NADPH oxidase expression in active multiple sclerosis lesions in relation to oxidative tissue damage and mitochondrial injury
نویسندگان
چکیده
Multiple sclerosis is a chronic inflammatory disease of the central nervous system, associated with demyelination and neurodegeneration. The mechanisms of tissue injury are poorly understood, but recent data suggest that mitochondrial injury may play an important role in this process. Mitochondrial injury can be triggered by reactive oxygen and nitric oxide species, and we recently provided evidence for oxidative damage of oligodendrocytes and dystrophic axons in early stages of active multiple sclerosis lesions. In this study, we identified potential sources of reactive oxygen and nitrogen species through gene expression in carefully staged and dissected lesion areas and by immunohistochemical analysis of protein expression. Genome-wide microarrays confirmed mitochondrial injury in active multiple sclerosis lesions, which may serve as an important source of reactive oxygen species. In addition, we found differences in the gene expression levels of various nicotinamide adenine dinucleotide phosphate oxidase subunits between initial multiple sclerosis lesions and control white matter. These results were confirmed at the protein level by means of immunohistochemistry, showing upregulation of the subunits gp91phox, p22phox, p47phox, nicotinamide adenine dinucleotide phosphate oxidase 1 and nicotinamide adenine dinucleotide phosphate oxidase organizer 1 in activated microglia in classical active as well as slowly expanding lesions. The subunits gp91phox and p22phox were constitutively expressed in microglia and were upregulated in the initial lesion. In contrast, p47phox, nicotinamide adenine dinucleotide phosphate oxidase 1 and nicotinamide adenine dinucleotide phosphate oxidase organizer 1 expression were more restricted to the zone of initial damage or to lesions from patients with acute or early relapsing/remitting multiple sclerosis. Double labelling showed co-expression of the nicotinamide adenine dinucleotide phosphate oxidase subunits in activated microglia and infiltrated macrophages, suggesting the assembly of functional complexes. Our data suggest that the inflammation-associated oxidative burst in activated microglia and macrophages plays an important role in demyelination and free radical-mediated tissue injury in the pathogenesis of multiple sclerosis.
منابع مشابه
Spironolactone Inhibits NADPH Oxidase-Mediated Oxidative Stress and Dysregulation of the Endothelial NO Synthase in Human Endothelial Cells
Accumulating evidence indicates that aldosterone plays a critical role in the mediation of oxidative stress and vascular damage. NADPH oxidase has been recognized as a major source of oxidative stress in vasculature. However, the relation between NADPH oxidase in aldosterone-mediated oxidative stress in endothelial cells remains to be ascertained. The present study aimed to investigate the rel...
متن کاملSpironolactone Inhibits NADPH Oxidase-Mediated Oxidative Stress and Dysregulation of the Endothelial NO Synthase in Human Endothelial Cells
Accumulating evidence indicates that aldosterone plays a critical role in the mediation of oxidative stress and vascular damage. NADPH oxidase has been recognized as a major source of oxidative stress in vasculature. However, the relation between NADPH oxidase in aldosterone-mediated oxidative stress in endothelial cells remains to be ascertained. The present study aimed to investigate the rel...
متن کاملP 153: Neuroinflammation in Multiple Sclerosis
Multiple sclerosis (MS) is a complex disease which is correlated with increasing inflammatory factors, demyelination and axonal loss. In this auto-immune disease, Neuroinflammation is mediated by different types of T cells with macrophage/microglial activation and B cells involvement that interact in a collaborative manner. Focal inflammation is the main cause for the onset of relapses and coul...
متن کاملMitochondrial defects in acute multiple sclerosis lesions
Multiple sclerosis is a chronic inflammatory disease, which leads to focal plaques of demyelination and tissue injury in the CNS. The structural and immunopathological patterns of demyelination suggest that different immune mechanisms may be involved in tissue damage. In a subtype of lesions, which are mainly found in patients with acute fulminant multiple sclerosis with Balo's type concentric ...
متن کاملAldosterone Induces Oxidative Stress Via NADPH Oxidase and Downregulates the Endothelial NO Synthesase in Human Endothelial Cells
Aldosterone is traditionally viewed as a hormone regulating electrolyte and blood pressure homeostasis. Recent studies suggest that Aldo can cause microvascular damage, oxidative stress and endothelial dysfunction. However, its exact cellular mechanisms remain obscure. This study was undertaken to examine the effect of Aldo on superoxide production in human umbilical artery endothelial cel...
متن کامل