Interferon-beta-1b protects against multiple sclerosis-induced endothelial cells apoptosis (original) (raw)
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Background & Aims: Multiple sclerosis (MS) is one of the chronic autoimmune diseases of the central nervous system with unknown etiology. The present study aimed to investigate the apoptosis and nitric oxide (NO) production of endothelial cells treated with serum of patients with MS and response to interferon beta (IFN-) therapy. Methods: Human umbilical vein endothelial cells were treated with sera from patients with active MS (in relapse), MS in remission, or sera from healthy volunteers (each n = 10). Nitric oxide (NO) levels were determined in culture supernatants by Greiss method and endothelial cell apoptosis was assessed by annexin V-propidium iodide staining. Effects of IFN-beta-1b on endothelial cell apoptosis and NO production were tested at increasing doses (10, 100, and 1000 U/ml). Results: Compared with healthy people, only apoptosis of endothelial cells treated with serum of patients with relapsing phase increased, P<0.01; while there was no significant difference between apoptosis of endothelial cells treated with serum of patients in remission phase and healthy controls. Apoptosis of endothelial cells treated with sera of patients in relapse was decreased by IFN-beta-1b at 10 U/ml, P<0.05. The same dose also led to a significant increase in nitric oxide production. Conclusion: The results suggest that endothelial cells injury and apoptosis may play a role in MS etiology and represents a potential therapeutic mechanism of action for IFN-beta-1b in MS therapy.
Multiple sclerosis as a vascular disease
Neurological Research, 2006
Multiple sclerosis (MS) has traditionally been viewed and researched as an immune-mediated disease with principal emphasis on the role of activated inflammatory cells, oligodendrocytes and astrocytes in its pathogenesis. Abnormalities of cerebral endothelial cells (CECs) is an under explored facet of MS pathogenesis and vascular abnormalities play a crucial role in formation of the MS lesions and disease progress, at least in the initial stages of disease. This review will focus on MS as a central nervous system (CNS) disease with a strong vascular constituent and examines abnormalities within CECs in MS and their role in the loss of blood-brain barrier and transendothelial migration of activated leukocytes into the CNS. One goal of this paper is to persuade and promote research on the endothelial abnormalities in pathogenesis of MS and to exploit existing knowledge on endothelial injury. A deeper understanding of endothelial pathophysiology in MS may help develop effective treatments through stabilization of endothelial function, translating into delay or arrest of MS disease onset and disability in MS patients.
Multiple sclerosis and cerebral endothelial dysfunction: Mechanisms
Pathophysiology, 2011
Multiple sclerosis (MS) is believed to be an immune-mediated neurodegenerative disorder of the human central nervous system which usually affects younger adults with certain genetic backgrounds. The causes and cure for MS remain elusive. Based on the recent advances in our understanding of the pathogenic mechanisms of MS, it appears to represents a heterogeneous group of disorders with dissimilar pathophysiology and neuropathology. Currently, there is no unifying hypothesis to explain the pathogenesis of this complex disease. The three prevailing concepts on the pathogenesis of MS include viral, immunological, and vascular hypotheses. This review presents MS as a neuroinflammatory disease with a significant vascular component and examines the existing evidence for the role of cerebral endothelial cell dysfunction in the pathogenesis of this progressive central nervous system (CNS) inflammatory disorder.
Emerging roles of endothelial cells in multiple sclerosis pathophysiology and therapy
Neurological Research, 2012
Although multiple sclerosis (MS) has traditionally been viewed and researched as an immune-mediated demyelinating and neurodegenerative disease of the human central nervous system (CNS), its highly complex pathogenesis clearly includes a significant vascular inflammatory component and many therapeutic approaches achieve benefit by direct or indirect effects on cerebrovascular endothelial cells. Cerebral endothelial cells create and separate the compartments of the peripheral circulation and CNS creating the blood-brain barrier (BBB), a selectively permeable boundary layer between these spaces. Interactions between activated leukocytes and cerebral endothelium play essential roles in mediating their trans-BBB diapedesis during normal immune surveillance and during pathogenesis of neuroinflammatory diseases like MS. Extravasation of activated and committed leukocytes from the peripheral circulation through the endothelial layer of the BBB into the CNS milieu is the most fundamental step in formation of MS lesions. During MS pathogenesis, once the activated leukocytes enter the CNS environment, they propagate a massive wave of destruction which culminates in the loss of both myelin/oligodendrocyte complex and neurodegeneration. Multiple clinical and basic scientific observations support endothelial cell 'stress' and apoptosis as a hallmark characteristic of MS. The manipulation of the endothelial biology aiming to block trans-endothelial migration of activated immune cells into the CNS is a potent form of treatment for MS achieving significant reductions in disease activity and new lesion formation. In particular, endothelial microparticles are now well-recognized as important biomarkers and mediators of this type of stress. In this review, we discuss recent findings and new advances in our knowledge regarding leukocyte migration through the endothelial frontier of the BBB and how this can be exploited toward treating MS patients.
Neuron, 2003
Neurological 3-to 4-fold risk for MS. Other genes within the HLA Sciences complex, including tumor necrosis factor (TNF)-␣, com-Beckman Center for Molecular Medicine ponents of the complement cascade, and myelin oligo-Stanford University dendrocyte glycoprotein (MOG), are also involved in MS Stanford, California 94305 pathogenesis. However, genes outside the HLA complex also contribute to MS pathogenesis. In fact, genome-based studies of multiplex MS families (more than Multiple sclerosis (MS) is an autoimmune central nerone family member affected) indicate that 10 to 15 chovous system (CNS) demyelinating disease that causes mosomal loci contribute to MS susceptibility. Multiple relapsing and chronic neurologic impairment. Recent genes acting in concert may elevate the risk for MS. observations have altered certain traditional concepts Myelin-Specific CD4 ؉ T Cells Initiate regarding MS pathogenesis. A greater diversity of cell CNS Inflammation types and molecules involved in MS is now evident.
SVOA Neurology, 2022
Authors: Manik Mathur, Bruno Gran, Radu Tanasescu, Cris S. Constantinescu, Ulvi Bayraktutan Abstract: Background: Breakdown of the blood-brain barrier (BBB) constitutes a key step in the pathogenesis of multiple sclerosis (MS). Aims: To investigate whether sera from MS patients in relapse or in remission may differently affect the BBB function and to assesses the putative barrier-restorative effects of major molecular mechanisms known to regulate BBB function. Methods: Sera were prepared by centrifugation of the whole blood samples of the study participants. A cell culture model of human BBB, consisting of human brain microvascular endothelial cells, astrocytes and pericytes, was established using transwell inserts. The integrity and function of BBB were studied by measurements of transendothelial electrical resistance (TEER) and paracellular flux of Evan's blue-labelled albumin (EBA), respectively. Results: Sera from MS patients in relapse possessed greater levels of inflammatory cytokines (TNF- and IL-1 ), apoptotic enzyme activity (caspase-3/7) and were more disruptive of BBB as evidenced by significant decreases in TEER and increases in EBA flux. Suppression of intracellular availability of reactive oxygen species or NADPH oxidase, Rho-kinase, protein kinase C- and matrix metalloproteinase-2 activity by specific inhibitors markedly attenuated the BBBdisruptive effects of sera obtained from MS patients in relapse or remission. Conclusions: A plethora of mechanisms affecting the overall status of oxidative stress, inflammation, cell viability and basement membrane integrity appear to contribute to the BBB damage in MS patients, especially those in relapse. Effective inhibition of the key elements associated with these mechanisms mitigate the deleterious effects of MS patients' sera on BBB integrity and function.
Cell Death & Disease, 2019
The blood-brain barrier (BBB) has a major role in maintaining brain homeostasis through the specialized function of brain endothelial cells (BECs). Inflammation of the BECs and loss of their neuroprotective properties is associated with several neurological disorders, including the chronic neuro-inflammatory disorder multiple sclerosis (MS). Yet, the underlying mechanisms of a defective BBB in MS remain largely unknown. Endothelial to mesenchymal transition (EndoMT) is a pathophysiological process in which endothelial cells lose their specialized function and de-differentiate into mesenchymal cells. This transition is characterized by an increase in EndoMT-related transcription factors (TFs), a downregulation of brain endothelial markers, and an upregulation of mesenchymal markers accompanied by morphological changes associated with cytoskeleton reorganization. Here, we postulate that EndoMT drives BEC dedifferentiation, mediates inflammation-induced human BECs dysfunction, and may play a role in MS pathophysiology. We provide evidence that stimulation of human BECs with transforming growth factor (TGF)-β1 and interleukin (IL)-1β promotes EndoMT, a process in which the TF SNAI1, a master regulator of EndoMT, plays a crucial role. We demonstrate the involvement of TGF-β activated kinase 1 (TAK1) in EndoMT induction in BECs. Finally, immunohistochemical analysis revealed EndoMT-associated alterations in the brain vasculature of human postmortem MS brain tissues. Taken together, our novel findings provide a better understanding of the molecular mechanisms underlying BECs dysfunction during MS pathology and can be used to develop new potential therapeutic strategies to restore BBB function.
Blood-brain barrier disruption in multiple sclerosis
Multiple Sclerosis, 2003
The blood-brain barrier (BBB) is a complex organization of cerebral endothelial cells (C EC), pericytes and their basal lamina, which are surrounded and supported by astrocytes and perivascular macrophages. C ollectively these cells separate and form the compartments of the cerebral vascular space and the cerebral interstitium under normal conditions. Without the BBB, the ‘interior milieu’ of the central nervous system (CNS) would be flooded by humoral neurotransmitters and formed blood elements that upset normal C NS functions and lead to vascular/neural injury. Dysregulation of the BBB and transendo thelial migration of activated leukocytes are among the earliest cerebrovascular abnormalities seen in multiple sclerosis (MS) brains and parallel the release of inflammatory cytokines/chemokines. Mechanisms for breakdown of the BBB in MS are incompletely understood, but appear to involve direct effects of these cytokines/chemokines on endothelial regulation of BBB components, as well ...
2021
The disruption of blood–brain barrier (BBB) for multiple sclerosis (MS) pathogenesis has a double effect: early on during the onset of the immune attack and later for the CNS self-sustained ‘inside-out’ demyelination and neurodegeneration processes. This review presents the characteristics of BBB malfunction in MS but mostly highlights current developments regarding the impairment of the neurovascular unit (NVU) and the metabolic and mitochondrial dysfunctions of the BBB’s endothelial cells. The hypoxic hypothesis is largely studied and agreed upon recently in the pathologic processes in MS. Hypoxia in MS might be produced per se by the NVU malfunction or secondary to mitochondria dysfunction. We present three different but related terms that denominate the ongoing neurodegenerative process in progressive forms of MS that are indirectly related to BBB disruption: progression independent of relapses, no evidence of disease activity and smoldering demyelination or silent progression. ...