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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

CD47 IR in control, FCD IIb, and TSC specimens. a, b CD47 IR in control specimens. a Strong somatic staining of CD47 in neurons (arrows and inset) within cortex. b Sporadic CD47 IR in glial cells (arrowheads) within white matter and co-localization of CD47 (green) and HLA-DR (red) in a microglia (inset). c, d CD47 IR in cortical lesions of FCD IIb. c Weak CD47 IR in dysmorphic neurons (arrows). d Negative balloon cells (arrowheads and inset) and weak CD47 IR in balloon cells (arrows). e–g CD47 IR in cortical tubers of TSC. e Negative dysmorphic neurons (arrowheads) and weak to moderate staining in dysmorphic neurons (arrows). f Weak CD47 IR in giant cells (arrows) and in a glial cell (arrowhead). g High magnification showing a giant cell with weak CD47 IR. h–j Double labeling in cortical lesions of FCDIIb specimens. h Co-localization of CD47 (green) with NF (red) in dysmorphic neurons. i Absence of co-localization between CD47 (green) and GFAP (red) in astrocytes (arrows: astrocytes, arrowhead: dysmorphic neuron). j Co-localization of CD47 (green) and HLA-DR (red) in a microglia (arrow; arrowhead: dysmorphic neuron). k–m Double labeling in cortical tubers of TSC specimens. k Co-localization of CD47 (green) with NF (red) in giant cells. l Absence of co-localization between CD47 (green) and GFAP (red) in astrocytes (arrows: astrocytes, arrowhead: giant cell). m Co-localization of CD47 (green) and HLA-DR (red) in microglia (arrows; arrowhead: giant cell). Scale bars: a 40 μm; b 35 μm; d, e: 50 μm; f 30 μm, g 20 μm; h–m 50 μm
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Fig3: CD47 IR in control, FCD IIb, and TSC specimens. a, b CD47 IR in control specimens. a Strong somatic staining of CD47 in neurons (arrows and inset) within cortex. b Sporadic CD47 IR in glial cells (arrowheads) within white matter and co-localization of CD47 (green) and HLA-DR (red) in a microglia (inset). c, d CD47 IR in cortical lesions of FCD IIb. c Weak CD47 IR in dysmorphic neurons (arrows). d Negative balloon cells (arrowheads and inset) and weak CD47 IR in balloon cells (arrows). e–g CD47 IR in cortical tubers of TSC. e Negative dysmorphic neurons (arrowheads) and weak to moderate staining in dysmorphic neurons (arrows). f Weak CD47 IR in giant cells (arrows) and in a glial cell (arrowhead). g High magnification showing a giant cell with weak CD47 IR. h–j Double labeling in cortical lesions of FCDIIb specimens. h Co-localization of CD47 (green) with NF (red) in dysmorphic neurons. i Absence of co-localization between CD47 (green) and GFAP (red) in astrocytes (arrows: astrocytes, arrowhead: dysmorphic neuron). j Co-localization of CD47 (green) and HLA-DR (red) in a microglia (arrow; arrowhead: dysmorphic neuron). k–m Double labeling in cortical tubers of TSC specimens. k Co-localization of CD47 (green) with NF (red) in giant cells. l Absence of co-localization between CD47 (green) and GFAP (red) in astrocytes (arrows: astrocytes, arrowhead: giant cell). m Co-localization of CD47 (green) and HLA-DR (red) in microglia (arrows; arrowhead: giant cell). Scale bars: a 40 μm; b 35 μm; d, e: 50 μm; f 30 μm, g 20 μm; h–m 50 μm

Mentions: Histologically normal autopsy cortex displayed strong somatic CD47 IR in pyramidal neurons (Fig. 3a) and showed moderate and sporadic CD47 IR in glial cells within white matter (Fig. 3b). In FCD IIb and TSC specimens, weak or undetectable CD47 IR was observed in dysmorphic neurons (Fig. 3c, e). Weak or undetectable CD47 IR was also detected in balloon cells of FCD IIb and in giant cells of TSC (Fig. 3d, f, and g). The CD47 IR score was significantly decreased in both the FCD IIb and TSC specimens compared with the controls (P < 0.05; Fig. 4a) and showed significant negative correlation with the number of HLA-DR-positive cells in FCD IIb (Fig. 5a) and TSC (Fig. 5d). Double labeling demonstrated the co-localization of CD47 IR with NF in certain dysmorphic neurons and giant cells (Fig. 3h, k) and with HLA-DR in certain microglia (Fig. 3j, m). GFAP-positive astrocytes did not display CD47 IR (Fig. 3i, l).Fig. 3


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)

CD47 IR in control, FCD IIb, and TSC specimens. a, b CD47 IR in control specimens. a Strong somatic staining of CD47 in neurons (arrows and inset) within cortex. b Sporadic CD47 IR in glial cells (arrowheads) within white matter and co-localization of CD47 (green) and HLA-DR (red) in a microglia (inset). c, d CD47 IR in cortical lesions of FCD IIb. c Weak CD47 IR in dysmorphic neurons (arrows). d Negative balloon cells (arrowheads and inset) and weak CD47 IR in balloon cells (arrows). e–g CD47 IR in cortical tubers of TSC. e Negative dysmorphic neurons (arrowheads) and weak to moderate staining in dysmorphic neurons (arrows). f Weak CD47 IR in giant cells (arrows) and in a glial cell (arrowhead). g High magnification showing a giant cell with weak CD47 IR. h–j Double labeling in cortical lesions of FCDIIb specimens. h Co-localization of CD47 (green) with NF (red) in dysmorphic neurons. i Absence of co-localization between CD47 (green) and GFAP (red) in astrocytes (arrows: astrocytes, arrowhead: dysmorphic neuron). j Co-localization of CD47 (green) and HLA-DR (red) in a microglia (arrow; arrowhead: dysmorphic neuron). k–m Double labeling in cortical tubers of TSC specimens. k Co-localization of CD47 (green) with NF (red) in giant cells. l Absence of co-localization between CD47 (green) and GFAP (red) in astrocytes (arrows: astrocytes, arrowhead: giant cell). m Co-localization of CD47 (green) and HLA-DR (red) in microglia (arrows; arrowhead: giant cell). Scale bars: a 40 μm; b 35 μm; d, e: 50 μm; f 30 μm, g 20 μm; h–m 50 μm
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4837553&req=5

Fig3: CD47 IR in control, FCD IIb, and TSC specimens. a, b CD47 IR in control specimens. a Strong somatic staining of CD47 in neurons (arrows and inset) within cortex. b Sporadic CD47 IR in glial cells (arrowheads) within white matter and co-localization of CD47 (green) and HLA-DR (red) in a microglia (inset). c, d CD47 IR in cortical lesions of FCD IIb. c Weak CD47 IR in dysmorphic neurons (arrows). d Negative balloon cells (arrowheads and inset) and weak CD47 IR in balloon cells (arrows). e–g CD47 IR in cortical tubers of TSC. e Negative dysmorphic neurons (arrowheads) and weak to moderate staining in dysmorphic neurons (arrows). f Weak CD47 IR in giant cells (arrows) and in a glial cell (arrowhead). g High magnification showing a giant cell with weak CD47 IR. h–j Double labeling in cortical lesions of FCDIIb specimens. h Co-localization of CD47 (green) with NF (red) in dysmorphic neurons. i Absence of co-localization between CD47 (green) and GFAP (red) in astrocytes (arrows: astrocytes, arrowhead: dysmorphic neuron). j Co-localization of CD47 (green) and HLA-DR (red) in a microglia (arrow; arrowhead: dysmorphic neuron). k–m Double labeling in cortical tubers of TSC specimens. k Co-localization of CD47 (green) with NF (red) in giant cells. l Absence of co-localization between CD47 (green) and GFAP (red) in astrocytes (arrows: astrocytes, arrowhead: giant cell). m Co-localization of CD47 (green) and HLA-DR (red) in microglia (arrows; arrowhead: giant cell). Scale bars: a 40 μm; b 35 μm; d, e: 50 μm; f 30 μm, g 20 μm; h–m 50 μm
Mentions: Histologically normal autopsy cortex displayed strong somatic CD47 IR in pyramidal neurons (Fig. 3a) and showed moderate and sporadic CD47 IR in glial cells within white matter (Fig. 3b). In FCD IIb and TSC specimens, weak or undetectable CD47 IR was observed in dysmorphic neurons (Fig. 3c, e). Weak or undetectable CD47 IR was also detected in balloon cells of FCD IIb and in giant cells of TSC (Fig. 3d, f, and g). The CD47 IR score was significantly decreased in both the FCD IIb and TSC specimens compared with the controls (P < 0.05; Fig. 4a) and showed significant negative correlation with the number of HLA-DR-positive cells in FCD IIb (Fig. 5a) and TSC (Fig. 5d). Double labeling demonstrated the co-localization of CD47 IR with NF in certain dysmorphic neurons and giant cells (Fig. 3h, k) and with HLA-DR in certain microglia (Fig. 3j, m). GFAP-positive astrocytes did not display CD47 IR (Fig. 3i, l).Fig. 3

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