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

• Published in: Journal of neuroinflammation Vol. 12; no. 1; p. 230
• Main Authors: Russo, Isabella, Berti, Giulia, Plotegher, Nicoletta, Bernardo, Greta, Filograna, Roberta, Bubacco, Luigi, Greggio, Elisa
• Format: Journal Article
• Language: English
• Published: England BioMed Central 09.12.2015
• Subjects: Animals; Cells, Cultured; Down-Regulation - physiology; Inflammation - metabolism; Inflammation - prevention & control; Inflammation Mediators - antagonists & inhibitors; Inflammation Mediators - metabolism; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Mice; Mice, Inbred C57BL; Mice, Knockout; Microglia - metabolism; NF-kappa B p50 Subunit - antagonists & inhibitors; NF-kappa B p50 Subunit - metabolism; Protein Serine-Threonine Kinases - deficiency; Signal Transduction - physiology
• ISSN: 1742-2094; 1742-2094
• DOI: 10.1186/s12974-015-0449-7

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. 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. 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 α-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. 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 α-synuclein holds the potential to provide novel targets for PD therapeutics.