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Updated: Nov 4, 2025
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Published on: January 30, 2014
Modulation of inflammatory responses by fractalkine signaling in microglia
Koichi Inoue1, Hiroyuki Morimoto1, Masahiro Ohgidani1
1Department of Integrative Anatomy, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
Abstract:
Reactive microglia are suggested to be involved in neurological disorders, and the mechanisms underlying microglial activity may provide insights into therapeutic strategies for neurological diseases. Microglia produce immunological responses to various stimuli, which include fractalkine (FKN or CX3CL1). CX3CR1, a FKN receptor, is present in microglial cells, and when FKN is applied before lipopolysaccharide (LPS) administration, LPS-induced inflammatory responses are inhibited, suggesting that the activation of the FKN signal is beneficial. Considering the practical administration for treatment, we investigated the influence of FKN on immunoreactive microglia using murine primary microglia and BV-2, a microglial cell line. The administration of LPS leads to nitric oxide (NO) production. NO was reduced when FKN was administered 4 h after LPS administration without a change in inducible nitric oxide synthase expression. In contrast, morphological changes, migratory activity, and proliferation were not altered by delayed FKN treatment. LPS decreases the CX3CR1 mRNA concentration, and the overexpression of CX3CR1 restores the FKN-mediated decrease in NO. CX3CR1 overexpression decreased the NO production that is mediated by LPS even without the application of FKN. ATP and ethanol also reduced CX3CR1 mRNA concentrations. In conclusion, the delayed FKN administration modified the LPS-induced microglial activation. The FKN signals were attenuated by a reduction in CX3CR1 by some inflammatory stimuli, and this modulated the inflammatory response of microglial cells, at least partially.
Insights
Delayed fractalkine (FKN) administration reduces nitric oxide production in activated microglia. This modulation of microglial response, linked to CX3CR1 receptor levels, offers therapeutic insights for neurological disorders.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Reactive microglia play a role in neurological disorders.
- Fractalkine (FKN/CX3CL1) signaling, via its receptor CX3CR1 on microglia, can be protective against inflammation.
- Understanding microglial responses to FKN is crucial for developing therapeutic strategies for neurological diseases.
Purpose of the Study:
- To investigate the therapeutic potential of delayed fractalkine (FKN) administration on activated microglia.
- To examine the impact of FKN on microglial activation markers, including nitric oxide (NO) production and CX3CR1 expression.
Main Methods:
- Primary murine microglia and BV-2 microglial cell lines were used.
- Lipopolysaccharide (LPS) was administered to induce microglial activation.
- Fractalkine (FKN) was administered at different time points relative to LPS.
- Nitric oxide (NO) production, inducible nitric oxide synthase (iNOS) expression, cell morphology, migration, proliferation, and CX3CR1 mRNA levels were assessed.
Main Results:
- Delayed FKN administration (4 hours post-LPS) reduced NO production without altering iNOS expression.
- Cell morphology, migration, and proliferation remained unchanged with delayed FKN treatment.
- LPS decreased CX3CR1 mRNA levels, which was restored by CX3CR1 overexpression, leading to reduced NO production.
- ATP and ethanol also decreased CX3CR1 mRNA.
Conclusions:
- Delayed FKN administration can modulate LPS-induced microglial activation, specifically reducing NO production.
- Inflammatory stimuli can attenuate FKN signaling by reducing CX3CR1 expression, thereby modulating microglial inflammatory responses.
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