Related Experiment Video
Updated: May 25, 2026
Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
Published on: January 30, 2014
LRRK2 inhibition attenuates microglial inflammatory responses
Mark S Moehle1, Philip J Webber, Tonia Tse
1Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
Abstract:
Missense mutations in leucine-rich repeat kinase 2 (LRRK2) cause late-onset Parkinson's disease (PD), and common genetic variation in LRRK2 modifies susceptibility to Crohn's disease and leprosy. High levels of LRRK2 expression in peripheral monocytes and macrophages suggest a role for LRRK2 in these cells, yet little is known about LRRK2 expression and function in immune cells of the brain. Here, we demonstrate a role for LRRK2 in mediating microglial proinflammatory responses and morphology. In a murine model of neuroinflammation, we observe robust induction of LRRK2 in microglia. Experiments with toll-like receptor 4 (TLR4)-stimulated rat primary microglia show that inflammation increases LRRK2 activity and expression, while inhibition of LRRK2 kinase activity or knockdown of protein attenuates TNFα secretion and nitric oxide synthase (iNOS) induction. LRRK2 inhibition blocks TLR4 stimulated microglial process outgrowth and impairs ADP stimulated microglial chemotaxis. However, actin inhibitors that phenocopy inhibition of process outgrowth and chemotaxis fail to modify TLR4 stimulation of TNFα secretion and inducible iNOS induction, suggesting that LRRK2 acts upstream of cytoskeleton control as a stress-responsive kinase. These data demonstrate LRRK2 in regulating responses in immune cells of the brain and further implicate microglial involvement in late-onset PD.
Insights
Leucine-rich repeat kinase 2 (LRRK2) regulates microglial inflammatory responses and morphology in the brain. Inhibiting LRRK2 kinase activity reduces pro-inflammatory mediators and affects microglial cell shape and movement.
Area of Science:
- Neuroimmunology
- Molecular Neuroscience
- Genetics of Neurodegenerative Diseases
Background:
- Missense mutations in leucine-rich repeat kinase 2 (LRRK2) are a known cause of late-onset Parkinson's disease (PD).
- LRRK2 is expressed in peripheral immune cells, but its role in brain-resident immune cells, like microglia, is largely unknown.
- Microglia are key immune cells in the brain implicated in neuroinflammation and neurodegenerative conditions.
Purpose of the Study:
- To investigate the role and regulation of LRRK2 in microglial inflammatory responses and morphology.
- To determine if LRRK2 kinase activity influences pro-inflammatory mediator release and cytoskeletal dynamics in microglia.
- To explore the potential involvement of LRRK2 in the pathogenesis of Parkinson's disease.
Main Methods:
- Utilized a murine model of neuroinflammation to observe LRRK2 induction in microglia.
- Employed toll-like receptor 4 (TLR4) stimulation in primary rat microglia to study LRRK2 activity and expression.
- Applied LRRK2 kinase inhibitors and protein knockdown, alongside actin inhibitors, to assess functional outcomes.
Main Results:
- Observed robust induction of LRRK2 in microglia during neuroinflammation.
- Demonstrated that TLR4 stimulation increases LRRK2 activity and expression in microglia.
- Showed that LRRK2 inhibition attenuates TNFα secretion and nitric oxide synthase (iNOS) induction.
- Found that LRRK2 inhibition impairs microglial process outgrowth and chemotaxis, acting upstream of cytoskeletal regulation.
Conclusions:
- LRRK2 plays a significant role in regulating microglial pro-inflammatory responses and morphological changes.
- LRRK2 functions as a stress-responsive kinase in microglia, influencing their activation and function.
- These findings highlight LRRK2's involvement in brain immune cell responses and implicate microglia in the pathophysiology of late-onset Parkinson's disease.