Cardona, A. E. et al. Control of microglial neurotoxicity by the fractalkine receptor. Nature Neurosci. 9, 917-924

Weizmann Institute of Science, Rhovot, Central District, Israel
Nature Neuroscience (Impact Factor: 16.1). 08/2006; 9(7):917-24. DOI: 10.1038/nn1715
Source: PubMed


Microglia, the resident inflammatory cells of the CNS, are the only CNS cells that express the fractalkine receptor (CX3CR1). Using three different in vivo models, we show that CX3CR1 deficiency dysregulates microglial responses, resulting in neurotoxicity. Following peripheral lipopolysaccharide injections, Cx3cr1-/- mice showed cell-autonomous microglial neurotoxicity. In a toxic model of Parkinson disease and a transgenic model of amyotrophic lateral sclerosis, Cx3cr1-/- mice showed more extensive neuronal cell loss than Cx3cr1+ littermate controls. Augmenting CX3CR1 signaling may protect against microglial neurotoxicity, whereas CNS penetration by pharmaceutical CX3CR1 antagonists could increase neuronal vulnerability.

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    • "sought to determine the degree to which an acute LPS injec - tion differed from the repeated LPS injection in the context of sickness behavior , glial cytokine induction , and morphological changes . To be consistent with other studies using repeated LPS injections , a higher dosage of LPS ( 20 lg per mouse ) was used ( Bodea et al . , 2014 ; Cardona et al . , 2006 ; Chen et al . , 2012 ; Puntener et al . , 2012 ) . This dose was twice as high as the LPS dosage used in Figs . 1 – 3 . The diagram provided ( Fig . 4A"
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    ABSTRACT: Activation of the peripheral immune system elicits a coordinated response from the central nervous system. Key to this immune to brain communication is that glia, microglia, and astrocytes, interpret and propagate inflammatory signals in the brain that influence physiological and behavioral responses. One issue in glial biology is that morphological analysis alone is used to report on glial activation state. Therefore, our objective was to compare behavioral responses after in vivo immune (lipopolysaccharide, LPS) challenge to glial specific mRNA and morphological profiles. Here, LPS challenge induced an immediate but transient sickness response with decreased locomotion and social interaction. Corresponding with active sickness behavior (2-12 h), inflammatory cytokine mRNA expression was elevated in enriched microglia and astrocytes. Although proinflammatory cytokine expression in microglia peaked 2-4 h after LPS, astrocyte cytokine, and chemokine induction was delayed and peaked at 12 h. Morphological alterations in microglia (Iba-1(+) ) and astrocytes (GFAP(+) ), however, were undetected during this 2-12 h timeframe. Increased Iba-1 immunoreactivity and de-ramified microglia were evident 24 and 48 h after LPS but corresponded to the resolution phase of activation. Morphological alterations in astrocytes were undetected after LPS. Additionally, glial cytokine expression did not correlate with morphology after four repeated LPS injections. In fact, repeated LPS challenge was associated with immune and behavioral tolerance and a less inflammatory microglial profile compared with acute LPS challenge. Overall, induction of glial cytokine expression was sequential, aligned with active sickness behavior, and preceded increased Iba-1 or GFAP immunoreactivity after LPS challenge. GLIA 2015.
    Full-text · Article · Oct 2015 · Glia
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    • "Among these factors there is fractalkine (CX3CL1), a chemokine constitutively expressed on neuronal membrane (Harrison et al., 1998) that is upregulated, cleaved and released upon excitotoxic insult (Chapman et al., 2000). The peculiarity of CX3CL1 is that, contrary to almost all chemokines, it binds a unique receptor, CX3CR1, that in the brain is expressed only by microglia (Harrison et al., 1998; Cardona et al., 2006): thus the CX3CL1/CX3CR1 pair represents an intriguing communication system between neuronal cells and microglia in order to maintain brain homeostasis and to fully guarantee central nervous system (CNS) functions. "

    Full-text · Article · Aug 2015 · Neural Regeneration Research
    • "This was followed soon after with creation of a Cx3cr1 Gfp/Gfp mouse (Jung et al., 2000), which not only deleted Cx3cr1 but also allowed for clear identification of CX3CR1 in microglial cells (Cardona et al., 2006; Jung et al., 2000). Indeed, microglial cells from the Cx3cr1 Gfp/Gfp mice produced higher levels of IL-1b in response to LPS (Cardona et al., 2006; Rogers et al., 2011). 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was originally synthesized as a by-product in the synthesis of a meperidine analog, desmethylprodine, in the late 1970s. "
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    ABSTRACT: Immunotoxicology assessments have historically focused on the effects that xenobiotics exhibit directly on immune cells. These studies are invaluable as they identify immune cell targets and help characterize mechanisms and/or adverse outcome pathways of xenobiotics within the immune system. However, leukocytes can receive environmental cues by cell-cell contact or via released mediators from cells of organs outside of the immune system. These organs include, but are not limited to, the mucosal areas such as the lung and the gut, the liver, and the central nervous system. Homeostatic perturbation in these organs induced directly by toxicants can initiate and alter the outcome of local and systemic immunity. This review will highlight some of the identified nonimmune influences on immune homeostasis and provide summaries of how immunotoxic mechanisms of selected xenobiotics involve nonimmune cells or mediators. Thus, this review will identify data gaps and provide possible alternative mechanisms by which xenobiotics alter immune function that could be considered during immunotoxicology safety assessment. © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail:
    No preview · Article · Jun 2015 · Toxicological Sciences
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