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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

IL-4 mRNA expression in control, FCD IIb, and TSC specimens and the correlation between IL-4 and CD200 mRNA levels in FCD IIb and TSC specimens. a Quantitative real-time PCR analysis showed that IL-4 mRNA level was significantly decreased in FCD IIb and TSC compared with control specimens. There was no significant difference in IL-4 mRNA expression between FCD IIb and TSC specimens. The bar charts represent mean ± SD, *P < 0.05, FCD IIb, TSC versus controls, Kruskal–Wallis test, and Bonferroni correction. Scatter plot showing the significant positive correlation between IL-4 and CD200 mRNA levels in FCD IIb (b) (P < 0.05, r = 0.79) and TSC (c) (P < 0.01, r = 0.82). Correlation analysis performed with Spearman’s rank correlation coefficient
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Fig10: IL-4 mRNA expression in control, FCD IIb, and TSC specimens and the correlation between IL-4 and CD200 mRNA levels in FCD IIb and TSC specimens. a Quantitative real-time PCR analysis showed that IL-4 mRNA level was significantly decreased in FCD IIb and TSC compared with control specimens. There was no significant difference in IL-4 mRNA expression between FCD IIb and TSC specimens. The bar charts represent mean ± SD, *P < 0.05, FCD IIb, TSC versus controls, Kruskal–Wallis test, and Bonferroni correction. Scatter plot showing the significant positive correlation between IL-4 and CD200 mRNA levels in FCD IIb (b) (P < 0.05, r = 0.79) and TSC (c) (P < 0.01, r = 0.82). Correlation analysis performed with Spearman’s rank correlation coefficient

Mentions: Previous studies showed that IL-4 and IL-13 increase the expression of CD200/CD200R [31, 32], so we investigated the mRNA expression of IL-4 and IL-13 in control, FCD IIb, and TSC specimens and the correlations with CD200 level. Quantitative real-time PCR analysis showed that IL-4 mRNA level was significantly decreased in FCD IIb and TSC compared with control specimens (P < 0.05; Fig. 10a). Scatter plot showing the significant positive correlation between IL-4 and CD200 mRNA levels in FCD IIb (P < 0.05, r = 0.79; Fig. 10b) and TSC (P < 0.01, r = 0.82; Fig. 10c). Consistent with a previous study [32], we fail to detect IL-13 expression in our study (data not shown).Fig. 10


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)

IL-4 mRNA expression in control, FCD IIb, and TSC specimens and the correlation between IL-4 and CD200 mRNA levels in FCD IIb and TSC specimens. a Quantitative real-time PCR analysis showed that IL-4 mRNA level was significantly decreased in FCD IIb and TSC compared with control specimens. There was no significant difference in IL-4 mRNA expression between FCD IIb and TSC specimens. The bar charts represent mean ± SD, *P < 0.05, FCD IIb, TSC versus controls, Kruskal–Wallis test, and Bonferroni correction. Scatter plot showing the significant positive correlation between IL-4 and CD200 mRNA levels in FCD IIb (b) (P < 0.05, r = 0.79) and TSC (c) (P < 0.01, r = 0.82). Correlation analysis performed with Spearman’s rank correlation coefficient
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig10: IL-4 mRNA expression in control, FCD IIb, and TSC specimens and the correlation between IL-4 and CD200 mRNA levels in FCD IIb and TSC specimens. a Quantitative real-time PCR analysis showed that IL-4 mRNA level was significantly decreased in FCD IIb and TSC compared with control specimens. There was no significant difference in IL-4 mRNA expression between FCD IIb and TSC specimens. The bar charts represent mean ± SD, *P < 0.05, FCD IIb, TSC versus controls, Kruskal–Wallis test, and Bonferroni correction. Scatter plot showing the significant positive correlation between IL-4 and CD200 mRNA levels in FCD IIb (b) (P < 0.05, r = 0.79) and TSC (c) (P < 0.01, r = 0.82). Correlation analysis performed with Spearman’s rank correlation coefficient
Mentions: Previous studies showed that IL-4 and IL-13 increase the expression of CD200/CD200R [31, 32], so we investigated the mRNA expression of IL-4 and IL-13 in control, FCD IIb, and TSC specimens and the correlations with CD200 level. Quantitative real-time PCR analysis showed that IL-4 mRNA level was significantly decreased in FCD IIb and TSC compared with control specimens (P < 0.05; Fig. 10a). Scatter plot showing the significant positive correlation between IL-4 and CD200 mRNA levels in FCD IIb (P < 0.05, r = 0.79; Fig. 10b) and TSC (P < 0.01, r = 0.82; Fig. 10c). Consistent with a previous study [32], we fail to detect IL-13 expression in our study (data not shown).Fig. 10

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