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Downregulation of CD47 and CD200 in patients with focal cortical dysplasia type IIb and tuberous sclerosis complex
Fei-Ji Sun1, Chun-Qing Zhang1, Xin Chen1
1Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University, 2-V Xinqiao Street, Chongqing, 400037, China.
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.
Insights
Reduced CD47/SIRP-α and CD200/CD200R pathways in focal cortical dysplasia type IIb (FCD IIb) and tuberous sclerosis complex (TSC) may drive neuroinflammation. Activating these immune checkpoints could offer new epilepsy treatments.
Area of Science:
- Neuroscience
- Immunology
- Epileptology
Background:
- Focal cortical dysplasia type IIb (FCD IIb) and tuberous sclerosis complex (TSC) are primary causes of pediatric intractable epilepsy.
- Neuroinflammation, involving microglia/macrophage activation, is implicated in seizure initiation and recurrence in FCD IIb and TSC.
- CD47/SIRP-α and CD200/CD200R pathways are crucial for regulating microglial immune responses.
Purpose of the Study:
- To investigate the expression of CD47/SIRP-α and CD200/CD200R in FCD IIb and TSC cortical lesions.
- To evaluate the effect of soluble CD47 Fc and CD200 Fc on pro-inflammatory cytokine production in vitro.
- To explore the role of interleukin-4 (IL-4) in modulating CD200.
Main Methods:
- Quantitative real-time PCR and western blot to assess CD47/SIRP-α and CD200/CD200R mRNA and protein levels.
- Immunohistochemistry to determine the expression patterns of CD47/SIRP-α and CD200/CD200R.
- Enzyme-linked immune-sorbent assays to measure cytokine concentrations and assess the impact of CD47 Fc and CD200 Fc.
Main Results:
- CD47, SIRP-α, CD200, and IL-4 mRNA levels were significantly downregulated in FCD IIb and TSC lesions compared to controls.
- CD200R levels showed no significant change, while CD47, SIRP-α, and CD200 expression decreased in specific cell types within lesions.
- CD47 Fc and CD200 Fc inhibited IL-6 release but did not affect IL-1β or IL-17 production.
Conclusions:
- Reduced expression of CD47/SIRP-α and CD200/CD200R pathways may contribute to microglial activation and neuroinflammation in FCD IIb and TSC.
- Targeting and upregulating CD47/SIRP-α and CD200/CD200R pathways presents a potential therapeutic strategy for managing neuroinflammation in these epilepsy conditions.
