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Protracted downregulation of CX3CR1 on microglia of aged mice after lipopolysaccharide challenge
Open accessAbstract
Fractalkine (CX(3)CL1) to fractalkine receptor (CX(3)CR1) interactions in the brain are involved in the modulation of microglial activation. Our recent findings indicate that there is microglial hyperactivity in the aged brain during an inflammatory challenge. The underlying cause of this amplified microglial response in the aged brain is unknown. Therefore, the purpose of this study was to determine the degree to which age-associated impairments of CX(3)CL1 and CX(3)CR1 in the brain contribute to exaggerated microglial activation after intraperitoneal (i.p.) injection of lipopolysaccharide (LPS). Here we show that CX(3)CL1 protein was reduced in the brain of aged (18-22 mo) BALB/c mice compared to adult (3-6 mo) controls. CX(3)CL1 protein, however, was unaltered by LPS injection. Next, CX(3)CR1 levels were determined in microglia (CD11b(+)/CD45(low)) isolated by Percoll density gradient separation at 4 and 24h after LPS injection. Flow cytometric and mRNA analyses of these microglia showed that LPS injection caused a marked decrease of CX(3)CR1 and a simultaneous increase of IL-1β at 4h after LPS injection. While surface expression of CX(3)CR1 was enhanced on microglia of adult mice by 24h, it was still significantly downregulated on a subset of microglia from aged mice. This protracted reduction of CX(3)CR1 corresponded with a delayed recovery from sickness behavior, prolonged IL-1β induction, and decreased TGFß expression in the aged brain. In the last set of studies BV2 microglia were used to determine effect of TGFß on CX(3)CR1. These results showed that TGFβ enhanced CX(3)CR1 expression and attenuated the LPS-induced increase in IL-1β expression.
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“Aged glial cells respond less efficiently to antigens, including amyloid-β (Aβ) and α-synuclein, and have reduced phagocytic and antiinflammatory capacity (161–163).”
From Connecting aging biology and inflammation in the omics era (2022) · cites this paper as [163]
Experimental — accuracy not yet measuredIn the citing paper
“For example, if a microglial gene relevant to neurodegeneration at an early stage is to be investigated, it would be most appropriate to use a conditional and cell-specific model, such as the tamoxifen-inducible Cx3cr1 Cre recombinase mouse, since Cx3cr1 is only expressed by homeostatic microglia and is downregulated by DAM [66].”
From Identification and therapeutic modulation of a pro-inflammatory subset of disease-associated-microglia in Alzheimer’s disease (2018) · cites this paper as [66]
In the citing paper
“Furthermore, in vitro treatment of microglial cells with LPS followed by TGFβ significantly attenuated LPS-induced IL-1β expression (Wynne et al, 2010).”
From Microglia Priming with Aging and Stress (2017) · cites this paper as Wynne et al, 2010
In the citing paper
“Aged mice, but not adults, showed reduced baseline levels of CX 3 CL 1 that remained unaltered after a systemic LPS challenge (Wynne et al, 2010).”
From Microglia Priming with Aging and Stress (2017) · cites this paper as Wynne et al, 2010
In the citing paper
“LPS-injected aged mice, however, showed protracted downregulation of CX 3 CR 1 and reduced social behavior, which was accompanied by elevated IL-1β and reduced TGFβ (Wynne et al, 2010).”
From Microglia Priming with Aging and Stress (2017) · cites this paper as Wynne et al, 2010
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Citations
Cites
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Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo
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ATP mediates rapid microglial response to local brain injury in vivo
Davalos, D., Grutzendler, J., Yang, G., Kim, J. V., Zuo, Y., Jung, S., Littman, D. R., Dustin, M. L., & Gan, W.-B. (2005) · Nature Neuroscience · doi:10.1038/nn1472 · Cited by 3,913
Control of microglial neurotoxicity by the fractalkine receptor
Cardona, A. E., Pioro, E. P., Sasse, M. E., Kostenko, V., Cardona, S. M., Dijkstra, I. M., Huang, D., Kidd, G., Dombrowski, S., Dutta, R., et al. (2006) · Nature Neuroscience · doi:10.1038/nn1715 · Cited by 1,531
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Self-citationInnate immunity: the missing link in neuroprotection and neurodegeneration?
Nguyen, M. D., Julien, J., & Rivest, S. (2002) · Nature reviews. Neuroscience · doi:10.1038/nrn752 · Cited by 710
Microglia derived from aging mice exhibit an altered inflammatory profile
Sierra, A., Gottfried‐Blackmore, A. C., McEwen, B. S., & Bulloch, K. (2007) · Glia · doi:10.1002/glia.20468 · Cited by 688
Henry, C. J., Huang, Y., Wynne, A., Hanke, M., Himler, J., Bailey, M. T., Sheridan, J. F., & Godbout, J. P. (2008) · Journal of Neuroinflammation · doi:10.1186/1742-2094-5-15 · Cited by 678
Self-citationNeurotactin, a membrane-anchored chemokine upregulated in brain inflammation
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DiSabato, D. J., Quan, N., & Godbout, J. P. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13607 · Cited by 1,640
Self-citationReview: microglia of the aged brain: primed to be activated and resistant to regulation
Norden, D. M., & Godbout, J. P. (2013) · Neuropathology and Applied Neurobiology · doi:10.1111/j.1365-2990.2012.01306.x · Cited by 792
Self-citationMicroglia and neurodegeneration: The role of systemic inflammation
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Wohleb, E. S., Hanke, M. L., Corona, A. W., Powell, N. D., Stiner, L. M., Bailey, M. T., Nelson, R. J., Godbout, J. P., & Sheridan, J. F. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.0450-11.2011 · Cited by 638
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Metadata
- Authors
- Wynne, A. M., Henry, C. J., Huang, Y., Cleland, A., & Godbout, J. P.
- Affiliations
- The Ohio State University (US)
- Corresponding author
- Godbout, Jonathan P.
- Venue
- Brain, Behavior, and Immunity
- Publisher
- Elsevier BV
- Published
- 2010-10
- Volume
- 24
- Issue
- 7
- Pages
- 1190-1201
- ISSN
- 0889-1591 (ISSN-L)
- PMC
- PMC2939290
- OpenAlex
- W2087771052
- Cited by
- 224
- References
- 50
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 8 · 2023: 9 · 2022: 17 · 2021: 19 · 2020: 14 · 2019: 13 · 2018: 18 · 2017: 10 · 2016: 18 · 2015: 17 · 2014: 21 · 2013: 18 · 2012: 15
- FWCI
- 9.68
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Brain Behavior and Immunity (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (R01AG033028, R01 AG-033028-01)
- National Institute of Mental Health (R21MH077817)
- National Institute of Allergy and Infectious Diseases (NIH T32-AI-055411, T32AI055411)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Health Sciences › Medicine › Oncology › Chemokine receptors and signaling
- Keywords
- CX3CR1, fractalkine, microglia, aging, lipopolysaccharide, neuroinflammation, microglial activation, IL-1β, TGF-beta, sickness behavior, BV-2 cells, aged mice
- MeSH terms
- CX3C Chemokine Receptor 1, Aging, Animals, Brain, Cell Count, Cells, Cultured, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Injections, Intraperitoneal, Lipopolysaccharides, Male, Mice, Inbred BALB C, RNA, Messenger, Down-Regulation, Up-Regulation, Polymerase Chain Reaction, Transforming Growth Factor beta, Leukocyte Common Antigens, Microglia, Receptors, Chemokine, CD11b Antigen, Mice, Interleukin-1beta, Chemokine CX3CL1
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