Downregulation of CD47 and CD200 in patients with focal cortical dysplasia type IIb and tuberous sclerosis complex.
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.
Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University, 2-V Xinqiao Street, Chongqing, 400037, China.
Fei-Ji
FJ
Sun
Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University, 2-V Xinqiao Street, Chongqing, 400037, China.
Chun-Qing
CQ
Zhang
Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University, 2-V Xinqiao Street, Chongqing, 400037, China.
Xin
X
Chen
Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University, 2-V Xinqiao Street, Chongqing, 400037, China.
Yu-Jia
YJ
Wei
Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University, 2-V Xinqiao Street, Chongqing, 400037, China.
Song
S
Li
Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University, 2-V Xinqiao Street, Chongqing, 400037, China.
Shi-Yong
SY
Liu
Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University, 2-V Xinqiao Street, Chongqing, 400037, China.
Zhen-le
ZL
Zang
Department of Neurosurgery, Lanzhou General Hospital of Chinese People's Liberation Army, Lanzhou, China.
Jiao-Jiang
JJ
He
Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xian, China.
Wei
W
Guo
Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University, 2-V Xinqiao Street, Chongqing, 400037, China. huiiyang64@yahoo.com.
Hui
H
Yang
D015703:Antigens, CD / Q000096:biosynthesis*; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism*; D051928:CD47 Antigen / Q000096:biosynthesis*; D002648:Child; D002675:Child, Preschool; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D004827:Epilepsy / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D008297:Male; D065703:Malformations of Cortical Development, Group I / Q000378:metabolism*; D017628:Microglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D014402:Tuberous Sclerosis / Q000378:metabolism*
D015703:Antigens, CD; D051928:CD47 Antigen; C497894:CD47 protein, human; C042739:antigens, CD200
CD200; CD200 receptor; CD47; Focal cortical dysplasia type IIb; Inflammation; Signal regulatory protein α; Tuberous sclerosis complex