Skip to main content
Top
Published in: Journal of Neuroinflammation 1/2014

Open Access 01-12-2014 | Research

RETRACTED ARTICLE: Chronic neuroinflammation and cognitive impairment following transient global cerebral ischemia: role of fractalkine/CX3CR1 signaling

Authors: Teresita L Briones, Julie Woods, Magdalena Wadowska

Published in: Journal of Neuroinflammation | Issue 1/2014

Login to get access

Abstract

Although neuroinflammation has been studied extensively in animal models of cerebral ischemia, their contrasting functions are still not completely understood. A major participant in neuroinflammation is microglia and microglial activation usually regulated by the chemokine CX3CL1 (fractalkine) and its receptor, CX3CR1. Here, we examined the involvement of CX3CR1 on ischemia-induced chronic neuroinflammation and cognitive function using small interfering RNA (siRNA). Forty adult male Wistar rats were included in the study and received either ischemia or sham surgery then were randomized to receive either CX3CR1 siRNA or scrambled RNA as control starting at 7 days after reperfusion. Behavioral testing commenced 28 days after siRNA delivery and all rats were euthanized after behavioral testing. Our data showed that: (i) transient global cerebral ischemia significantly decreased fractalkine/CX3CR1 signaling in the hippocampus; (ii) inhibition of CX3CR1 function exacerbated the ischemia-induced chronic increase in microglial activation and pro-inflammatory cytokine levels; (iii) inhibition of CX3CR1 function worsened ischemia-induced chronic cognitive impairment; (iv) inhibition of CX3CR1 function in sham rats resulted in increased IL-1β expression and impaired behavioral performance. However, no significant effect of CX3CR1 on ischemia-induced neurodegeneration was seen. The present study provides important insight to understanding the involvement of CX3CR1 in chronic neuroinflammation and cognitive impairment.
Appendix
Available only for authorised users
Literature
1.
go back to reference McColl BW, Allan SM, Rothwell NJ: Systemic inflammation and stroke: aetiology, pathology and targets for therapy. Biochem Soc Trans. 2007, 35: 1163-1165. 10.1042/BST0351163.CrossRefPubMed McColl BW, Allan SM, Rothwell NJ: Systemic inflammation and stroke: aetiology, pathology and targets for therapy. Biochem Soc Trans. 2007, 35: 1163-1165. 10.1042/BST0351163.CrossRefPubMed
2.
go back to reference Muir KW, Tyrrell PJ, Sattar N, Warburton EC: Inflammation and ischaemic stroke. Curr Opin Neurol. 2007, 20: 334-342. 10.1097/WCO.0b013e32813ba151.CrossRefPubMed Muir KW, Tyrrell PJ, Sattar N, Warburton EC: Inflammation and ischaemic stroke. Curr Opin Neurol. 2007, 20: 334-342. 10.1097/WCO.0b013e32813ba151.CrossRefPubMed
3.
go back to reference Selakovic V, Raicevic R, Radenovic L: Temporal patterns of souluble adhesion molecules in cerebrospinal fluid and plasma in patients with the acute brain infraction. Dis Markers. 2009, 26: 65-74. 10.1155/2009/490867.CrossRefPubMedPubMedCentral Selakovic V, Raicevic R, Radenovic L: Temporal patterns of souluble adhesion molecules in cerebrospinal fluid and plasma in patients with the acute brain infraction. Dis Markers. 2009, 26: 65-74. 10.1155/2009/490867.CrossRefPubMedPubMedCentral
4.
go back to reference Pluta R, Ulamek-Koziol M, Januszewski S, Scislewska M, Bogucka-Kocka A, Kocki J: Alzheimer’s factors in postischemic dementia. Rom J Morphol Embryol. 2012, 53: 461-466.PubMed Pluta R, Ulamek-Koziol M, Januszewski S, Scislewska M, Bogucka-Kocka A, Kocki J: Alzheimer’s factors in postischemic dementia. Rom J Morphol Embryol. 2012, 53: 461-466.PubMed
5.
go back to reference Eggen BJL, Raj D, Hanisch UK, Boddeke HW: Microglial phenotype and adaptation. J Neuroimmune Pharmacol. 2013, 8: 807-823. 10.1007/s11481-013-9490-4.CrossRefPubMed Eggen BJL, Raj D, Hanisch UK, Boddeke HW: Microglial phenotype and adaptation. J Neuroimmune Pharmacol. 2013, 8: 807-823. 10.1007/s11481-013-9490-4.CrossRefPubMed
6.
go back to reference Neumann J, Sauerzweig S, Ronicke R, Gunzer F, Dinkel K, Ullrich O, Gunzer M, Reymann KG: Microglia cells protect neurons by direct engulfment of invading neutrophil granulocytes: a new mechanism of CNS immune privilege. J Neurosci. 2008, 28: 5965-5975. 10.1523/JNEUROSCI.0060-08.2008.CrossRefPubMed Neumann J, Sauerzweig S, Ronicke R, Gunzer F, Dinkel K, Ullrich O, Gunzer M, Reymann KG: Microglia cells protect neurons by direct engulfment of invading neutrophil granulocytes: a new mechanism of CNS immune privilege. J Neurosci. 2008, 28: 5965-5975. 10.1523/JNEUROSCI.0060-08.2008.CrossRefPubMed
7.
go back to reference Lalancette-Hebert M, Gowing G, Simard A, Weng YG, Kriz J: Selective ablation of proliferating microglial cells exacerbates ischemic injury in the brain. J Neurosci. 2007, 27: 2596-2605. 10.1523/JNEUROSCI.5360-06.2007.CrossRefPubMed Lalancette-Hebert M, Gowing G, Simard A, Weng YG, Kriz J: Selective ablation of proliferating microglial cells exacerbates ischemic injury in the brain. J Neurosci. 2007, 27: 2596-2605. 10.1523/JNEUROSCI.5360-06.2007.CrossRefPubMed
8.
go back to reference Harrison JK, Jiang Y, Chen SF, Xia Y, Maciejewski D, McNamara RK, Streit WJ, Salafranca MN, Adhikari S, Thompson DA, et al: Role for neuronally derived fractalkine in mediating interactions between neurons and CX3CR1-expressing microglia. Proc Natl Acad Sci USA. 1998, 95: 10896-10901. 10.1073/pnas.95.18.10896.CrossRefPubMedPubMedCentral Harrison JK, Jiang Y, Chen SF, Xia Y, Maciejewski D, McNamara RK, Streit WJ, Salafranca MN, Adhikari S, Thompson DA, et al: Role for neuronally derived fractalkine in mediating interactions between neurons and CX3CR1-expressing microglia. Proc Natl Acad Sci USA. 1998, 95: 10896-10901. 10.1073/pnas.95.18.10896.CrossRefPubMedPubMedCentral
9.
go back to reference Ransohoff RM, Liu L, Cardona AE: Chemokines and chemokine receptors: multipurpose players in neuroinflammation. Int Rev Neurobiol. 2007, 82: 187-204.CrossRefPubMed Ransohoff RM, Liu L, Cardona AE: Chemokines and chemokine receptors: multipurpose players in neuroinflammation. Int Rev Neurobiol. 2007, 82: 187-204.CrossRefPubMed
10.
go back to reference Desforges NM, Hebron ML, Algarzae NK, Lonskaya I, Moussa CE: Fractalkine mediates communication between pathogenic proteins and microglia: implications of anti-inflammatory treatments in different stages of neurodegenerative diseases. Int J Alzheimers Dis. 2012, 2012: 345472.PubMedPubMedCentral Desforges NM, Hebron ML, Algarzae NK, Lonskaya I, Moussa CE: Fractalkine mediates communication between pathogenic proteins and microglia: implications of anti-inflammatory treatments in different stages of neurodegenerative diseases. Int J Alzheimers Dis. 2012, 2012: 345472.PubMedPubMedCentral
11.
go back to reference Maggi L, Scianni M, Branchi I, D’Andrea I, Lauro C, Limatola C: CX(3)CR1 deficiency alters hippocampal-dependent plasticity phenomena blunting the effects of enriched environment. Front Cell Neurosci. 2011, 5: 22.CrossRefPubMedPubMedCentral Maggi L, Scianni M, Branchi I, D’Andrea I, Lauro C, Limatola C: CX(3)CR1 deficiency alters hippocampal-dependent plasticity phenomena blunting the effects of enriched environment. Front Cell Neurosci. 2011, 5: 22.CrossRefPubMedPubMedCentral
12.
go back to reference Cardona AE, Pioro EP, Sasse ME, Kostenko V, Cardona SM, Dijkstra IM, Huang D, Kidd G, Dombrowski S, Dutta R, Lee JC, Cook DN, Jung S, Lira SA, Littman DR, Ransohoff RM: Control of microglial neurotoxicity by the fractalkine receptor. Nat Neurosci. 2006, 9: 917-924. 10.1038/nn1715.CrossRefPubMed Cardona AE, Pioro EP, Sasse ME, Kostenko V, Cardona SM, Dijkstra IM, Huang D, Kidd G, Dombrowski S, Dutta R, Lee JC, Cook DN, Jung S, Lira SA, Littman DR, Ransohoff RM: Control of microglial neurotoxicity by the fractalkine receptor. Nat Neurosci. 2006, 9: 917-924. 10.1038/nn1715.CrossRefPubMed
13.
go back to reference Pabon MM, Bachstetter AD, Hudson CE, Gemma C, Bickford PC: CX3CL1 reduces neurotoxicity and microglial activation in a rat model of Parkinson's disease. J Neuroinflammation. 2011, 8: 9-10.1186/1742-2094-8-9.CrossRefPubMedPubMedCentral Pabon MM, Bachstetter AD, Hudson CE, Gemma C, Bickford PC: CX3CL1 reduces neurotoxicity and microglial activation in a rat model of Parkinson's disease. J Neuroinflammation. 2011, 8: 9-10.1186/1742-2094-8-9.CrossRefPubMedPubMedCentral
14.
go back to reference Cho S-H, Sun B, Zhou Y, Kauppinen TM, Halbisky B, Wes P, Ransohoff RM, Gan L: CX3CR1 protein signaling modulates microglial activation and protects against plaque-independent cognitive deficits in a mouse model of Alzheimer disease. J Biol Chem. 2011, 286: 32713-32722. 10.1074/jbc.M111.254268.CrossRefPubMedPubMedCentral Cho S-H, Sun B, Zhou Y, Kauppinen TM, Halbisky B, Wes P, Ransohoff RM, Gan L: CX3CR1 protein signaling modulates microglial activation and protects against plaque-independent cognitive deficits in a mouse model of Alzheimer disease. J Biol Chem. 2011, 286: 32713-32722. 10.1074/jbc.M111.254268.CrossRefPubMedPubMedCentral
15.
go back to reference Ladecola C, Anrather J: The immunology of stroke: from mechanims to translation. Nat Med. 2011, 17: 796-808. 10.1038/nm.2399.CrossRef Ladecola C, Anrather J: The immunology of stroke: from mechanims to translation. Nat Med. 2011, 17: 796-808. 10.1038/nm.2399.CrossRef
16.
go back to reference Fumagalli S, Perego C, Ortolano F, De Simoni MG: CX3CR1 deficiency induces an early protective inflammatory environment in ischemic mice. Glia. 2013, 61: 827-842. 10.1002/glia.22474.CrossRefPubMed Fumagalli S, Perego C, Ortolano F, De Simoni MG: CX3CR1 deficiency induces an early protective inflammatory environment in ischemic mice. Glia. 2013, 61: 827-842. 10.1002/glia.22474.CrossRefPubMed
17.
go back to reference Cipriani R, Villa P, Chece G, Lauro C, Paladini A, Micotti E, Perego C, De Simoni MG, Fredholm BB, Eusebi F, Limatola C: CX3CL1 is neuroprotective in permanent focal cerebral ischemia in rodents. J Neurosci. 2011, 31: 16327-16335. 10.1523/JNEUROSCI.3611-11.2011.CrossRefPubMed Cipriani R, Villa P, Chece G, Lauro C, Paladini A, Micotti E, Perego C, De Simoni MG, Fredholm BB, Eusebi F, Limatola C: CX3CL1 is neuroprotective in permanent focal cerebral ischemia in rodents. J Neurosci. 2011, 31: 16327-16335. 10.1523/JNEUROSCI.3611-11.2011.CrossRefPubMed
18.
go back to reference Denes A, Ferenczi S, Halasz J, Kornyei Z, Kovacs K: Role of CX3CR1 (fractalkine receptor) in brain damage and neuroinflammation induced by focal cerebral ischemia in mouse. J Cereb Blood Flow Metab. 2008, 28: 1707-1721. 10.1038/jcbfm.2008.64.CrossRefPubMed Denes A, Ferenczi S, Halasz J, Kornyei Z, Kovacs K: Role of CX3CR1 (fractalkine receptor) in brain damage and neuroinflammation induced by focal cerebral ischemia in mouse. J Cereb Blood Flow Metab. 2008, 28: 1707-1721. 10.1038/jcbfm.2008.64.CrossRefPubMed
19.
go back to reference Briones TL, Suh E, Jozsa L, Hattar H, Chai J, Wadowska M: Behaviorally-induced ultrastructural plasticity in the hippocampal region after cerebral ischemia. Brain Res. 2004, 997: 137-146. 10.1016/j.brainres.2003.10.030.CrossRefPubMed Briones TL, Suh E, Jozsa L, Hattar H, Chai J, Wadowska M: Behaviorally-induced ultrastructural plasticity in the hippocampal region after cerebral ischemia. Brain Res. 2004, 997: 137-146. 10.1016/j.brainres.2003.10.030.CrossRefPubMed
20.
go back to reference Paxinos G, Watson C: The Rat Brain in Stereotaxic Coordinates. 1997, London: Academic Press, 3 Paxinos G, Watson C: The Rat Brain in Stereotaxic Coordinates. 1997, London: Academic Press, 3
21.
go back to reference Lourbopoulos A, Grigoriadis N, Karacostas D, Spandou E, Artemis N, Milonas I, Tascos N, Simeonidou C: Predictable ventricular shift after focal cerebral ischemia in rats: practical considerations for intraventricular therapeutic interventions. Lab Anim. 2011, 44: 71-78.CrossRef Lourbopoulos A, Grigoriadis N, Karacostas D, Spandou E, Artemis N, Milonas I, Tascos N, Simeonidou C: Predictable ventricular shift after focal cerebral ischemia in rats: practical considerations for intraventricular therapeutic interventions. Lab Anim. 2011, 44: 71-78.CrossRef
22.
go back to reference Wu J, Bie B, Yang H, Xu JJ, Brown DL, Naguib M: Suppression of central chemokine fractalkine receptor signaling alleviates amyloid-induced memory deficiency. Neurobiol Aging. 2013, 34: 2843-2852. 10.1016/j.neurobiolaging.2013.06.003.CrossRefPubMed Wu J, Bie B, Yang H, Xu JJ, Brown DL, Naguib M: Suppression of central chemokine fractalkine receptor signaling alleviates amyloid-induced memory deficiency. Neurobiol Aging. 2013, 34: 2843-2852. 10.1016/j.neurobiolaging.2013.06.003.CrossRefPubMed
23.
go back to reference Sioud M: siRNA delivery in vivo. Methods Mol Biol. 2005, 309: 237-249.PubMed Sioud M: siRNA delivery in vivo. Methods Mol Biol. 2005, 309: 237-249.PubMed
25.
go back to reference Winocur G, Hasher L: Age and time-of-day effects on learning and memory in a non-matching-to-sample test. Neurobiol Aging. 2004, 25: 1107-1115. 10.1016/j.neurobiolaging.2003.10.005.CrossRefPubMed Winocur G, Hasher L: Age and time-of-day effects on learning and memory in a non-matching-to-sample test. Neurobiol Aging. 2004, 25: 1107-1115. 10.1016/j.neurobiolaging.2003.10.005.CrossRefPubMed
26.
go back to reference Briones TL, Rogozinska M, Woods J: Modulation of ischemia-induced NMDAR1 activation by environmental enrichment decreases oxidative damage. J Neurotrauma. 2011, 28: 2485-2492. 10.1089/neu.2011.1842.CrossRefPubMedPubMedCentral Briones TL, Rogozinska M, Woods J: Modulation of ischemia-induced NMDAR1 activation by environmental enrichment decreases oxidative damage. J Neurotrauma. 2011, 28: 2485-2492. 10.1089/neu.2011.1842.CrossRefPubMedPubMedCentral
27.
go back to reference Livak KJ, Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2−∆∆CT method. Methods. 2001, 25: 402-408. 10.1006/meth.2001.1262.CrossRefPubMed Livak KJ, Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2−∆∆CT method. Methods. 2001, 25: 402-408. 10.1006/meth.2001.1262.CrossRefPubMed
28.
go back to reference Hassani Z, Lemkine GF, Erbacher P, Palmier K, Alfama G, Behr C, Demeneix J-P: Lipid-mediated siRNA delivery downregulates exogenous gene expression in the mouse brain at picomolar levels. J Gene Med. 2005, 7: 198-207.CrossRefPubMed Hassani Z, Lemkine GF, Erbacher P, Palmier K, Alfama G, Behr C, Demeneix J-P: Lipid-mediated siRNA delivery downregulates exogenous gene expression in the mouse brain at picomolar levels. J Gene Med. 2005, 7: 198-207.CrossRefPubMed
29.
go back to reference Soriano SG, Amaravadi LS, Wang YF, Zhou H, Yu GX, Tonra JR, Fairchild-Huntress V, Fang Q: Mice deficient in fractalkine are less susceptible to cerebral ischemia-reperfusion injury. J Neuroimmunol. 2002, 125: 59-65. 10.1016/S0165-5728(02)00033-4.CrossRefPubMed Soriano SG, Amaravadi LS, Wang YF, Zhou H, Yu GX, Tonra JR, Fairchild-Huntress V, Fang Q: Mice deficient in fractalkine are less susceptible to cerebral ischemia-reperfusion injury. J Neuroimmunol. 2002, 125: 59-65. 10.1016/S0165-5728(02)00033-4.CrossRefPubMed
30.
go back to reference Tarozzo G, Campanella M, Ghiani M, Bulfone A, Beltramo M: Expression of fractalkine and its receptor, CX3CR1, in response to ischemia-reperfusion brain injury in the rat. Eur J Neuroscie. 2002, 15: 1663-1668. 10.1046/j.1460-9568.2002.02007.x.CrossRef Tarozzo G, Campanella M, Ghiani M, Bulfone A, Beltramo M: Expression of fractalkine and its receptor, CX3CR1, in response to ischemia-reperfusion brain injury in the rat. Eur J Neuroscie. 2002, 15: 1663-1668. 10.1046/j.1460-9568.2002.02007.x.CrossRef
32.
go back to reference Gaikward SM, Heneka MT: Studying M1 and M2 states in adult microglia. Methods Mol Biol. 2013, 1041: 185-197. 10.1007/978-1-62703-520-0_18.CrossRef Gaikward SM, Heneka MT: Studying M1 and M2 states in adult microglia. Methods Mol Biol. 2013, 1041: 185-197. 10.1007/978-1-62703-520-0_18.CrossRef
33.
go back to reference Wang J, Yang Z, Liu CL, Zhao Y, Chen Y: Activated microglia provide a neuroprotective role by balancing glial cell-line derived neurotrophic factor and tumor necrosis factor-alpha secretion after subacute cerebral ischemia. Int J Mol Med. 2013, 31: 172-178.PubMedPubMedCentral Wang J, Yang Z, Liu CL, Zhao Y, Chen Y: Activated microglia provide a neuroprotective role by balancing glial cell-line derived neurotrophic factor and tumor necrosis factor-alpha secretion after subacute cerebral ischemia. Int J Mol Med. 2013, 31: 172-178.PubMedPubMedCentral
34.
go back to reference Rogers JT, Morganti JM, Bachstetter AD, Hudson CE, Peters MM, Grimmig BA, Weeber EJ, Bickford PC, Gemma C: CX3CR1 deficiency leads to impairment of hippocampal cognitive function and synaptic plasticity. J Neurosci. 2011, 31: 16241-16250. 10.1523/JNEUROSCI.3667-11.2011.CrossRefPubMed Rogers JT, Morganti JM, Bachstetter AD, Hudson CE, Peters MM, Grimmig BA, Weeber EJ, Bickford PC, Gemma C: CX3CR1 deficiency leads to impairment of hippocampal cognitive function and synaptic plasticity. J Neurosci. 2011, 31: 16241-16250. 10.1523/JNEUROSCI.3667-11.2011.CrossRefPubMed
Metadata
Title
RETRACTED ARTICLE: Chronic neuroinflammation and cognitive impairment following transient global cerebral ischemia: role of fractalkine/CX3CR1 signaling
Authors
Teresita L Briones
Julie Woods
Magdalena Wadowska
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2014
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/1742-2094-11-13

Other articles of this Issue 1/2014

Journal of Neuroinflammation 1/2014 Go to the issue