Expression of fractalkine (CX3CL1) and its receptor, CX3CR1, during acute and chronic inflammation in the rodent CNS

Hughes, P.; Botham, Michelle Sandra; Frentzel, Stefan; Mir, Anis K.; Perry, V. Hugh

doi:10.1002/glia.10037

Cited by 218 publications

(117 citation statements)

References 46 publications

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“…It was reported recently that IL-1b induces neuronal death through an astrocyte-dependent mechanism (Thornton et al, 2006). In a prion model of chronic neurodegeneration and inflammation, CX3CL1 immunoreactivity is upregulated in astrocytes and CX3CR1 expression is elevated on microglia (Hughes et al, 2002). Our results might also indicate that fractalkine-CX3CR1 signaling could modulate synthesis, cleavage, and/ or release of IL-1b directly.…”

Section: Discussionsupporting

confidence: 67%

Role of CX3CR1 (Fractalkine Receptor) in Brain Damage and Inflammation Induced by Focal Cerebral Ischemia in Mouse

Dénes

Ferenczi

Halász

et al. 2008

J Cereb Blood Flow Metab

243

220

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CX3CR1 (fractalkine receptor) is important for sustaining normal microglial activity in the brain. Lack of CX3CR1 reportedly results in neurotoxic microglial phenotype in disease models. The objective of this study was to test the hypothesis that the absence of CX3CR1 worsens the outcome in cerebral ischemia. We observed significantly smaller (56%) infarcts and blood-brain barrier damage in CX3CR1-deficient (CX3CR1À/À) animals compared with CX3CR1 + /À and wild-type mice after transient occlusion of the middle cerebral artery (MCAo). Functional recovery of CX3CR1À/À animals was enhanced, while less number of apoptotic cells and infiltrating leukocytes were found in the ipsilateral hemisphere. Expression of IL-1b mRNA, protein, and interleukin (IL)-1Ra and tumor necrosis factor (TNF)-a mRNAs was lower in CX3CR1À/À mice, whereas no difference was observed in the number of IL-1b-expressing microglia or plasma IL-1b concentration. We observed early IL-1b expression in astrocytes in vivo after MCAo and after oxygen-glucose deprivation in vitro, which might contribute to the ischemic damage. Our findings indicate that lack of CX3CR1 does not result in microglial neurotoxicity after MCAo, but rather significantly reduces ischemic damage and inflammation. Reduced IL-1b and TNFa expression as well as decreased leukocyte infiltration might be involved in the development of smaller infarcts in CX3CR1À/À animals.

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Section: Discussionsupporting

confidence: 67%

Role of CX3CR1 (Fractalkine Receptor) in Brain Damage and Inflammation Induced by Focal Cerebral Ischemia in Mouse

Dénes

Ferenczi

Halász

et al. 2008

J Cereb Blood Flow Metab

243

220

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“…Fractalkine is exceptional among other chemokines because it binds selectively to the CX3CR1, and this receptor binds only to fractalkine. 13,15,33 Thus, it is an interesting idea that blocking a single chemokine receptor might influence abdominal pain sensation, inflammation and may be also fibrosis in CP. Therefore, further studies are needed to elucidate the particular role of CX3CR1 in CP and to assess its potential role as a novel therapeutic target.…”

Section: Discussionmentioning

confidence: 99%

“…Fractalkine (CX3CL1), the unique member of the fourth class of chemokines (CX3C), is expressed on endothelial cells and lymphocytes, and is the only other known chemokine to be expressed on spinal neurons and sensory afferents, other than monocyte chemoattractant protein-1 (MCP-1). [11][12][13][14][15] The highly selective fractalkine receptor CX3CR1 is expressed on cytotoxic effector lymphocytes, including natural killer cells, cytotoxic T cells and macrophages. 16 In the nervous system, CX3CR1 is expressed in microglia in the spinal cord, by satellite cells in the dorsal root ganglia (DRG) and in human embryonic neurons.…”

mentioning

confidence: 99%

Neural fractalkine expression is closely linked to pain and pancreatic neuritis in human chronic pancreatitis

Ceyhan

Deucker

Demir

et al. 2009

Laboratory Investigation

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The chemokine fractalkine induces migration of inflammatory cells into inflamed tissues, thereby aggravating inflammatory tissue damage and fibrosis. Furthermore, fractalkine increases neuropathic pain through glial activation, which can be diminished by blocking of its receptor, CX3CR1, through neutralizing antibodies. As chronic pancreatitis (CP) is characterized by tissue infiltration of inflammatory cells, fibrosis, pancreatic neuritis and severe pain, the roles of fractalkine and CX3CR1 were investigated in CP (n ¼ 61) and normal pancreas (NP, n ¼ 21) by QRT-PCR, western blot and immunohistochemistry analyses. Their expression correlated with the severity of pancreatic neuritis, fibrosis, intrapancreatic nerve fiber density and hypertrophy, pain, CP duration and with the amount of inflammatory cell infiltrate immuno-positive for CD45 and CD68. To investigate the influence of fractalkine on pancreatic fibrogenesis, human pancreatic stellate cells (hPSCs) were isolated from patients with CP, incubated with fractalkine and then Collagen-1 and a-smooth muscle actin (a-SMA) expressions were measured. CX3CR1, but not fractalkine, mRNA was overexpressed in CP. In contrast, the protein levels of both CX3CR1 and fractalkine were upregulated. Neuro-immunoreactivity for fractalkine and CX3CR1 was strongest in patients suffering from severe pain and pancreatic neuritis. Long-term suffering from CP was noticeably related to increased neural immunoreactivity of fractalkine. Furthermore, fractalkine and CX3CR1 mRNA overexpressions were associated with enhanced lymphocyte and macrophage infiltration. Advanced fibrosis was associated with increased fractalkine expression, whereas in vitro fractalkine had no significant impact on collagen-1 and a-SMA expressions in hPSCs. Therefore, pancreatic fractalkine expression appears to be linked to visceral pain and to the recruitment of inflammatory cells into the pancreatic tissue and nerve fibers, with subsequent pancreatic neuritis. However, pancreatic fibrogenesis is probably indirectly influenced by fractalkine. Taken together, these novel findings suggest that CX3CR1 represents a potential novel therapeutic target to reduce inflammation and modulate pain in CP.

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“…It is converted to a soluble form on cleavage from the plasma membrane through the action of metalloproteinases, like a disintegrin and metalloproteinase domains (ADAM) 10 and ADAM17 on leukocytes (Hundhausen et al, 2003) or cathepsin S in the spinal cord (Clark et al, 2007). CX3CL1 is constitutively expressed in the nervous system, but levels in the brain can be modulated under diverse pathological conditions (Pan et al, 1997;Hughes et al, 2002;Kastenbauer et al, 2003;Sunnemark et al, 2005;Huang et al, 2006). The presence and the stimulation (Zujovic et al, 2000(Zujovic et al, , 2001Mizuno et al, 2003;Cardona et al, 2006;Lyons et al, 2009) of the CX3CL1 receptor CX3CR1 has been correlated with a reduced release of interleukin-1-b (IL-1-b) and tumor necrosis factor-a (TNF-a) from microglial cells and a lower rate of neuronal degeneration in different experimental models of neuropathologies such as experimental autoimmune encephalomyelitis, 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine hydrochloride striatal injection, lipopolysaccharide administration, and superoxide dismutase (SOD1) mutation (Huang et al, 2006;Cardona et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Adenosine A1 Receptors and Microglial Cells Mediate CX3CL1-Induced Protection of Hippocampal Neurons Against Glu-Induced Death

Lauro

Cipriani

Catalano

et al. 2010

Neuropsychopharmacol

110

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Fractalkine/CX3CL1 is a neuron-associated chemokine, which modulates microglia-induced neurotoxicity activating the specific and unique receptor CX3CR1. CX3CL1/CX3CR1 interaction modulates the release of cytokines from microglia, reducing the level of tumor necrosis factor-a, interleukin-1-b, and nitric oxide and induces the production of neurotrophic substances, both in vivo and in vitro. We have recently shown that blocking adenosine A 1 receptors (A 1 R) with the specific antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) abolishes CX3CL1-mediated rescue of neuronal excitotoxic death and that CX3CL1 induces the release of adenosine from microglia. In this study, we show that the presence of extracellular adenosine is mandatory for the neurotrophic effect of CX3CL1 as reducing adenosine levels in hippocampal cultures, by adenosine deaminase treatment, strongly impairs CX3CL1-mediated neuroprotection. Furthermore, we confirm the predominant role of microglia in mediating the neuronal effects of CX3CL1, because the selective depletion of microglia from hippocampal cultures treated with clodronate-filled liposomes causes the complete loss of effect of CX3CL1. We also show that hippocampal neurons obtained from A 1 R À/À mice are not protected by CX3CL1 whereas A 2A R À/À neurons are. The requirement of functional A 1 R for neuroprotection is not unique for CX3CL1 as A 1 R À/À hippocampal neurons are not rescued from Glu-induced cell death by other neurotrophins such as brain-derived neurotrophic factor and erythropoietin, which are fully active on wt neurons.

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Expression of fractalkine (CX3CL1) and its receptor, CX3CR1, during acute and chronic inflammation in the rodent CNS

Cited by 218 publications

References 46 publications

Role of CX3CR1 (Fractalkine Receptor) in Brain Damage and Inflammation Induced by Focal Cerebral Ischemia in Mouse

Role of CX3CR1 (Fractalkine Receptor) in Brain Damage and Inflammation Induced by Focal Cerebral Ischemia in Mouse

Neural fractalkine expression is closely linked to pain and pancreatic neuritis in human chronic pancreatitis

Adenosine A1 Receptors and Microglial Cells Mediate CX3CL1-Induced Protection of Hippocampal Neurons Against Glu-Induced Death

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