β2 glycoprotein I participates in phagocytosis of apoptotic neurons and in vascular injury in experimental brain stroke

Claudia Grossi, Carolina Artusi, Pier Luigi Meroni, Maria Orietta Borghi, Laura Neglia, Paola Adele Lonati, Marco Oggioni, Francesco Tedesco, Maria Grazia De Simoni, Stefano Fumagalli

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)2038-2053
Number of pages16
JournalJournal of Cerebral Blood Flow and Metabolism
Volume41
Issue number8
DOIs
Publication statusPublished - Aug 2021

Keywords

  • Brain ischemia
  • complement system
  • mannose-binding lectin
  • thromboinflammation
  • β2 glycoprotein I

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

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