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Downregulation of CD47 and CD200 in patients with focal cortical dysplasia type IIb and tuberous sclerosis complex.

Sun FJ, Zhang CQ, Chen X, Wei YJ, Li S, Liu SY, Zang ZL, He JJ, Guo W, Yang H - J Neuroinflammation (2016)

Bottom Line: We investigate the levels and expression pattern of CD47/SIRP-α and CD200/CD200R in surgically resected brain tissues from patients with FCD IIb and TSC, and the potential effect of soluble human CD47 Fc and CD200 Fc on the inhibition of several proinflammatory cytokines associated with FCD IIb and TSC in living epileptogenic brain slices in vitro.Both the messenger RNA and protein levels of CD47, SIRP-α, and CD200, as well as the mRNA level of IL-4, were downregulated in epileptogenic lesions of FCD IIb and TSC compared with the control specimens, whereas CD200R levels were not significantly changed.CD47 Fc and CD200 Fc could inhibit IL-6 release but did not suppress IL-1β or IL-17 production.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University, 2-V Xinqiao Street, Chongqing, 400037, China.

ABSTRACT

Background: Focal cortical dysplasia type IIb (FCD IIb) and tuberous sclerosis complex (TSC) are well-recognized causes of chronic intractable epilepsy in children. Accumulating evidence suggests that activation of the microglia/macrophage and concomitant inflammatory response in FCD IIb and TSC may contribute to the initiation and recurrence of seizures. The membrane glycoproteins CD47 and CD200, which are highly expressed in neurons and other cells, mediate inhibitory signals through their receptors, signal regulatory protein α (SIRP-α) and CD200R, respectively, in microglia/macrophages. We investigate the levels and expression pattern of CD47/SIRP-α and CD200/CD200R in surgically resected brain tissues from patients with FCD IIb and TSC, and the potential effect of soluble human CD47 Fc and CD200 Fc on the inhibition of several proinflammatory cytokines associated with FCD IIb and TSC in living epileptogenic brain slices in vitro. The level of interleukin-4 (IL-4), a modulator of CD200, was also investigated.

Methods: Twelve FCD IIb (range 1.8-9.5 years), 13 TSC (range 1.5-10 years) patients, and 6 control cases (range 1.5-11 years) were enrolled. The levels of CD47/SIRP-α and CD200/CD200R were assessed by quantitative real-time polymerase chain reaction and western blot. The expression pattern of CD47/SIRP-α and CD200/CD200R was investigated by immunohistochemical analysis, and the cytokine concentrations were measured by enzyme-linked immune-sorbent assays.

Results: Both the messenger RNA and protein levels of CD47, SIRP-α, and CD200, as well as the mRNA level of IL-4, were downregulated in epileptogenic lesions of FCD IIb and TSC compared with the control specimens, whereas CD200R levels were not significantly changed. CD47, SIRP-α, and CD200 were decreasingly expressed in dysmorphic neuron, balloon cells, and giant cells. CD47 Fc and CD200 Fc could inhibit IL-6 release but did not suppress IL-1β or IL-17 production.

Conclusions: Our results suggest that microglial activation may be partially caused by CD47/SIRP-α- and CD200/CD200R-mediated reductions in the immune inhibitory pathways within FCD IIb and TSC cortical lesions where chronic neuroinflammation has been established. Upregulation or activation of CD47/SIRP-α and CD200/CD200R may have therapeutic potential for controlling neuroinflammation in human FCD IIb and TSC.

No MeSH data available.


Related in: MedlinePlus

CD200 IR in control, FCD IIb, and TSC specimens. a, b CD200 IR in control specimens. a Moderate to strong somatic CD200 IR in neurons (arrows and inset) within cortex. b Weak CD200 IR in white matter (arrowheads). c, d CD200 IR in cortical lesions of FCD IIb specimens. c Weak CD200 IR in dysmorphic neurons (arrows). d Weak CD200 IR in balloon cells (arrows). e, f CD200 IR in cortical tubers of TSC specimens. e Weak CD200 IR in dysmorphic neurons (arrows and inset). f Weak CD200 IR in a giant cell (inset) and negative giant cells (arrowheads). g–i Double labeling in cortical lesions of FCD IIb specimens. g Co-localization of CD200 (green) with NF (red) in dysmorphic neurons (arrows). h Co-localization of CD200 (green) with GFAP (red) in reactive astrocytes (arrows: astrocytes, arrowhead: dysmorphic neuron). i Absence of co-localization between CD200 (green) with HLA-DR (red) in microglia (arrow: microglia, arrowhead: dysmorphic neuron). j–l Double labeling in cortical tubers of TSC specimens. j Co-localization of CD200 (green) and NF (red) in certain giant cell (arrow). k Co-localization of CD200 (green) with GFAP (red) in reactive astrocytes (arrows: astrocytes, arrowhead: giant cell). l Absence of co-localization between CD200 (green) and HLA-DR (red) in microglia (arrows: microglia, arrowhead: giant cell). Scale bars: a 30 μm; b–l 50 μm
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Fig7: CD200 IR in control, FCD IIb, and TSC specimens. a, b CD200 IR in control specimens. a Moderate to strong somatic CD200 IR in neurons (arrows and inset) within cortex. b Weak CD200 IR in white matter (arrowheads). c, d CD200 IR in cortical lesions of FCD IIb specimens. c Weak CD200 IR in dysmorphic neurons (arrows). d Weak CD200 IR in balloon cells (arrows). e, f CD200 IR in cortical tubers of TSC specimens. e Weak CD200 IR in dysmorphic neurons (arrows and inset). f Weak CD200 IR in a giant cell (inset) and negative giant cells (arrowheads). g–i Double labeling in cortical lesions of FCD IIb specimens. g Co-localization of CD200 (green) with NF (red) in dysmorphic neurons (arrows). h Co-localization of CD200 (green) with GFAP (red) in reactive astrocytes (arrows: astrocytes, arrowhead: dysmorphic neuron). i Absence of co-localization between CD200 (green) with HLA-DR (red) in microglia (arrow: microglia, arrowhead: dysmorphic neuron). j–l Double labeling in cortical tubers of TSC specimens. j Co-localization of CD200 (green) and NF (red) in certain giant cell (arrow). k Co-localization of CD200 (green) with GFAP (red) in reactive astrocytes (arrows: astrocytes, arrowhead: giant cell). l Absence of co-localization between CD200 (green) and HLA-DR (red) in microglia (arrows: microglia, arrowhead: giant cell). Scale bars: a 30 μm; b–l 50 μm

Mentions: In histologically normal autopsy specimens, moderate to strong CD200 IR was observed in pyramidal neurons within cortex (Fig. 7a). Weak and sporadic CD200 IR was detected within white matter (Fig. 7b). In FCD IIb and TSC specimens, weak CD200 IR was observed in dysmorphic neurons (Fig. 7c, e). Weak CD200 IR was also detected in balloon cells of FCD IIb (Fig. 7d). Giant cells of TSC exhibited weak or undetectable CD200 IR (Fig. 7f). The IR score of CD200 was significantly downregulated in both FCD IIb and TSC specimens versus the controls (P < 0.05; Fig. 4c) and showed significant negative correlation with the number of HLA-DR-positive cells in FCD IIb (Fig. 5c) and TSC (Fig. 5f). Double labeling showed that CD200 IR was co-localized with NF and GFAP in certain dysmorphic neurons, giant cells, and reactive astrocytes (Fig. 7g, h, j, and k). HLA-DR-positive microglia did not express CD200 (Fig. 7i, l).Fig. 7


Downregulation of CD47 and CD200 in patients with focal cortical dysplasia type IIb and tuberous sclerosis complex.

Sun FJ, Zhang CQ, Chen X, Wei YJ, Li S, Liu SY, Zang ZL, He JJ, Guo W, Yang H - J Neuroinflammation (2016)

CD200 IR in control, FCD IIb, and TSC specimens. a, b CD200 IR in control specimens. a Moderate to strong somatic CD200 IR in neurons (arrows and inset) within cortex. b Weak CD200 IR in white matter (arrowheads). c, d CD200 IR in cortical lesions of FCD IIb specimens. c Weak CD200 IR in dysmorphic neurons (arrows). d Weak CD200 IR in balloon cells (arrows). e, f CD200 IR in cortical tubers of TSC specimens. e Weak CD200 IR in dysmorphic neurons (arrows and inset). f Weak CD200 IR in a giant cell (inset) and negative giant cells (arrowheads). g–i Double labeling in cortical lesions of FCD IIb specimens. g Co-localization of CD200 (green) with NF (red) in dysmorphic neurons (arrows). h Co-localization of CD200 (green) with GFAP (red) in reactive astrocytes (arrows: astrocytes, arrowhead: dysmorphic neuron). i Absence of co-localization between CD200 (green) with HLA-DR (red) in microglia (arrow: microglia, arrowhead: dysmorphic neuron). j–l Double labeling in cortical tubers of TSC specimens. j Co-localization of CD200 (green) and NF (red) in certain giant cell (arrow). k Co-localization of CD200 (green) with GFAP (red) in reactive astrocytes (arrows: astrocytes, arrowhead: giant cell). l Absence of co-localization between CD200 (green) and HLA-DR (red) in microglia (arrows: microglia, arrowhead: giant cell). Scale bars: a 30 μm; b–l 50 μm
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Fig7: CD200 IR in control, FCD IIb, and TSC specimens. a, b CD200 IR in control specimens. a Moderate to strong somatic CD200 IR in neurons (arrows and inset) within cortex. b Weak CD200 IR in white matter (arrowheads). c, d CD200 IR in cortical lesions of FCD IIb specimens. c Weak CD200 IR in dysmorphic neurons (arrows). d Weak CD200 IR in balloon cells (arrows). e, f CD200 IR in cortical tubers of TSC specimens. e Weak CD200 IR in dysmorphic neurons (arrows and inset). f Weak CD200 IR in a giant cell (inset) and negative giant cells (arrowheads). g–i Double labeling in cortical lesions of FCD IIb specimens. g Co-localization of CD200 (green) with NF (red) in dysmorphic neurons (arrows). h Co-localization of CD200 (green) with GFAP (red) in reactive astrocytes (arrows: astrocytes, arrowhead: dysmorphic neuron). i Absence of co-localization between CD200 (green) with HLA-DR (red) in microglia (arrow: microglia, arrowhead: dysmorphic neuron). j–l Double labeling in cortical tubers of TSC specimens. j Co-localization of CD200 (green) and NF (red) in certain giant cell (arrow). k Co-localization of CD200 (green) with GFAP (red) in reactive astrocytes (arrows: astrocytes, arrowhead: giant cell). l Absence of co-localization between CD200 (green) and HLA-DR (red) in microglia (arrows: microglia, arrowhead: giant cell). Scale bars: a 30 μm; b–l 50 μm
Mentions: In histologically normal autopsy specimens, moderate to strong CD200 IR was observed in pyramidal neurons within cortex (Fig. 7a). Weak and sporadic CD200 IR was detected within white matter (Fig. 7b). In FCD IIb and TSC specimens, weak CD200 IR was observed in dysmorphic neurons (Fig. 7c, e). Weak CD200 IR was also detected in balloon cells of FCD IIb (Fig. 7d). Giant cells of TSC exhibited weak or undetectable CD200 IR (Fig. 7f). The IR score of CD200 was significantly downregulated in both FCD IIb and TSC specimens versus the controls (P < 0.05; Fig. 4c) and showed significant negative correlation with the number of HLA-DR-positive cells in FCD IIb (Fig. 5c) and TSC (Fig. 5f). Double labeling showed that CD200 IR was co-localized with NF and GFAP in certain dysmorphic neurons, giant cells, and reactive astrocytes (Fig. 7g, h, j, and k). HLA-DR-positive microglia did not express CD200 (Fig. 7i, l).Fig. 7

Bottom Line: We investigate the levels and expression pattern of CD47/SIRP-α and CD200/CD200R in surgically resected brain tissues from patients with FCD IIb and TSC, and the potential effect of soluble human CD47 Fc and CD200 Fc on the inhibition of several proinflammatory cytokines associated with FCD IIb and TSC in living epileptogenic brain slices in vitro.Both the messenger RNA and protein levels of CD47, SIRP-α, and CD200, as well as the mRNA level of IL-4, were downregulated in epileptogenic lesions of FCD IIb and TSC compared with the control specimens, whereas CD200R levels were not significantly changed.CD47 Fc and CD200 Fc could inhibit IL-6 release but did not suppress IL-1β or IL-17 production.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University, 2-V Xinqiao Street, Chongqing, 400037, China.

ABSTRACT

Background: Focal cortical dysplasia type IIb (FCD IIb) and tuberous sclerosis complex (TSC) are well-recognized causes of chronic intractable epilepsy in children. Accumulating evidence suggests that activation of the microglia/macrophage and concomitant inflammatory response in FCD IIb and TSC may contribute to the initiation and recurrence of seizures. The membrane glycoproteins CD47 and CD200, which are highly expressed in neurons and other cells, mediate inhibitory signals through their receptors, signal regulatory protein α (SIRP-α) and CD200R, respectively, in microglia/macrophages. We investigate the levels and expression pattern of CD47/SIRP-α and CD200/CD200R in surgically resected brain tissues from patients with FCD IIb and TSC, and the potential effect of soluble human CD47 Fc and CD200 Fc on the inhibition of several proinflammatory cytokines associated with FCD IIb and TSC in living epileptogenic brain slices in vitro. The level of interleukin-4 (IL-4), a modulator of CD200, was also investigated.

Methods: Twelve FCD IIb (range 1.8-9.5 years), 13 TSC (range 1.5-10 years) patients, and 6 control cases (range 1.5-11 years) were enrolled. The levels of CD47/SIRP-α and CD200/CD200R were assessed by quantitative real-time polymerase chain reaction and western blot. The expression pattern of CD47/SIRP-α and CD200/CD200R was investigated by immunohistochemical analysis, and the cytokine concentrations were measured by enzyme-linked immune-sorbent assays.

Results: Both the messenger RNA and protein levels of CD47, SIRP-α, and CD200, as well as the mRNA level of IL-4, were downregulated in epileptogenic lesions of FCD IIb and TSC compared with the control specimens, whereas CD200R levels were not significantly changed. CD47, SIRP-α, and CD200 were decreasingly expressed in dysmorphic neuron, balloon cells, and giant cells. CD47 Fc and CD200 Fc could inhibit IL-6 release but did not suppress IL-1β or IL-17 production.

Conclusions: Our results suggest that microglial activation may be partially caused by CD47/SIRP-α- and CD200/CD200R-mediated reductions in the immune inhibitory pathways within FCD IIb and TSC cortical lesions where chronic neuroinflammation has been established. Upregulation or activation of CD47/SIRP-α and CD200/CD200R may have therapeutic potential for controlling neuroinflammation in human FCD IIb and TSC.

No MeSH data available.


Related in: MedlinePlus