LRRK2 Inhibition Attenuates Microglial Inflammatory Responses
Open accessAbstract
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.
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TLR2 or TLR4 stimulation can increase the expression and phosphorylation of LRRK2 in microglia.
“Research on microglia has shown that TLR2 or TLR4 stimulation can increase the expression and phosphorylation of LRRK2.259,260”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [259]
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- Authors
- Moehle, M. S., Webber, P. J., Tse, T., Sukar, N., Standaert, D. G., DeSilva, T. M., Cowell, R. M., & West, A. B.
- Affiliations
- University of Alabama at Birmingham (US)
- Corresponding author
- West, Andrew B.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2012-02-01
- Volume
- 32
- Issue
- 5
- Pages
- 1602-1611
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3532034
- OpenAlex
- W2143811842
- Cited by
- 463
- References
- 27
- Citations by year
- 2026: 17 · 2025: 28 · 2024: 36 · 2023: 37 · 2022: 26 · 2021: 35 · 2020: 37 · 2019: 38 · 2018: 42 · 2017: 33 · 2016: 29 · 2015: 35 · 2014: 30 · 2013: 24 · 2012: 14
- FWCI
- 16.60
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (P30NS047466, R00NS058111, NS047466, NS061788, NS064934, R01NS064934, T32NS061788)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- LRRK2, leucine-rich repeat kinase 2, microglia, neuroinflammation, Parkinson's disease, LRRK2 kinase inhibition, TLR4, TNF-alpha secretion, inducible nitric oxide synthase, microglial chemotaxis, actin cytoskeleton, microglial morphology
- MeSH terms
- Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Animals, Cells, Cultured, Chemotaxis, Female, Humans, Inflammation, Male, Mice, Inbred C57BL, Random Allocation, Protein Serine-Threonine Kinases, Microglia, Mice, Knockout, Mice, Rats, HEK293 Cells
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