Estrogen protects the blood–brain barrier from inflammation-induced disruption and increased lymphocyte trafficking

Maggioli, E., McArthur, S., Mauro, C., Kieswich, J., Kusters, D.H.M., Reutelingsperger, C.P.M., Yaqoob, M.M. and Solito, E. 2015. Estrogen protects the blood–brain barrier from inflammation-induced disruption and increased lymphocyte trafficking. Brain Behavior & Immunity. 51, p. 212–222. doi:10.1016/j.bbi.2015.08.020

TitleEstrogen protects the blood–brain barrier from inflammation-induced disruption and increased lymphocyte trafficking
AuthorsMaggioli, E., McArthur, S., Mauro, C., Kieswich, J., Kusters, D.H.M., Reutelingsperger, C.P.M., Yaqoob, M.M. and Solito, E.
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.

KeywordsBlood–brain barrier; Estrogen; Tight junction; Annexin A1; Lymphocytes
JournalBrain Behavior & Immunity
Journal citation51, p. 212–222
ISSN 0889-1591
Year2015
PublisherElsevier
Accepted author manuscriptMaggioli_etal_2015.pdf
Digital Object Identifier (DOI)doi:10.1016/j.bbi.2015.08.020
Publication dates
Published29 Aug 2015
PublishedJan 2016

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