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Impaired inflammatory responses in murine Lrrk2-knockdown brain microglia

Kim, B; Yang, MS; Choi, D; Kim, JH; Kim, HS; Seol, W; Choi, S; Jou, I; Kim, EY; Joe, EH
PloS one, 7(4):e34693-e34693, 2012
Journal Title
PloS one
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.
MeSH terms
AnimalsBrain/*metabolismCell LineEncephalitis/*metabolismGene Knockdown TechniquesInterleukin-1beta/biosynthesisLipopolysaccharides/pharmacologyMAP Kinase Kinase 4/metabolismMiceMicroglia/*metabolismNF-kappa B/metabolismNitric Oxide Synthase Type II/biosynthesisPhosphorylation/drug effectsProtein-Serine-Threonine Kinases/genetics/*metabolismTumor Necrosis Factor-alpha/biosynthesisp38 Mitogen-Activated Protein Kinases/metabolism
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Pharmacology
Journal Papers > School of Medicine / Graduate School of Medicine > Brain Science
AJOU Authors
김, 범수주, 일로김, 은영조, 은혜
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