages: English
• ISSNs: 0271-678X

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.