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

Neuroinflammation Research Center and Department of Neurosciences, Lerner Research Institute, Cleveland, Ohio 44195, USA.
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.
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    • "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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    • "Because T cells can barely be detected in healthy CNS parenchyma, T cells likely interact with microglia via secreted factors (Ziv and Schwartz, 2008b). CX3CR1 is expressed primarily in microglia (Cardona et al., 2006; Harrison et al., 1998) and is located in hippocampal neurons (Sheridan and Murphy, 2013). Its ligand, CX3CL1/fractalkine, can act as a signaling molecule when cleaved (Chapman et al., 2000). "
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