Proteomic Analysis of Human Cerebral Endothelial Cells Activated by Multiple Sclerosis Serum and IFNβ-1b

Alexander, J. Steven; Minagar, Alireza; Harper, Michael; Robinson-Jackson, Sherry A.; Jennings, Merilyn H.; Smith, Stacy J.

doi:10.1007/s12031-007-0018-3

Cited by 32 publications

(30 citation statements)

References 44 publications

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“…At present, the reasons for this difference are unclear, but may reflect a brain-intrinsic source of degeneration and inflammation in Parkinson and Alzheimer's disease, as opposed to the inappropriate activation of the peripheral immune system seen in the autoimmune disease MS. This idea is indirectly supported by independent previous reports indicating that serum from patients with MS can decrease transendothelial resistance in vitro (37), and that such serum can induce a downregulation in ANXA1 among other proteins (38). Our data confirm and extend these two studies, not only providing a clear rationale for a correlation between ANXA1 expression and changes in BBB permeability in MS, but also revealing a potential therapeutic strategy aimed at reversing the defect in BBB function seen in MS.…”

Section: Discussionsupporting

confidence: 89%

Identification of an essential endogenous regulator of blood–brain barrier integrity, and its pathological and therapeutic implications

Cristante

McArthur

Mauro

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

173

218

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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.T he presence of narrow and dense tight junctions between adjacent endothelial cells is peculiar to the cerebral vasculature, and their integrity is essential for the maintenance of correct blood-brain barrier (BBB) function as the primary regulator of cross-talk between the brain and the rest of the body (1). Increasing evidence indicates that the integrity of this structural and functional barrier is compromised in neurological conditions such as multiple sclerosis (MS), Alzheimer's, and Parkinson diseases, leading to the failure of the normal mechanisms controlling passage of substances into the brain (2) and to the sensitization and/or worsening of pathologic conditions. Pharmacological intervention to prevent or correct BBB alteration in such diseases is a difficult task, but potential therapeutic leads can be gained from the study of endogenous mediators regulating barrier integrity.Annexin A1 (ANXA1) is an important anti-inflammatory protein, principally known as a regulator of peripheral leukocyte migration and a promoter of macrophage phagocytosis (3). ANXA1 is expressed in several cell types within the brain, including ependyma and microglia, but in particular in the endothelium of the brain microvasculature (4), although its role in these cells remains obscure. We have previously shown glucocorticoids to up-regulate expression of ANXA1 in the cerebral endothelium (5), and, given that glucocorticoids enhance BBB tightness (6), we hypothesized that ANXA1 may play a role in the regulation of BBB permeability. Through combined in vitro and in vivo approaches, we have identified a dual role for ANXA1 in organizing the interendothelial cell...

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Section: Discussionsupporting

confidence: 89%

Identification of an essential endogenous regulator of blood–brain barrier integrity, and its pathological and therapeutic implications

Cristante

McArthur

Mauro

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

173

218

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“…-binding ability and is found mainly in the ER, similar to other CREC family proteins that have been associated with a number of human diseases including cancer and neuromuscular-cardiovascular disease (Honore 2009). It has been shown also that RCN3 is up-regulated in endothelial cells activated by multiple sclerosis serum (Alexander et al 2007) and accumulates in GH4C1 cells when overexpressing the a1-antitrypsin RVRR variant, an inhibitor of PACE4, which belongs to the SPC (subtilisin-like proprotein convertase) family (Tsuji et al 2006). Furthermore, RCN3 possesses chaperone activity toward the proPACE4 (the precursor of PACE4) protein through a direct association.…”

Section: Discussionmentioning

confidence: 99%

Characterization of the role of protein–cysteine residues in the binding with sodium arsenite

Kuo

Hsu

et al. 2012

Arch Toxicol

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“…These are small (∼30 kDa) acidic proteins normally expressed by neurons within the CNS and astrocytes (Kawamoto et al 2006). We previously demonstrated that cerebral endothelial cells expressed 14-3-3 protein in response to treatment with serum patients with active MS (relapsing) disease (Alexander et al 2007). In our current study, the expression of epsilon isoform of 14-3-3 was also decreased in cerebral endothelial cells in response to incubation with 1 and 10 mM glutamate.…”

Section: Discussionmentioning

confidence: 99%

Proteomic Analysis of Human Cerebral Endothelial Cells Activated by Glutamate/MK-801: Significance in Ischemic Stroke Injury

et al. 2008

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Glutamate is a major excitatory neurotransmitter in the central nervous system and plays a significant role in the pathophysiology of ischemic stroke. During acute ischemic cerebrovascular disease, glutamate efflux in the CNS produces excitotoxicity in neurons and may mediate forms of stress in other tissues expressing glutamate ionotropic (N-methyl-D-aspartate (NMDA)) receptors, e.g., cerebral endothelial cells. While endothelial cell stress in response to glutamate has been reported (oxidant stress, loss of barrier function), changes in protein expression produced by glutamate (an agonist of metabotropic and NMDA receptors) have not been documented. Here, we have examined how exposure of human cerebral endothelial cells to glutamate, in the presence and absence of the NMDA receptor antagonist MK-801, can alter the proteomic profile of cerebral endothelial cells. We found several important changes in the proteins expressed by cerebral endothelial cells in response to glutamate. Interestingly, MK-801 itself had some direct effects on cerebral endothelial cells. Taken together, our findings demonstrate that cerebral endothelial cells respond to glutamate by altering their protein expression profile. We assume that protein alterations found in the cerebral endothelial proteome, in response to glutamate and which were blocked by MK-801, may be important vascular targets in better understanding the pathogenesis of ischemic stroke.

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Proteomic Analysis of Human Cerebral Endothelial Cells Activated by Multiple Sclerosis Serum and IFNβ-1b

Cited by 32 publications

References 44 publications

Identification of an essential endogenous regulator of blood–brain barrier integrity, and its pathological and therapeutic implications

Identification of an essential endogenous regulator of blood–brain barrier integrity, and its pathological and therapeutic implications

Characterization of the role of protein–cysteine residues in the binding with sodium arsenite

Proteomic Analysis of Human Cerebral Endothelial Cells Activated by Glutamate/MK-801: Significance in Ischemic Stroke Injury

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