Regulation of astrocyte inflammatory responses by the Parkinson's disease-associated gene DJ-1.
The Parkinson's disease (PD)-associated gene DJ-1 mediates direct neuroprotection. The up-regulation of DJ-1 in reactive astrocytes also suggests a role in glia. Here we show that DJ-1 regulates proinflammatory responses in mouse astrocyte-rich primary cultures. When treated with a Toll-like receptor 4 agonist, the bacterial endotoxin lipopolysaccharide (LPS), Dj-1-knockout astrocytes generated >10 times more nitric oxide (NO) than littermate controls. Lentiviral reintroduction of DJ-1 restored the NO response to LPS. The enhanced NO production in Dj-1(-/-) astrocytes was mediated by a signaling pathway involving reactive oxygen species leading to specific hyperinduction of type II NO synthase [inducible NO synthase (iNOS)]. These effects coincided with significantly increased phosphorylation of p38 mitogen-activated protein kinase (MAPK), and p38(MAPK) inhibition suppressed NO production and iNOS mRNA and protein induction. Dj-1(-/-) astrocytes also induced the proinflammatory mediators cyclooxygenase-2 and interleukin-6 significantly more strongly, but not nerve growth factor. Finally, primary neuron cultures grown on Dj-1(-/-) astrocytes became apoptotic in response to LPS in an iNOS-dependent manner, directly demonstrating the neurotoxic potential of astrocytic DJ-1 deficiency. These findings identify DJ-1 as a regulator of proinflammatory responses and suggest that loss of DJ-1 contributes to PD pathogenesis by deregulation of astrocytic neuroinflammatory damage.
Waak
Jens
J
Laboratory of Functional Neurogenetics, Dept. of Neurodegeneration, Hertie Institute for Clinical Brain Research, University Clinics Tübingen, Otfried Müller Str. 27, 72076 Tübingen, Germany.
Weber
Stephanie S
SS
Waldenmaier
Andrea
A
Görner
Karin
K
Alunni-Fabbroni
Marianna
M
Schell
Heinrich
H
Vogt-Weisenhorn
Daniela
D
Pham
Thu-Trang
TT
Reumers
Veerle
V
Baekelandt
Veerle
V
Wurst
Wolfgang
W
Kahle
Philipp J
PJ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D001483:Base Sequence; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000235:genetics; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D015513:Oncogene Proteins / Q000172:deficiency / Q000235:genetics*; D020734:Parkinsonian Disorders / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D054464:Peroxiredoxins; D000071617:Protein Deglycase DJ-1; D011725:Pyridines / Q000494:pharmacology; D051197:Toll-Like Receptor 4 / Q000819:agonists; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D018076:DNA, Complementary; D004791:Enzyme Inhibitors; C090509:Icam1 protein, mouse; D007093:Imidazoles; D015850:Interleukin-6; D008070:Lipopolysaccharides; D015513:Oncogene Proteins; D011725:Pyridines; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D018799:Intercellular Adhesion Molecule-1; D009569:Nitric Oxide; D054464:Peroxiredoxins; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D048051:p38 Mitogen-Activated Protein Kinases; C503466:PARK7 protein, mouse; D000071617:Protein Deglycase DJ-1; C093642:SB 203580