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CX3CL1 Is Neuroprotective in Permanent Focal Cerebral Ischemia in Rodents

Cipriani, Raffaela, Villa, Pia, Chece, Giuseppina, Lauro, Clotilde, Paladini, Alessandra, Micotti, Edoardo, Perego, Carlo, De Simoni, Maria-Grazia, Fredholm, Bertil B., Eusebi, Fabrizio, Limatola, Cristina·2011·The Journal of Neuroscience
DOI 10.1523/jneurosci.3611-11.2011
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Abstract

The chemokine CX3CL1 and its receptor CX3CR1 are constitutively expressed in the nervous system. In this study, we used in vivo murine models of permanent middle cerebral artery occlusion (pMCAO) to investigate the protective potential of CX3CL1. We report that exogenous CX3CL1 reduced ischemia-induced cerebral infarct size, neurological deficits, and caspase-3 activation. CX3CL1-induced neuroprotective effects were long lasting, being observed up to 50 d after pMCAO in rats. The neuroprotective action of CX3CL1 in different models of brain injuries is mediated by its inhibitory activity on microglia and, in vitro , requires the activation of adenosine receptor 1 (A 1 R). We show that, in the presence of the A 1 R antagonist 1,3-dipropyl-8-cyclopentylxanthine and in A 1 R −/− mice, the neuroprotective effect of CX3CL1 on pMCAO was abolished, indicating the critical importance of the adenosine system in CX3CL1 protection also in vivo . In apparent contrast with the above reported data but in agreement with previous findings, cx3cl1 −/− and cx3cr1 GFP/GFP mice, respectively, deficient in CX3CL1 or CX3CR1, had less severe brain injury on pMCAO, and the administration of exogenous CX3CL1 increased brain damage in cx3cl1 −/− ischemic mice. We also report that CX3CL1 induced a different phagocytic activity in wild type and cx3cl1 −/− microglia in vitro during cotreatment with the medium conditioned by neurons damaged by oxygen-glucose deprivation. Together, these data suggest that acute administration of CX3CL1 reduces ischemic damage via an adenosine-dependent mechanism and that the absence of constitutive CX3CL1–CX3CR1 signaling changes the outcome of microglia-mediated effects during CX3CL1 administration to ischemic brain.

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Figures

Figure 1 Permanent MCAO in cx3cr1 GFP/GFP and cx3cl1 -/ -mice. Brain infarct volume is reduced in both cx3cr1 GFP/GFP and cx3cl1 -/ -mice during pMCAO (C) compared with wt mice. The effect of CX3CL1 treatment on infarct brain volume in pMCAO wt, cx3cr1 GFP/GFP , and cx3cl1 -/ -mice is reported. Data are mean ± SE; n = 5-18, indicated in brackets on top of eachcolumn.Student's t test: * p < 0.05and** p < 0.01versusCwt; # p < 0.05and ## p < 0.01 versus C for corresponding genotype.
Figure 1 Permanent MCAO in cx3cr1 GFP/GFP and cx3cl1 -/ -mice. Brain infarct volume is reduced in both cx3cr1 GFP/GFP and cx3cl1 -/ -mice during pMCAO (C) compared with wt mice. The effect of CX3CL1 treatment on infarct brain volume in pMCAO wt, cx3cr1 GFP/GFP , and cx3cl1 -/ -mice is reported. Data are mean ± SE; n = 5-18, indicated in brackets on top of eachcolumn.Student's t test: * p < 0.05and** p < 0.01versusCwt; # p < 0.05and ## p < 0.01 versus C for corresponding genotype.CC-BY-NC-SA · From the PDF
Figure2 Phagocytic activity and TNF𝛂 release of wt and cx3cl1 -/ -microglia. Phagocytic activity of wt and cx3cl1 -/ -microglia exposed to OGD-CM. a , Results expressed as the percentage of phagocyting cells. b , Results expressed as the number of phagocyted microspheres per cell as detailed in Materials and Methods. Data are the mean ± SE, n = 6 -7 (total number of cells counted for each condition: 1350 for wt; 900 for cx3cl1 -/ -). Student's t test: ** p < 0.01. c , TNF𝛂 released in culture medium of microglia, expressed as picograms per milliliter per milligram of total cell proteins. Data are the mean ± SE, n = 6 -14. Student's t test: * p < 0.05.
Figure2 Phagocytic activity and TNF𝛂 release of wt and cx3cl1 -/ -microglia. Phagocytic activity of wt and cx3cl1 -/ -microglia exposed to OGD-CM. a , Results expressed as the percentage of phagocyting cells. b , Results expressed as the number of phagocyted microspheres per cell as detailed in Materials and Methods. Data are the mean ± SE, n = 6 -7 (total number of cells counted for each condition: 1350 for wt; 900 for cx3cl1 -/ -). Student's t test: ** p < 0.01. c , TNF𝛂 released in culture medium of microglia, expressed as picograms per milliliter per milligram of total cell proteins. Data are the mean ± SE, n = 6 -14. Student's t test: * p < 0.05.CC-BY-NC-SA · From the PDF
Image 3
CC-BY-NC-SA · From the PDF
Figure 4 Long-term effects of CX3CL1 on ischemic brain. a , Study paradigm. b , Results of Bederson's (top), De Ryck's (middle), and foot-fault(bottom)testsinvehicle-treated(blackcircles)andCX3CL1-treated(whitecircles)ratsatdifferentdaysafterpMCAO( n = 11).In the foot-fault test, values for sham-operated rats were similar to those obtained at 24 h. c , Results of structural MRI data analysis of brain lesions in ischemic rats treated with CX3CL1 and saline, 50 d after pMCAO. Volumes of cortex for ipsilateral (I) and contralateral (C) hemispheres and total lesion volume are shown for vehicle- and CX3CL1-treated rats. Representative images of ischemic brains are shown for vehicle- and CX3CL1-treated rats. d , DTI data analysis showing ADC of the ipsilateral and contralateral hemisphere of CX3CL1- and vehicletreated rats in cortex and external capsula. Representative ADC images are shown. All data are mean ± SE from six rats for each experimental condition. Two-way ANOVA followed by the Bonferroni's post hoc test: * p < 0.05, ** p < 0.01, *** p < 0.001.
Figure 4 Long-term effects of CX3CL1 on ischemic brain. a , Study paradigm. b , Results of Bederson's (top), De Ryck's (middle), and foot-fault(bottom)testsinvehicle-treated(blackcircles)andCX3CL1-treated(whitecircles)ratsatdifferentdaysafterpMCAO( n = 11).In the foot-fault test, values for sham-operated rats were similar to those obtained at 24 h. c , Results of structural MRI data analysis of brain lesions in ischemic rats treated with CX3CL1 and saline, 50 d after pMCAO. Volumes of cortex for ipsilateral (I) and contralateral (C) hemispheres and total lesion volume are shown for vehicle- and CX3CL1-treated rats. Representative images of ischemic brains are shown for vehicle- and CX3CL1-treated rats. d , DTI data analysis showing ADC of the ipsilateral and contralateral hemisphere of CX3CL1- and vehicletreated rats in cortex and external capsula. Representative ADC images are shown. All data are mean ± SE from six rats for each experimental condition. Two-way ANOVA followed by the Bonferroni's post hoc test: * p < 0.05, ** p < 0.01, *** p < 0.001.CC-BY-NC-SA · From the PDF
Figure 5 A 1 R inhibition or deficiency abolishes the neuroprotective effect of CX3CL1. a , Results of Bederson's, De Ryck's, and foot-fault tests 24 h after pMCAO in vehicle- and CX3CL1treated rats, in the presence of DPCPX ( n = 13). Dotted line indicates the maximal scores for sham-operated rats. Results for each experimental group are obtained from two independent sets of experiments. b , Infarct volume in vehicle- and CX3CL1-treated rats. Vehicle-treated (black bars) and CX3CL1-treated (white bars) rats received DPCPX ( n = 12). Data are mean ± SE. c , A 1 R-deficient mice are not protected by CX3CL1 during pMCAO. Data are the mean ± SE from four to five mice. Mann-Whitney U and Student's t tests.
Figure 5 A 1 R inhibition or deficiency abolishes the neuroprotective effect of CX3CL1. a , Results of Bederson's, De Ryck's, and foot-fault tests 24 h after pMCAO in vehicle- and CX3CL1treated rats, in the presence of DPCPX ( n = 13). Dotted line indicates the maximal scores for sham-operated rats. Results for each experimental group are obtained from two independent sets of experiments. b , Infarct volume in vehicle- and CX3CL1-treated rats. Vehicle-treated (black bars) and CX3CL1-treated (white bars) rats received DPCPX ( n = 12). Data are mean ± SE. c , A 1 R-deficient mice are not protected by CX3CL1 during pMCAO. Data are the mean ± SE from four to five mice. Mann-Whitney U and Student's t tests.CC-BY-NC-SA · From the PDF
Figure 6 CX3CL1-reduced activation of caspase 3 pathway during pMCAO is A 1 R dependent. Brain coronal sections from ischemic rats treated as in Figure 3 were analyzed by Western blot. The same amount of proteins (50 𝛍 g) was analyzed for each sample. a , Active form of caspase-3 (17-19 kDa) in the ipsilateral hemisphere of sham-operated (left) or pMCAO rats treated with vehicle or CX3CL1 in the presence of DMSO (control, C; middle) in the presence of DPCPX (right). Results are reported as arbitrary units (a.u.). The inset shows a representative blot: top, active form of caspase-3; bottom: actin, used to normalize signals. b , PARP (116 kDa) in sham-operated (left) or treated rats in the presence or in the absence of DPCPX. Data are expressed as the ratio of PARPintheipsilateral (I) to the contralateral (C) hemisphere. The inset shows a representative blot. Top, Full-length form of PARP; bottom, AKT, used to normalize signals. Bars indicate the mean ± SE from 6 to 18 rats. Statistical differences are analyzed for each experimental condition for CX3CL1 versus vehicle; * p < 0.05, ** p < 0.01 using Student's t test.
Figure 6 CX3CL1-reduced activation of caspase 3 pathway during pMCAO is A 1 R dependent. Brain coronal sections from ischemic rats treated as in Figure 3 were analyzed by Western blot. The same amount of proteins (50 𝛍 g) was analyzed for each sample. a , Active form of caspase-3 (17-19 kDa) in the ipsilateral hemisphere of sham-operated (left) or pMCAO rats treated with vehicle or CX3CL1 in the presence of DMSO (control, C; middle) in the presence of DPCPX (right). Results are reported as arbitrary units (a.u.). The inset shows a representative blot: top, active form of caspase-3; bottom: actin, used to normalize signals. b , PARP (116 kDa) in sham-operated (left) or treated rats in the presence or in the absence of DPCPX. Data are expressed as the ratio of PARPintheipsilateral (I) to the contralateral (C) hemisphere. The inset shows a representative blot. Top, Full-length form of PARP; bottom, AKT, used to normalize signals. Bars indicate the mean ± SE from 6 to 18 rats. Statistical differences are analyzed for each experimental condition for CX3CL1 versus vehicle; * p < 0.05, ** p < 0.01 using Student's t test.CC-BY-NC-SA · From the PDF

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Metadata

Authors
Cipriani, R., Villa, P., Chece, G., Lauro, C., Paladini, A., Micotti, E., Perego, C., De Simoni, M.-G., Fredholm, B. B., Eusebi, F., & Limatola, C.
Venue
The Journal of Neuroscience
Publisher
Society for Neuroscience
Published
2011-11-09
Volume
31
Issue
45
Pages
16327-16335
ISSN
  • 0270-6474
  • 1529-2401
DOI
10.1523/jneurosci.3611-11.2011
Cited by
166
References
11
Language
en
Licence
creativecommons.org/licenses/by-nc-sa/4.0/ (vor, 182 d)

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