PloS one, 2012-04, Vol.7 (4), p.e34693-e34693
2012
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- Autor(en) / Beteiligte
- Titel
- Impaired inflammatory responses in murine Lrrk2-knockdown brain microglia
- Ist Teil von
- PloS one, 2012-04, Vol.7 (4), p.e34693-e34693
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2012
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- LRRK2, a Parkinson's disease associated gene, is highly expressed in microglia in addition to neurons; however, its function in microglia has not been evaluated. Using Lrrk2 knockdown (Lrrk2-KD) murine microglia prepared by lentiviral-mediated transfer of Lrrk2-specific small inhibitory hairpin RNA (shRNA), we found that Lrrk2 deficiency attenuated lipopolysaccharide (LPS)-induced mRNA and/or protein expression of inducible nitric oxide synthase, TNF-α, IL-1β and IL-6. LPS-induced phosphorylation of p38 mitogen-activated protein kinase and stimulation of NF-κB-responsive luciferase reporter activity was also decreased in Lrrk2-KD cells. Interestingly, the decrease in NF-κB transcriptional activity measured by luciferase assays appeared to reflect increased binding of the inhibitory NF-κB homodimer, p50/p50, to DNA. In LPS-responsive HEK293T cells, overexpression of the human LRRK2 pathologic, kinase-active mutant G2019S increased basal and LPS-induced levels of phosphorylated p38 and JNK, whereas wild-type and other pathologic (R1441C and G2385R) or artificial kinase-dead (D1994A) LRRK2 mutants either enhanced or did not change basal and LPS-induced p38 and JNK phosphorylation levels. However, wild-type LRRK2 and all LRRK2 mutant variants equally enhanced NF-κB transcriptional activity. Taken together, these results suggest that LRRK2 is a positive regulator of inflammation in murine microglia, and LRRK2 mutations may alter the microenvironment of the brain to favor neuroinflammation.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1932-6203eISSN: 1932-6203DOI: 10.1371/journal.pone.0034693Titel-ID: cdi_plos_journals_1324448677
- Format
- –
- Schlagworte
- Alzheimer's disease, Animals, B cells, Biology, Biotechnology, Brain, Brain - metabolism, Brain research, c-Jun amino-terminal kinase, Cell Line, Cloning, Deoxyribonucleic acid, DNA, Encephalitis - metabolism, Gene expression, Gene Knockdown Techniques, Genes, Immunoglobulins, Inflammation, Inflammatory diseases, Interleukin 1, Interleukin 6, Interleukin-1beta - biosynthesis, JNK protein, Kinases, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Lipopolysaccharides, Lipopolysaccharides - pharmacology, LRRK2 protein, Luciferase, MAP kinase, MAP Kinase Kinase 4 - metabolism, Medicine, Mice, Microenvironments, Microglia, Microglia - metabolism, Mitogens, Movement disorders, Mutants, Mutation, Neurodegeneration, Neurodegenerative diseases, Neurosciences, NF- Kappa B protein, NF-kappa B - metabolism, NF-κB protein, Nitric oxide, Nitric Oxide Synthase Type II - biosynthesis, Nitric-oxide synthase, p38 Mitogen-Activated Protein Kinases - metabolism, Parkinson's disease, Pharmacology, Phosphorylation, Phosphorylation - drug effects, Polymerase chain reaction, Protein kinase, Protein kinases, Protein-Serine-Threonine Kinases - genetics, Protein-Serine-Threonine Kinases - metabolism, Ribonucleic acid, RNA, Rodents, Transcription, Tumor necrosis factor, Tumor necrosis factor- alpha, Tumor Necrosis Factor-alpha - biosynthesis, Tumor necrosis factor-α