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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

SIRP-α IR in control, FCD IIb, and TSC specimens. a, b SIRP-α IR in control specimens. a Strong somatic SIRP-α IR in neurons (arrows) within cortex. b Moderate SIRP-α IR in glial cells (arrowheads) within white matter and co-localization of SIRP-α (green) and HLA-DR (red) in a microglia (inset). c, d SIRP-α IR in cortical lesions of FCD IIb specimens. c Weak SIRP-α IR was occasionally detected in some dysmorphic neurons (arrows). d Negative balloon cells (arrowheads). e, f SIRP-α IR in cortical tubers of TSC specimens. e Weak SIRP-α IR in dysmorphic neurons (arrows) and a negative dysmorphic neurons (arrowheads). f Negative giant cells (arrowheads). g–i Double labeling in cortical lesions of FCD IIb specimens. g Co-localization of SIRP-α (green) with NF (red) in some dysmorphic neurons (arrows). h Absence of co-localization between SIRP-α (green) and GFAP (red) in astrocytes (arrows: astrocytes, arrowhead: dysmorphic neuron). i Co-localization of SIRP-α (green) with HLA-DR (red) in microglia (arrow). j–l Double labeling in cortical tubers of TSC specimens. j Absence of co-localization between SIRP-α (green) and NF (red) in giant cells (arrowheads). k Absence of co-localization between SIRP-α (green) and GFAP (red) in astrocytes (arrows: astrocytes, arrowhead: giant cell). l Co-localization of SIRP-α (green) with HLA-DR (red) in microglia (arrow). Scale bars: a 30 μm; b, e = 50 μm; c 35 μm; d 35 μm; f 30 μm; g, h, j, and k 50 μm; i, l 25 μm
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Fig6: SIRP-α IR in control, FCD IIb, and TSC specimens. a, b SIRP-α IR in control specimens. a Strong somatic SIRP-α IR in neurons (arrows) within cortex. b Moderate SIRP-α IR in glial cells (arrowheads) within white matter and co-localization of SIRP-α (green) and HLA-DR (red) in a microglia (inset). c, d SIRP-α IR in cortical lesions of FCD IIb specimens. c Weak SIRP-α IR was occasionally detected in some dysmorphic neurons (arrows). d Negative balloon cells (arrowheads). e, f SIRP-α IR in cortical tubers of TSC specimens. e Weak SIRP-α IR in dysmorphic neurons (arrows) and a negative dysmorphic neurons (arrowheads). f Negative giant cells (arrowheads). g–i Double labeling in cortical lesions of FCD IIb specimens. g Co-localization of SIRP-α (green) with NF (red) in some dysmorphic neurons (arrows). h Absence of co-localization between SIRP-α (green) and GFAP (red) in astrocytes (arrows: astrocytes, arrowhead: dysmorphic neuron). i Co-localization of SIRP-α (green) with HLA-DR (red) in microglia (arrow). j–l Double labeling in cortical tubers of TSC specimens. j Absence of co-localization between SIRP-α (green) and NF (red) in giant cells (arrowheads). k Absence of co-localization between SIRP-α (green) and GFAP (red) in astrocytes (arrows: astrocytes, arrowhead: giant cell). l Co-localization of SIRP-α (green) with HLA-DR (red) in microglia (arrow). Scale bars: a 30 μm; b, e = 50 μm; c 35 μm; d 35 μm; f 30 μm; g, h, j, and k 50 μm; i, l 25 μm

Mentions: In histologically normal autopsy specimens, SIRP-α strongly expressed in pyramidal neurons within cortex (Fig. 6a) and showed moderate IR in glial cells within white matter (Fig. 6b). FCD IIb and TSC specimens displayed weak or undetectable SIRP-α IR in dysmorphic neurons (Fig. 6c, e). Balloon cells of FCD IIb and giant cells of TSC did not exhibit detectable SIRP-α IR (Fig. 6d, f). The IR score of SIRP-α was dramatically lower in both the FCD IIb and TSC specimens than that in controls (P < 0.05; Fig. 4b) but showed no significant correlation with the number of HLA-DR-positive cells in FCD IIb (Fig. 5b) and TSC (Fig. 5e). Double labeling demonstrated the co-expression of SIRP-α IR with NF in some dysmorphic neurons and giant cells (Fig. 6g, j) and with HLA-DR in certain microglia (Fig. 6i, l), whereas the absence of SIRP-α IR was observed in GFAP-positive astrocytes (Fig. 6h, k).Fig. 6


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)

SIRP-α IR in control, FCD IIb, and TSC specimens. a, b SIRP-α IR in control specimens. a Strong somatic SIRP-α IR in neurons (arrows) within cortex. b Moderate SIRP-α IR in glial cells (arrowheads) within white matter and co-localization of SIRP-α (green) and HLA-DR (red) in a microglia (inset). c, d SIRP-α IR in cortical lesions of FCD IIb specimens. c Weak SIRP-α IR was occasionally detected in some dysmorphic neurons (arrows). d Negative balloon cells (arrowheads). e, f SIRP-α IR in cortical tubers of TSC specimens. e Weak SIRP-α IR in dysmorphic neurons (arrows) and a negative dysmorphic neurons (arrowheads). f Negative giant cells (arrowheads). g–i Double labeling in cortical lesions of FCD IIb specimens. g Co-localization of SIRP-α (green) with NF (red) in some dysmorphic neurons (arrows). h Absence of co-localization between SIRP-α (green) and GFAP (red) in astrocytes (arrows: astrocytes, arrowhead: dysmorphic neuron). i Co-localization of SIRP-α (green) with HLA-DR (red) in microglia (arrow). j–l Double labeling in cortical tubers of TSC specimens. j Absence of co-localization between SIRP-α (green) and NF (red) in giant cells (arrowheads). k Absence of co-localization between SIRP-α (green) and GFAP (red) in astrocytes (arrows: astrocytes, arrowhead: giant cell). l Co-localization of SIRP-α (green) with HLA-DR (red) in microglia (arrow). Scale bars: a 30 μm; b, e = 50 μm; c 35 μm; d 35 μm; f 30 μm; g, h, j, and k 50 μm; i, l 25 μm
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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Show All Figures
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Fig6: SIRP-α IR in control, FCD IIb, and TSC specimens. a, b SIRP-α IR in control specimens. a Strong somatic SIRP-α IR in neurons (arrows) within cortex. b Moderate SIRP-α IR in glial cells (arrowheads) within white matter and co-localization of SIRP-α (green) and HLA-DR (red) in a microglia (inset). c, d SIRP-α IR in cortical lesions of FCD IIb specimens. c Weak SIRP-α IR was occasionally detected in some dysmorphic neurons (arrows). d Negative balloon cells (arrowheads). e, f SIRP-α IR in cortical tubers of TSC specimens. e Weak SIRP-α IR in dysmorphic neurons (arrows) and a negative dysmorphic neurons (arrowheads). f Negative giant cells (arrowheads). g–i Double labeling in cortical lesions of FCD IIb specimens. g Co-localization of SIRP-α (green) with NF (red) in some dysmorphic neurons (arrows). h Absence of co-localization between SIRP-α (green) and GFAP (red) in astrocytes (arrows: astrocytes, arrowhead: dysmorphic neuron). i Co-localization of SIRP-α (green) with HLA-DR (red) in microglia (arrow). j–l Double labeling in cortical tubers of TSC specimens. j Absence of co-localization between SIRP-α (green) and NF (red) in giant cells (arrowheads). k Absence of co-localization between SIRP-α (green) and GFAP (red) in astrocytes (arrows: astrocytes, arrowhead: giant cell). l Co-localization of SIRP-α (green) with HLA-DR (red) in microglia (arrow). Scale bars: a 30 μm; b, e = 50 μm; c 35 μm; d 35 μm; f 30 μm; g, h, j, and k 50 μm; i, l 25 μm
Mentions: In histologically normal autopsy specimens, SIRP-α strongly expressed in pyramidal neurons within cortex (Fig. 6a) and showed moderate IR in glial cells within white matter (Fig. 6b). FCD IIb and TSC specimens displayed weak or undetectable SIRP-α IR in dysmorphic neurons (Fig. 6c, e). Balloon cells of FCD IIb and giant cells of TSC did not exhibit detectable SIRP-α IR (Fig. 6d, f). The IR score of SIRP-α was dramatically lower in both the FCD IIb and TSC specimens than that in controls (P < 0.05; Fig. 4b) but showed no significant correlation with the number of HLA-DR-positive cells in FCD IIb (Fig. 5b) and TSC (Fig. 5e). Double labeling demonstrated the co-expression of SIRP-α IR with NF in some dysmorphic neurons and giant cells (Fig. 6g, j) and with HLA-DR in certain microglia (Fig. 6i, l), whereas the absence of SIRP-α IR was observed in GFAP-positive astrocytes (Fig. 6h, k).Fig. 6

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