Chronic neuroinflammation and cognitive impairment following transient global cerebral ischemia: role of fractalkine/CX3CR1 signaling

Briones, Teresita L.; Woods, Julie; Wadowska, Magdalena

doi:10.1186/1742-2094-11-13

Cited by 29 publications

(28 citation statements)

References 34 publications

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“…Over the last few years, there have been escalating reports implying that the absence of CX3CR1 is associated with a worse outcome possibly due to the lack of CX3CL1-mediated capture of microglia resulting in activation and neuroinflammation [12,41–43]. Conflicting reports have also suggested that loss of signaling via CX3CR1 can either be protective [44–46] or have no effect at all [47,48].…”

Section: Discussionmentioning

confidence: 99%

HIV-1 Tat Disrupts CX3CL1-CX3CR1 Axis in Microglia via the NF-κBYY1 Pathway

Duan¹,

Yao²,

Cai³

et al. 2014

CHR

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Microglia play a central role in the pathogenesis of HIV-associated dementia not only by acting as conduits of viral entry but also as reservoirs for productive and latent virus infection, and as producers of neurotoxins. Interaction between CX3CL1 (fractalkine) and FKN receptor (CX3CR1) is highly functional in the brain, and is known to regulate a complex network of paracrine and autocrine interactions between neurons and microglia. The purpose of the present study was to determine what extent HIV-1 Tat protein causes the alteration of CX3CR1 expression and to investigate the regulatory mechanism for CX3CR1 expression. Here we showed that exposure of primary microglia and BV2 cells to exogenous Tat protein resulted in down-regulation of CX3CR1 expression at both the mRNA and protein levels, with a concomitant induction of proinflammatory responses. Next, we further showed that NF-κB activation by Tat treatment negatively regulated CX3CR1 expression. Since a YY1 binding site ~10kb upstream of CX3CR1 promoter was predicted in rats, mice and humans, the classical NF-κB-YY1 regulatory pathway was considered. Our findings indicated that Tat repressed CX3CR1 expression via NF-κB-YY1 regulatory pathway. To gain insight into the effect of Tat on CX3CL1-CX3CR1 communication, calcium mobilization, MAPK activation and microglial migration, respectively, were tested in microglial cells after successive treatment with Tat and CX3CL1. The results suggested that Tat disrupted the responses of microglia to CX3CL1. Taken together, these results demonstrate that HIV-1 Tat protein suppresses CX3CR1 expression in microglia via NF-κB-YY1 pathway and attenuates CX3CL1-induced functional response of microglia.

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Section: Discussionmentioning

confidence: 99%

HIV-1 Tat Disrupts CX3CL1-CX3CR1 Axis in Microglia via the NF-κBYY1 Pathway

Duan¹,

Yao²,

Cai³

et al. 2014

CHR

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“…Conversely, the only study evaluating the delayed (but not the acute) effects of CX3CR1 deficiency following tMCAo showed a worsening of cognitive outcome associated with an increase in M1 polarized microglial cells. 14 After spinal cord injury (SCI), when CX3CL1:CX3CR1 signaling was abolished, neurological recovery was improved, spinal cord pathology reduced, and the phenotype and function of M/l were different from that normally present after SCI 18 at both 5 days and 35 days. A follow up study showed, however, an impaired locomotor function associated with an increase in infiltrating M/l cells when assessed at 42 days post-injury.…”

Section: Discussionmentioning

confidence: 99%

“…11,12 Following an acute brain insult, affected neurons significantly reduce the release of CX3CL1, allowing microglial activation. 13,14 An early protective effect of CX3CR1 deletion was reported in different models of acute brain injury, including ischemia or spinal cord injury. [15][16][17][18][19] At variance, in neurodegenerative disorders, disruption of the CX3CL1:CX3CR1 axis led to different results.…”

Section: Nflammation Is a Central Component Of Traumatic Brain Injumentioning

confidence: 99%

Fractalkine Receptor Deficiency Is Associated with Early Protection but Late Worsening of Outcome following Brain Trauma in Mice

Zanier

Marchesi

Ortolano

et al. 2016

Journal of Neurotrauma

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An impaired ability to regulate microglia activation by fractalkine (CX3CL1) leads to microglia chronic sub-activation. How this condition affects outcome after acute brain injury is still debated, with studies showing contrasting results depending on the timing and the brain pathology. Here, we investigated the early and delayed consequences of fractalkine receptor (CX3CR1) deletion on neurological outcome and on the phenotypical features of the myeloid cells present in the lesions of mice with traumatic brain injury (TBI). Wild type (WT) and CX3CR1 -/-C57Bl/6 mice were subjected to sham or controlled cortical impact brain injury. Outcome was assessed at 4 days and 5 weeks after TBI by neuroscore, neuronal count, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Compared with WT mice, CX3CR1 -/-TBI mice showed a significant reduction of sensorimotor deficits and lower cellular damage in the injured cortex 4 days post-TBI. Conversely, at 5 weeks, they showed a worsening of sensorimotor deficits and pericontusional cell death. Microglia (M) and macrophage (l) activation and polarization were assessed by quantitative immunohistochemistry for CD11b, CD68, Ym1, and inducible nitric oxide synthase (iNOS)-markers of M/l activation, phagocytosis, M2, and M1 phenotypes, respectively. Morphological analysis revealed a decreased area and perimeter of CD11b + cells in CX3CR1 -/-mice at 4 days post-TBI, whereas, at 5 weeks, both parameters were significantly higher, compared with WT mice. At 4 days, CX3CR1 -/-mice showed significantly decreased CD68 and iNOS immunoreactivity, while at 5 weeks post-injury, they showed a selective increase of iNOS. Gene expression on CD11b + sorted cells revealed an increase of interleukin 10 and insulin-like growth factor 1 (IGF1) at 1 day and a decrease of IGF1 4 days and 5 weeks post-TBI in CX3CR1 -/-, compared with WT mice. These data show an early protection followed by a chronic exacerbation of TBI outcome in the absence of CX3CR1. Thus, longitudinal effects of myeloid cell manipulation at different stages of pathology should be investigated to understand how and when their modulation may offer therapeutic chances.

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“…Fractalkine/CX3CR1 signaling has been demonstrated in numerous studies to dampen neuroinflammation, with fractalkine signaling being shown to reduce IL-1β secretion in lipopolysaccharide-treated microglia [14]. This has also been shown in vivo as rats with cerebral ischemia administered CX3CR1 siRNA were found to have increased microglia activation and proinflammatory cytokine expression compared to ischemic controls [15]. In addition to this, in a variety of inflammatory conditions there is a reciprocal relationship between fractalkine and CCL2, though whether these chemokines have a direct effect on each other or are inversely affected by an extraneous signal is unknown [16, 17].…”

Section: Introductionmentioning

confidence: 99%

Fractalkine suppression during hepatic encephalopathy promotes neuroinflammation in mice

McMillin

Grant

Frampton

et al. 2016

J Neuroinflammation

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BackgroundAcute liver failure is associated with numerous systemic consequences including neurological dysfunction, termed hepatic encephalopathy, which contributes to mortality and is a challenge to manage in the clinic. During hepatic encephalopathy, microglia activation and neuroinflammation occur due to dysregulated cell signaling and an increase of toxic metabolites in the brain. Fractalkine is a chemokine that is expressed primarily in neurons and through signaling with its receptor CX3CR1 on microglia, leads to microglia remaining in a quiescent state. Fractalkine is often suppressed during neuropathies that are characterized by neuroinflammation. However, the expression and subsequent role of fractalkine on microglia activation and the pathogenesis of hepatic encephalopathy due to acute liver failure is unknown.MethodsHepatic encephalopathy was induced in mice via injection of azoxymethane (AOM) or saline for controls. Subsets of these mice were implanted with osmotic minipumps that infused soluble fractalkine or saline into the lateral ventricle of the brain. Neurological decline and the latency to coma were recorded in these mice, and brain, serum, and liver samples were collected. Neurons or microglia were isolated from whole brain samples using immunoprecipitation. Liver damage was assessed using hematoxylin and eosin staining and by measuring serum liver enzyme concentrations. Fractalkine and CX3CR1 expression were assessed by real-time PCR, and proinflammatory cytokine expression was assessed using ELISA assays.ResultsFollowing AOM administration, fractalkine expression is suppressed in the cortex and in isolated neurons compared to vehicle-treated mice. CX3CR1 is suppressed in isolated microglia from AOM-treated mice. Soluble fractalkine infusion into the brain significantly reduced neurological decline in AOM-treated mice compared to saline-infused AOM-treated mice. Infusion of soluble fractalkine into AOM-treated mice reduced liver damage, lessened microglia activation, and suppressed expression of chemokine ligand 2, interleukin-6, and tumor necrosis factor alpha compared to saline-infused mice.ConclusionsThese findings suggest that fractalkine-mediated signaling is suppressed in the brain following the development of hepatic encephalopathy. Supplementation of AOM-treated mice with soluble fractalkine led to improved outcomes, which identifies this pathway as a possible therapeutic target for the management of hepatic encephalopathy following acute liver injury.

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Chronic neuroinflammation and cognitive impairment following transient global cerebral ischemia: role of fractalkine/CX3CR1 signaling

Cited by 29 publications

References 34 publications

HIV-1 Tat Disrupts CX3CL1-CX3CR1 Axis in Microglia via the NF-κBYY1 Pathway

HIV-1 Tat Disrupts CX3CL1-CX3CR1 Axis in Microglia via the NF-κBYY1 Pathway

Fractalkine Receptor Deficiency Is Associated with Early Protection but Late Worsening of Outcome following Brain Trauma in Mice

Fractalkine suppression during hepatic encephalopathy promotes neuroinflammation in mice

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