Abstract
BackgroundFocal 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.MethodsTwelve 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.ResultsBoth 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.ConclusionsOur 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0546-2) contains supplementary material, which is available to authorized users.
Highlights
Focal cortical dysplasia type focal cortical dysplasia type IIb (IIb) (FCD IIb) and tuberous sclerosis complex (TSC) are well-recognized causes of chronic intractable epilepsy in children
To assess the potential roles of CD47 and CD200 on the epileptogenesis of Focal cortical dysplasia type IIb (FCD IIb) and TSC, we examined the concentrations of several proinflammatory cytokines (IL1-β, IL-6, and IL-17), which are associated with the epileptogenesis of FCD IIb and TSC [15,16,17, 30], in living epileptogenic brain slices treated with soluble recombinant human CD47 Fc chimera protein or CD200 Fc chimera protein compared with the vehicle-treated controls
IL-1β and IL-17 that were closely associated with IL-6 in Discussion In the present study, we demonstrate that the expression of the immune inhibitory molecules CD47 and its receptor, signal regulatory protein α (SIRP-α), and CD200 are downregulated in surgically resected brain tissues from patients with FCD IIb and TSC, both of which are associated with medically
Summary
Focal cortical dysplasia type IIb (FCD IIb) and tuberous sclerosis complex (TSC) are well-recognized causes of chronic intractable epilepsy in children. In addition to having progressive and recurrent seizures in common, TSC cortical tubers have a number of histopathological features similar to focal cortical dysplasia type IIb (FCD IIb), such as disorganized lamination, dysmorphic neurons, and giant cells, suggesting common mechanisms responsible for structural abnormalities and epileptogenesis [5]. Mammalian target of rapamycin complex 1 activation and autophagy defect are observed in both the TSC giant cells and FCD IIb balloon cells [6, 7] Both TSC and FCD IIb cortical lesions express abnormally phosphorylated tau protein, an important microtubule-associated protein that in aging adults produces dementia but in immature brain interferes with cellular lineage, neuroblast polarity and migration, and especially cellular growth and morphogenesis, features they share with hemimegalencephaly [8, 9]. Many studies have indicated that seizures are likely to originate within the dysplastic cortical lesions in FCD IIb and the cortical tubers in TSC [5], the cellular and molecular mechanisms underlying the epileptogenesis of FCD IIb and TSC are still unknown
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