Leucine-rich repeat kinase 2 positively regulates inflammation and down-regulates NF-κB p50 signaling in cultured microglia cells

Background: over-activated microglia and chronic neuroinflammation contribute to dopaminergic neuron degeneration and progression of parkinson's disease (pd). leucine-rich repeat kinase 2 (lrrk2),a kinase mutated in autosomal dominantly inherited and sporadic pd cases,is highly expressed in immune cells,in which it regulates inflammation through a yet unclear mechanism. methods: here,using pharmacological inhibition and cultured lrrk2 --/- primary microglia cells,we validated lrrk2 as a positive modulator of inflammation and we investigated its specific function in microglia cells. results: inhibition or genetic deletion of lrrk2 causes reduction of interleukin-1β and cyclooxygenase-2 expression upon lipopolysaccharide-mediated inflammation. lrrk2 also takes part of the signaling trigged by aα-synuclein fibrils,which culminates in induction of inflammatory mediators. at the molecular level,loss of lrrk2 or inhibition of its kinase activity results in increased phosphorylation of nuclear factor kappa-b (nf-κb) inhibitory subunit p50 at s337,a protein kinase a (pka)-specific phosphorylation site,with consequent accumulation of p50 in the nucleus. conclusions: taken together,these findings point to a role of lrrk2 in microglia activation and sustainment of neuroinflammation and in controlling of nf-κb p50 inhibitory signaling. understanding the molecular pathways coordinated by lrrk2 in activated microglia cells after pathological stimuli such us fibrillar aα-synuclein holds the potential to provide novel targets for pd therapeutics. © 2015 russo et al.