Astroglial PGC-1alpha increases mitochondrial antioxidant capacity and suppresses inflammation: implications for multiple sclerosis

被引：78

作者：

Nijland, Philip G. ^{[1
,2
]}

Witte, Maarten E. ^{[2
,4
]}

van het Hof, Bert ^{[2
]}

van der Pol, Susanne ^{[2
]}

Bauer, Jan ^{[3
]}

Lassmann, Hans ^{[3
]}

van der Valk, Paul ^{[1
]}

de Vries, Helga E. ^{[2
]}

van Horssen, Jack ^{[2
]}

机构：

[1] Vrije Univ Amsterdam, MS Ctr Amsterdam, Dept Pathol, Med Ctr, Amsterdam, Netherlands

[2] Vrije Univ Amsterdam, Neurosci Campus Amsterdam, Dept Mol Cell Biol & Immunol, Med Ctr, Amsterdam, Netherlands

[3] Med Univ Vienna, Dept Neuroimmunol, Ctr Brain Res, Vienna, Austria

[4] Ludwig Maximilians Univ Munchen, Inst Clin Neuroimmunol, Munich, Germany

来源：

ACTA NEUROPATHOLOGICA COMMUNICATIONS | 2014年 / 2卷

关键词：

Reactive astrocytes; Neurodegeneration; Prx3; Trx2; ROS; TRANSCRIPTIONAL CONTROL; REACTIVE ASTROCYTES; OXIDATIVE DAMAGE; EXPRESSION; ACTIVATION; NEURONS; LESIONS; NEURODEGENERATION; THIOREDOXIN; PGC-1-ALPHA;

D O I：

10.1186/s40478-014-0170-2

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

Recent evidence suggests that reactive oxygen species (ROS) produced by inflammatory cells drive axonal degeneration in active multiple sclerosis (MS) lesions by inducing mitochondrial dysfunction. Mitochondria are endowed with a variety of antioxidant enzymes, including peroxiredoxin-3 and thioredoxin-2, which are involved in limiting ROS-induced damage. In this study, we explored the distribution and role of the mitochondrial antioxidants peroxiredoxin-3 and thioredoxin-2 as well as their regulator peroxisome proliferator-activated receptor gamma coactivator1-alpha (PGC-1 alpha) in MS pathogenesis. Immunohistochemical analysis of a large cohort of MS patients revealed a striking upregulation of PGC-1 alpha and downstream mitochondrial antioxidants in active demyelinating MS lesions. Enhanced expression was predominantly observed in reactive astrocytes. To elucidate the functional role of astrocytic PGC-1 alpha in MS pathology, we generated human primary astrocytes that genetically overexpressed PGC-1 alpha. Upon an oxidative insult, these cells were shown to produce less ROS and were found to be more resistant to ROS-induced cell death compared to control cells. Intriguingly, also neuronal cells co-cultured with PGC-1 alpha-overexpressing astrocytes were protected against an exogenous oxidative attack compared to neuronal cells co-cultured with control astrocytes. Finally, enhanced astrocytic PGC-1a levels markedly reduced the production and secretion of the pro-inflammatory mediators interleukin-6 and chemokine (C-C motif) ligand 2. Our findings suggest that increased astrocytic PGC-1 alpha in active MS lesions might initially function as an endogenous protective mechanism to dampen oxidative damage and inflammation thereby reducing neurodegeneration. Activation of PGC-1 alpha therefore represents a promising therapeutic strategy to improve mitochondrial function and repress inflammation.

引用

页数：13

共 62 条

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