title: Astroglial PGC-1alpha increases mitochondrial antioxidant capacity and suppresses inflammation: implications for multiple sclerosis.
abstract: 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-1α) in MS pathogenesis. Immunohistochemical analysis of a large cohort of MS patients revealed a striking upregulation of PGC-1α 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-1α in MS pathology, we generated human primary astrocytes that genetically overexpressed PGC-1α. 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-1α-overexpressing astrocytes were protected against an exogenous oxidative attack compared to neuronal cells co-cultured with control astrocytes. Finally, enhanced astrocytic PGC-1α 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-1α in active MS lesions might initially function as an endogenous protective mechanism to dampen oxidative damage and inflammation thereby reducing neurodegeneration. Activation of PGC-1α therefore represents a promising therapeutic strategy to improve mitochondrial function and repress inflammation.
authors.forename: Philip G
authors.initials: PG
authors.lastname: Nijland
authors.forename: Maarten E
authors.initials: ME
authors.lastname: Witte
authors.forename: Bert
authors.initials: B
authors.lastname: van het Hof
authors.forename: Susanne
authors.initials: S
authors.lastname: van der Pol
authors.forename: Jan
authors.initials: J
authors.lastname: Bauer
authors.forename: Hans
authors.initials: H
authors.lastname: Lassmann
authors.forename: Paul
authors.initials: P
authors.lastname: van der Valk
authors.forename: Helga E
authors.initials: HE
authors.lastname: de Vries
authors.forename: Jack
authors.initials: J
authors.lastname: van Horssen
mesh_terms: D000328:Adult; D000368:Aged; D000975:Antioxidants / Q000378:metabolism; D001253:Astrocytes / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D016022:Case-Control Studies; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004660:Encephalitis / Q000209:etiology* / Q000473:pathology*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000150:complications* / Q000473:pathology; D018991:Myelin Proteolipid Protein / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D061105:Peroxiredoxin III / Q000235:genetics / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017382:Reactive Oxygen Species; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D066127:White Matter / Q000378:metabolism / Q000473:pathology
chemical_list: D000975:Antioxidants; D016207:Cytokines; D018991:Myelin Proteolipid Protein; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D013879:Thioredoxins; C516115:PRDX3 protein, human; D061105:Peroxiredoxin III