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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.



Autor: Beomsue Kim, Myung-Soon Yang, Dongjoo Choi, Jong-Hyeon Kim, Hye-Sun Kim, Wongi Seol, Sangdun Choi, Ilo Jou, Eun-Young Kim, Eun-hy

Fuente: http://plos.srce.hr/



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