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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

CD200R IR in control, FCD IIb, and TSC specimens. a, b CD200R IR in control specimens. a Undetectable CD200 IR in neurons (arrows and inset) within cortex. b Weak and sporadic CD200R IR in white matter (arrowheads) and co-localization of CD200R (green) and HLA-DR (red) in a microglia (inset). c, d CD200 IR in cortical lesions of FCD IIb specimens. c CD200R IR was not observed in dysmorphic neurons (arrowheads). d CD200R IR was not found in balloon cells (arrows) but was detected in certain glial cells (arrowheads). e, f CD200R IR in cortical tubers of TSC specimens. e Negative dysmorphic neurons (arrowheads). f Weak CD200R IR in glial cells (arrowheads) and negative giant cells (arrows). g–i Double labeling in cortical lesions of FCD IIb specimens shows co-localization of CD200R (green) with HLA-DR (red) in microglia (arrow). j–l Double labeling in cortical tubers of TSC specimens shows co-localization of CD200R (green) with HLA-DR (red) in microglia (arrow). Scale bars: a–c, e–f 50 μm; d 40 μm; g–l 35 μm
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Fig8: CD200R IR in control, FCD IIb, and TSC specimens. a, b CD200R IR in control specimens. a Undetectable CD200 IR in neurons (arrows and inset) within cortex. b Weak and sporadic CD200R IR in white matter (arrowheads) and co-localization of CD200R (green) and HLA-DR (red) in a microglia (inset). c, d CD200 IR in cortical lesions of FCD IIb specimens. c CD200R IR was not observed in dysmorphic neurons (arrowheads). d CD200R IR was not found in balloon cells (arrows) but was detected in certain glial cells (arrowheads). e, f CD200R IR in cortical tubers of TSC specimens. e Negative dysmorphic neurons (arrowheads). f Weak CD200R IR in glial cells (arrowheads) and negative giant cells (arrows). g–i Double labeling in cortical lesions of FCD IIb specimens shows co-localization of CD200R (green) with HLA-DR (red) in microglia (arrow). j–l Double labeling in cortical tubers of TSC specimens shows co-localization of CD200R (green) with HLA-DR (red) in microglia (arrow). Scale bars: a–c, e–f 50 μm; d 40 μm; g–l 35 μm

Mentions: In histologically normal autopsy specimens, we did not detect CD200R IR in neurons within the cortex but observed weak and sporadic IR in glial cells within white matter (Fig. 8a, b). In FCD IIb and TSC specimens, CD200 IR was not observed in dysmorphic neurons (Fig. 8c, e), balloon cells (Fig. 8d), or giant cells (Fig. 8f) but was detected in certain glial cells with weak IR (Fig. 8d, f). The IR score of CD200R was not significantly changed in both the FCD IIb and TSC specimens compared with the controls (P > 0.05; Fig. 4d). Double labeling showed that CD200R IR was co-localized with HLA-DR in certain microglia (Fig. 8g–l).Fig. 8


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)

CD200R IR in control, FCD IIb, and TSC specimens. a, b CD200R IR in control specimens. a Undetectable CD200 IR in neurons (arrows and inset) within cortex. b Weak and sporadic CD200R IR in white matter (arrowheads) and co-localization of CD200R (green) and HLA-DR (red) in a microglia (inset). c, d CD200 IR in cortical lesions of FCD IIb specimens. c CD200R IR was not observed in dysmorphic neurons (arrowheads). d CD200R IR was not found in balloon cells (arrows) but was detected in certain glial cells (arrowheads). e, f CD200R IR in cortical tubers of TSC specimens. e Negative dysmorphic neurons (arrowheads). f Weak CD200R IR in glial cells (arrowheads) and negative giant cells (arrows). g–i Double labeling in cortical lesions of FCD IIb specimens shows co-localization of CD200R (green) with HLA-DR (red) in microglia (arrow). j–l Double labeling in cortical tubers of TSC specimens shows co-localization of CD200R (green) with HLA-DR (red) in microglia (arrow). Scale bars: a–c, e–f 50 μm; d 40 μm; g–l 35 μm
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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Fig8: CD200R IR in control, FCD IIb, and TSC specimens. a, b CD200R IR in control specimens. a Undetectable CD200 IR in neurons (arrows and inset) within cortex. b Weak and sporadic CD200R IR in white matter (arrowheads) and co-localization of CD200R (green) and HLA-DR (red) in a microglia (inset). c, d CD200 IR in cortical lesions of FCD IIb specimens. c CD200R IR was not observed in dysmorphic neurons (arrowheads). d CD200R IR was not found in balloon cells (arrows) but was detected in certain glial cells (arrowheads). e, f CD200R IR in cortical tubers of TSC specimens. e Negative dysmorphic neurons (arrowheads). f Weak CD200R IR in glial cells (arrowheads) and negative giant cells (arrows). g–i Double labeling in cortical lesions of FCD IIb specimens shows co-localization of CD200R (green) with HLA-DR (red) in microglia (arrow). j–l Double labeling in cortical tubers of TSC specimens shows co-localization of CD200R (green) with HLA-DR (red) in microglia (arrow). Scale bars: a–c, e–f 50 μm; d 40 μm; g–l 35 μm
Mentions: In histologically normal autopsy specimens, we did not detect CD200R IR in neurons within the cortex but observed weak and sporadic IR in glial cells within white matter (Fig. 8a, b). In FCD IIb and TSC specimens, CD200 IR was not observed in dysmorphic neurons (Fig. 8c, e), balloon cells (Fig. 8d), or giant cells (Fig. 8f) but was detected in certain glial cells with weak IR (Fig. 8d, f). The IR score of CD200R was not significantly changed in both the FCD IIb and TSC specimens compared with the controls (P > 0.05; Fig. 4d). Double labeling showed that CD200R IR was co-localized with HLA-DR in certain microglia (Fig. 8g–l).Fig. 8

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