Related Experiment Video
Updated: Jun 5, 2026
Murine Model of Epicutaneously-Induced Immunomodulation
Published on: June 24, 2025
Fractalkine receptor (CX3CR1) deficiency sensitizes mice to the behavioral changes induced by lipopolysaccharide
Angela W Corona1, Yan Huang, Jason C O'Connor
1Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, 333 W. 10th Ave., Columbus, OH 43210, USA. Angela.Wynne@osumc.edu
Background:
Interactions between fractalkine (CX3CL1) and fractalkine receptor (CX3CR1) regulate microglial activation in the CNS. Recent findings indicate that age-associated impairments in CX3CL1 and CX3CR1 are directly associated with exaggerated microglial activation and an impaired recovery from sickness behavior after peripheral injection of lipopolysaccharide (LPS). Therefore, the purpose of this study was to determine the extent to which an acute LPS injection causes amplified and prolonged microglial activation and behavioral deficits in CX3CR1-deficient mice (CX3CR1-/-).
Methods:
CX3CR1-/- mice or control heterozygote mice (CX3CR1+/-) were injected with LPS (0.5 mg/kg i.p.) or saline and behavior (i.e., sickness and depression-like behavior), microglial activation, and markers of tryptophan metabolism were determined. All data were analyzed using Statistical Analysis Systems General Linear Model procedures and were subjected to one-, two-, or three-way ANOVA to determine significant main effects and interactions.
Results:
LPS injection caused a prolonged duration of social withdrawal in CX3CR1-/- mice compared to control mice. This extended social withdrawal was associated with enhanced mRNA expression of IL-1β, indolamine 2,3-dioxygenase (IDO) and kynurenine monooxygenase (KMO) in microglia 4 h after LPS. Moreover, elevated expression of IL-1β and CD14 was still detected in microglia of CX3CR1-/- mice 24 h after LPS. There was also increased turnover of tryptophan, serotonin, and dopamine in the brain 24 h after LPS, but these increases were independent of CX3CR1 expression. When submitted to the tail suspension test 48 and 72 h after LPS, an increased duration of immobility was evident only in CX3CR1-/- mice. This depression-like behavior in CX3CR1-/- mice was associated with a persistent activated microglial phenotype in the hippocampus and prefrontal cortex.
Conclusions:
Taken together, these data indicate that a deficiency of CX3CR1 is permissive to protracted microglial activation and prolonged behavioral alterations in response to transient activation of the innate immune system.
Insights
Mice lacking the fractalkine receptor (CX3CR1) exhibit prolonged microglial activation and behavioral deficits after lipopolysaccharide (LPS) exposure. This highlights CX3CR1
Area of Science:
- Neuroimmunology
- Microglial Biology
- Neuroinflammation
Background:
- Fractalkine (CX3CL1) and its receptor (CX3CR1) are key regulators of microglial activation in the central nervous system (CNS).
- Impaired CX3CL1/CX3CR1 signaling is linked to heightened microglial activation and delayed recovery from sickness behavior following lipopolysaccharide (LPS) administration.
- Age-associated deficits in CX3CL1/CX3CR1 function exacerbate these neuroinflammatory responses.
Purpose of the Study:
- To investigate the impact of lipopolysaccharide (LPS) injection on microglial activation and behavior in CX3CR1-deficient (CX3CR1-/-) mice.
- To determine if LPS induces amplified and prolonged neuroinflammation and behavioral impairments in the absence of functional CX3CR1.
Main Methods:
- CX3CR1-/- and control (CX3CR1+/-) mice received intraperitoneal injections of LPS or saline.
- Behavioral tests (sickness, depression-like), microglial activation markers, and tryptophan metabolism were assessed.
- Statistical analysis involved one-, two-, or three-way ANOVA.
Main Results:
- LPS induced prolonged social withdrawal in CX3CR1-/- mice, associated with increased IL-1β, IDO, and KMO mRNA in microglia.
- Elevated IL-1β and CD14 expression persisted in microglia of CX3CR1-/- mice 24 hours post-LPS.
- CX3CR1-/- mice displayed increased depression-like behavior (tail suspension test) and persistent microglial activation in the hippocampus and prefrontal cortex.
Conclusions:
- CX3CR1 deficiency permits protracted microglial activation following innate immune system stimulation.
- Absence of CX3CR1 leads to prolonged behavioral alterations in response to transient immune challenges.
- These findings underscore the critical role of the CX3CL1/CX3CR1 axis in resolving neuroinflammation and restoring normal behavior.
