title: Estrogen protects the blood-brain barrier from inflammation-induced disruption and increased lymphocyte trafficking.
abstract: Sex differences have been widely reported in neuroinflammatory disorders, focusing on the contributory role of estrogen. The microvascular endothelium of the brain is a critical component of the blood-brain barrier (BBB) and it is recognized as a major interface for communication between the periphery and the brain. As such, the cerebral capillary endothelium represents an important target for the peripheral estrogen neuroprotective functions, leading us to hypothesize that estrogen can limit BBB breakdown following the onset of peripheral inflammation. Comparison of male and female murine responses to peripheral LPS challenge revealed a short-term inflammation-induced deficit in BBB integrity in males that was not apparent in young females, but was notable in older, reproductively senescent females. Importantly, ovariectomy and hence estrogen loss recapitulated an aged phenotype in young females, which was reversible upon estradiol replacement. Using a well-established model of human cerebrovascular endothelial cells we investigated the effects of estradiol upon key barrier features, namely paracellular permeability, transendothelial electrical resistance, tight junction integrity and lymphocyte transmigration under basal and inflammatory conditions, modeled by treatment with TNFα and IFNγ. In all cases estradiol prevented inflammation-induced defects in barrier function, action mediated in large part through up-regulation of the central coordinator of tight junction integrity, annexin A1. The key role of this protein was then further confirmed in studies of human or murine annexin A1 genetic ablation models. Together, our data provide novel mechanisms for the protective effects of estrogen, and enhance our understanding of the beneficial role it plays in neurovascular/neuroimmune disease.
authors: William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
authors: E
authors: E
authors: Maggioli
authors: William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK; Department of Biomedical Sciences, Faculty of Science & Technology, University of Westminster, New Cavendish Street, London W1W 6UW, UK.
authors: S
authors: S
authors: McArthur
authors: William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
authors: C
authors: C
authors: Mauro
authors: William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
authors: J
authors: J
authors: Kieswich
authors: Cardiovascular Research Institute, Department of Biochemistry, Maastricht University, 6200 Maastricht, The Netherlands; Department of Pathology, University of Michigan Health System, 109 Zina Pitcher Place, 4062 BSRB, Ann Arbor, MI 48109-2200, United States.
authors: D H M
authors: DHM
authors: Kusters
authors: Cardiovascular Research Institute, Department of Biochemistry, Maastricht University, 6200 Maastricht, The Netherlands.
authors: C P M
authors: CPM
authors: Reutelingsperger
authors: William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
authors: M
authors: M
authors: Yaqoob
authors: William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK. Electronic address: e.solito@qmul.ac.uk.
authors: E
authors: E
authors: Solito
mesh_terms: D000818:Animals; D017305:Annexin A1 / Q000008:administration & dosage / Q000502:physiology*; D001812:Blood-Brain Barrier / Q000276:immunology* / Q000378:metabolism*; D002465:Cell Movement / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004958:Estradiol / Q000008:administration & dosage / Q000502:physiology*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology* / Q000503:physiopathology*; D008070:Lipopolysaccharides; D008214:Lymphocytes / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008810:Mice, Inbred C57BL; D011960:Receptors, Estrogen / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism
chemical_list: D017305:Annexin A1; D016207:Cytokines; C532507:GPER1 protein, mouse; D008070:Lipopolysaccharides; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D004958:Estradiol
keywords: Annexin A1; Blood–brain barrier; Estrogen; Lymphocytes; Tight junction