%0 Journal Article
%T Impaired Inflammatory Responses in Murine Lrrk2-Knockdown Brain Microglia
%A Beomsue Kim
%A Myung-Soon Yang
%A Dongjoo Choi
%A Jong-Hyeon Kim
%A Hye-Sun Kim
%A Wongi Seol
%A Sangdun Choi
%A Ilo Jou
%A Eun-Young Kim
%A Eun-hye Joe
%J PLOS ONE
%D 2012
%I Public Library of Science (PLoS)
%R 10.1371/journal.pone.0034693
%X 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-¦Á, IL-1¦Â and IL-6. LPS-induced phosphorylation of p38 mitogen-activated protein kinase and stimulation of NF-¦ÊB-responsive luciferase reporter activity was also decreased in Lrrk2-KD cells. Interestingly, the decrease in NF-¦ÊB transcriptional activity measured by luciferase assays appeared to reflect increased binding of the inhibitory NF-¦ÊB 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-¦ÊB 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.
%U http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0034693