Regulation of Microglial Phagocytosis by RhoA/ROCK-Inhibiting Drugs
Open accessAbstract
Inflammation within the central nervous system (CNS) is a major component of many neurodegenerative diseases. The underlying mechanisms of neuronal loss are not fully understood, but the activation of CNS resident phagocytic microglia seems to be a significant element contributing to neurodegeneration. At the onset of inflammation, high levels of microglial phagocytosis may serve as an essential prerequisite for creating a favorable environment for neuronal regeneration. However, the excessive and long-lasting activation of microglia and the augmented engulfment of neurons have been suggested to eventually govern widespread neurodegeneration. Here, we investigated in a functional assay of acute inflammation how the small GTPase RhoA and its main target the Rho kinase (ROCK) influence microglial phagocytosis of neuronal debris. Using BV-2 microglia and human NT2 model neurons, we demonstrate that the pain reliever Ibuprofen decreases RhoA activation and microglial phagocytosis of neuronal cell fragments. Inhibition of the downstream effector ROCK with the small-molecule agents Y-27632 and Fasudil reduces the engulfment of neuronal debris and attenuates the production of the inflammatory mediator nitric oxide during stimulation with lipopolysaccharide. Our results support a therapeutic potential for RhoA/ROCK-inhibiting agents as an effective treatment of excessive inflammation and the resulting progression of microglia-mediated neurodegeneration in the CNS.
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Increasing evidence indicates that RhoA/ROCK signaling has an important role in microglial activation by regulating microglial migration, phagocytosis, and release of inflammatory factors such as ROS, TNFα, IL-6, IL-1β, and NO.
“Increasing evidence indicates that RhoA/ROCK signaling has an important role in microglial activation by regulating microglial migration, phagocytosis, and release of inflammatory factors such as ROS, tumor necrosis factor α (TNFα), interleukin-6 (IL-6), IL-1β, and NO [152,153].”
From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [152]
The Introduction reports that inhibiting RhoA/ROCK reduces microglial phagocytosis and that ROCK inhibitors reduce nitric oxide production. Functional Implications says activated microglia release cytokines and free radicals, but does not link RhoA/ROCK to their release. The cited paper does not establish the claimed regulation of microglial migration or release of ROS, TNFα, IL-6, and IL-1β. (LLM, conf=0.88)
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Cites
Microglia and inflammation-mediated neurodegeneration: Multiple triggers with a common mechanism
Block, M. L., & Hong, J.-S. (2005) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2005.06.004 · Cited by 1,557 · see citing works
Inhibition of Microglial Phagocytosis Is Sufficient To Prevent Inflammatory Neuronal Death
Neher, J. J., Neniskyte, U., Zhao, J.-W., Bal-Price, A., Tolkovsky, A. M., & Brown, G. C. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1003600 · Cited by 373 · see citing works
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Research works printed but not linked: 2
- Degasperi A, Birtwistle MR, Volinsky N, Rauch J, Kolch W, Kholodenko BN (2014) Evaluating strategies to normalise biological replicates of western blot data. PLoS ONE 9(1):e87293
- Scheiblich H, Bicker G (2015b) Nitric oxide regulates antagonistically phagocytic and neurite outgrowth inhibiting capacities of microglia. Dev Neurobiol. doi:10.1002/dneu.22333 in press · DOI
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RhoA Signaling in Neurodegenerative Diseases
Schmidt, S. I., Blaabjerg, M., Freude, K., & Meyer, M. (2022) · Cells · doi:10.3390/cells11091520 · Cited by 110 · see citing works
Zheng, Y., Zhang, X., Zhang, R., Wang, Z., Gan, J., Gao, Q., Yang, L., Xu, P., & Jiang, X. (2023) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2023.5314 · Cited by 52 · see citing works
- Authors
- Scheiblich, H., & Bicker, G.
- Affiliations
- University of Veterinary Medicine Hannover, Foundation (DE)
- Corresponding author
- Bicker, Gerd
- Venue
- Cellular and Molecular Neurobiology
- Published
- 2016-05-13
- Volume
- 37
- Issue
- 3
- Pages
- 461-473
- ISSN
- 0272-4340 (ISSN-L)
- 1573-6830
- PMC
- PMC11482106
- OpenAlex
- W2362632603
- Cited by
- 44
- References
- 2
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 7 · 2023: 4 · 2022: 6 · 2021: 7 · 2020: 6 · 2019: 3 · 2018: 3 · 2017: 1
- FWCI
- 1.28
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Cellular and Molecular Neurobiology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (BI 262/16-2)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- microglial phagocytosis, RhoA, Rho kinase, ROCK inhibition, ibuprofen, Y-27632, fasudil, neuroinflammation, neurodegeneration, nitric oxide, lipopolysaccharide, BV-2 cells
- MeSH terms
- Amides, Animals, Biological Assay, Cell Line, Humans, Ibuprofen, Lysophospholipids, Nitric Oxide, Phagocytosis, Pyridines, Signal Transduction, Down-Regulation, Microglia, 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine, rhoA GTP-Binding Protein, Protein Kinase Inhibitors, Mice, rho-Associated Kinases
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