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 recognised 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 hypothesise 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, modelled by treatment with TNFα and IFNγ. In all cases estradiol prevented inflammationinduced 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.

Increased blood-brain barrier permeability in contralateral hemisphere predicts worse outcome in acute ischemic stroke after reperfusion therapy

“…Females had lower BBBP in our study, which was consistent with a previous study 9. An animal study demonstrated estradiol could prevent inflammation-induced tight junction breakdown by regulating inter-endothelial cell permeability and limiting the transmigration of lymphocyte 28. Hence, females might benefit from the protective effect of estradiol on BBB.…”

Role of the protein annexin A1 on the efficacy of anti-TNF treatment in a murine model of acute colitis

“…The exact mechanism of AnxA1 on IFX effects is not well understood, but a prominent role of AnxA1 on epithelial integrity is hypothesized, as AnxA1 promotes proliferation and migration of epithelial cells, playing an important role in tissue regeneration [19,20]. Moreover, this supports tight junction integrity, such as in the bloodbrain-barrier [28][29][30]. Furthermore, we speculate that the preservation of the epithelial layer by IFX is not related to the direct blockade of the pro-inflammatory actions of TNF-a on the epithelial cells, but instead is indirectly linked with the AnxA1 action in protecting the mucosal histoarchitecture [19,20].…”

Sex differences in the peripheral and central immune responses following lipopolysaccharide treatment in pubertal and adult CD‐1 mice

“…Estrogen targets the BBB by exerting protective effects (Burek et al, 2010, 2014; Suzuki et al, 2006) such as up‐regulating proteins involved in tight junction expression. This thereby limits barrier permeability (Maggioli et al, 2016; Nadkarni and McArthur, 2013). Whether the females in the current study display higher up‐regulation of tight junction proteins relative to their male counterparts warrants further investigation.…”