Research: Annexin 1 affects blood brain barrier

Epub: Cristante et al. Identification of an essential endogenous regulator of blood-brain barrier integrity, and its pathological and therapeutic implications. Proc Natl Acad Sci U S A. 2012 Dec 31.

The blood-brain barrier (BBB), a critical guardian of communication between the periphery and the brain, is frequently compromised in neurological diseases such as multiple sclerosis (MS), resulting in the inappropriate passage of molecules and leukocytes into the brain. Here we show that the glucocorticoid anti-inflammatory messenger annexin A1 (ANXA1) is expressed in brain microvascular endothelial cells, where it regulates BBB integrity. In particular, ANXA1(-/-) mice exhibit significantly increased BBB permeability as a result of disrupted interendothelial cell tight junctions, essentially related to changes in the actin cytoskeleton, which stabilizes tight and adherens junctions. This situation is reminiscent of early MS pathology, a relationship confirmed by our detection of a selective loss of ANXA1 in the plasma and cerebrovascular endothelium of patients with MS. Importantly, this loss is swiftly restored by i.v. administration of human recombinant ANXA1. Analysis in vitro confirms that treatment of cerebrovascular endothelial cells with recombinant ANXA1 restores cell polarity, cytoskeleton integrity, and paracellular permeability through inhibition of the small G protein RhoA. We thus propose ANXA1 as a critical physiological regulator of BBB integrity and suggest it may have utility in the treatment of MS, correcting BBB function and hence ameliorating disease.

Annexin A1 also known as lipocortin . It has been reported that lipocortin 1 is a molecule produced in response to steroid hormones and it was increased in lesions in animal models of MS and could decrease the severity of EAE. In this study it reports that Annexin 1 contributes to the integrity of the blood brain barrier, by facilitating the formation of impermeable, tight, junctions between cells by allowing the cell skeleton (actin) to change. Delivery of annexin increased the barrier function and we know this can inhibit white cell migration into the CNS. This is a therapeutic target upstream of RhoA a signalling molecule that allows actin (the cell skeleton to move). Whilst this may influence junctional proteins at the edge of the cells in the blood vessel wall, it allows the skeleton to move so that white cells can go through the blood cells cells, the junctions are too strong to facilitate this. This a therapeutic target as we have shown many moons ago with Rho inhibitors and statins, which would be downstream of Annexin1. However statins have not been that startling in suppressing BBB disfunction.

CoI: This work was done at Barts

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