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Cell-specific distribution of IL-17 in cortical tubers of TSC. (A and B) IL-17 IR in CTX. Weak to moderate IL-17 IR in neurons (arrows in A) and glial cells (arrowheads in B), and weak IL-17 IR in endothelial cells (inset, A) in gray matter (GM) and white matter (WM). (C and D) IL-17 IR in TSC. Strong IL-17 IR in glial cells (arrowheads in C and D), DNs (arrows in C, D and inset b in D) and GCs (double arrows in C, D and inset a in D). Moderate to strong IL-17 IR in endothelial cells (inset, C). (E and I) The merged images show the colocalization of IL-17 (green) with GFAP (red) in glial cells (arrowheads in E) and HLA (red) in microglia (arrowheads in I) but not in DNs (arrows in I). (F–H) Confocal image showing IL-17 IR DNs (F) and GCs with different sizes and shapes (G and H) colabeled with NF200 (red). (J and K) Double labeling staining shows the colocalization of IL-17 (green) with CD4 (red, arrows in J) but not CD8 (red, arrows in K) in T-lymphocytes. Sections are counterstained with hematoxylin (A–D) or DAPI (E–K). The bars indicate (A–D) 50μm; (E, K) 30μm; and (F–J) 20μm.
Source publication
The role of interleukin 17 (IL-17) to epilepsy-associated cortical tubers of tuberous sclerosis complex (TSC) is unknown. We investigated the expression patterns of the IL-17 and IL-17 receptor (IL-17R) in cortical tubers of TSC compared with normal control cortex (CTX). We found that IL-17 and IL-17R were clearly upregulated in cortical tubers at...
Contexts in source publication
Context 1
... to moderate IL-17 IR was detected in neurons and glial cells throughout all of the cortical layers in the CTX specimens ( Fig. 2A, B); weak staining was observed in the endothelial cells of blood vessels ( Fig. 2A, ...Context 2
... to moderate IL-17 IR was detected in neurons and glial cells throughout all of the cortical layers in the CTX specimens ( Fig. 2A, B); weak staining was observed in the endothelial cells of blood vessels ( Fig. 2A, ...Context 3
... the cortical tuber, there was strong IL-17 IR in 89% ± 2.1% of the DNs (n = 584) (Fig. 2C, D) and in 91% ± 1.3% of the GCs (n = 409) (Fig. 2C, D), along with moderate to strong IL-17 IR in the glial cells (Fig. 2C, D). Additionally, strong IL-17 IR staining was found in the endothelial cells of blood vessels (Fig. 2C, inset). The intensity scores of IL-17 IR in the cortical tuber were dramatically higher than those in the CTX ...Context 4
... the cortical tuber, there was strong IL-17 IR in 89% ± 2.1% of the DNs (n = 584) (Fig. 2C, D) and in 91% ± 1.3% of the GCs (n = 409) (Fig. 2C, D), along with moderate to strong IL-17 IR in the glial cells (Fig. 2C, D). Additionally, strong IL-17 IR staining was found in the endothelial cells of blood vessels (Fig. 2C, inset). The intensity scores of IL-17 IR in the cortical tuber were dramatically higher than those in the CTX samples (Table 2). Double-labeling experiments ...Context 5
... the cortical tuber, there was strong IL-17 IR in 89% ± 2.1% of the DNs (n = 584) (Fig. 2C, D) and in 91% ± 1.3% of the GCs (n = 409) (Fig. 2C, D), along with moderate to strong IL-17 IR in the glial cells (Fig. 2C, D). Additionally, strong IL-17 IR staining was found in the endothelial cells of blood vessels (Fig. 2C, inset). The intensity scores of IL-17 IR in the cortical tuber were dramatically higher than those in the CTX samples (Table 2). Double-labeling experiments revealed that NF200-positive (NF200 + ) DNs (Fig. 2F) and GCs (Fig. 2G, H) ...Context 6
... the cortical tuber, there was strong IL-17 IR in 89% ± 2.1% of the DNs (n = 584) (Fig. 2C, D) and in 91% ± 1.3% of the GCs (n = 409) (Fig. 2C, D), along with moderate to strong IL-17 IR in the glial cells (Fig. 2C, D). Additionally, strong IL-17 IR staining was found in the endothelial cells of blood vessels (Fig. 2C, inset). The intensity scores of IL-17 IR in the cortical tuber were dramatically higher than those in the CTX samples (Table 2). Double-labeling experiments revealed that NF200-positive (NF200 + ) DNs (Fig. 2F) and GCs (Fig. 2G, H) both expressed IL-17. Moreover, most of the IL-17 + glial cells were the GFAP + astrocytes (Fig. 2E) and HLA + ...Context 7
... IL-17 IR in the glial cells (Fig. 2C, D). Additionally, strong IL-17 IR staining was found in the endothelial cells of blood vessels (Fig. 2C, inset). The intensity scores of IL-17 IR in the cortical tuber were dramatically higher than those in the CTX samples (Table 2). Double-labeling experiments revealed that NF200-positive (NF200 + ) DNs (Fig. 2F) and GCs (Fig. 2G, H) both expressed IL-17. Moreover, most of the IL-17 + glial cells were the GFAP + astrocytes (Fig. 2E) and HLA + microglia (Fig. 2I). In this study, we also observed a few CD4 + (Fig. 2J) but not CD8 + (Fig. 2K) cells that expressed IL-17 in the TSC ...Context 8
... glial cells (Fig. 2C, D). Additionally, strong IL-17 IR staining was found in the endothelial cells of blood vessels (Fig. 2C, inset). The intensity scores of IL-17 IR in the cortical tuber were dramatically higher than those in the CTX samples (Table 2). Double-labeling experiments revealed that NF200-positive (NF200 + ) DNs (Fig. 2F) and GCs (Fig. 2G, H) both expressed IL-17. Moreover, most of the IL-17 + glial cells were the GFAP + astrocytes (Fig. 2E) and HLA + microglia (Fig. 2I). In this study, we also observed a few CD4 + (Fig. 2J) but not CD8 + (Fig. 2K) cells that expressed IL-17 in the TSC ...Context 9
... blood vessels (Fig. 2C, inset). The intensity scores of IL-17 IR in the cortical tuber were dramatically higher than those in the CTX samples (Table 2). Double-labeling experiments revealed that NF200-positive (NF200 + ) DNs (Fig. 2F) and GCs (Fig. 2G, H) both expressed IL-17. Moreover, most of the IL-17 + glial cells were the GFAP + astrocytes (Fig. 2E) and HLA + microglia (Fig. 2I). In this study, we also observed a few CD4 + (Fig. 2J) but not CD8 + (Fig. 2K) cells that expressed IL-17 in the TSC ...Context 10
... The intensity scores of IL-17 IR in the cortical tuber were dramatically higher than those in the CTX samples (Table 2). Double-labeling experiments revealed that NF200-positive (NF200 + ) DNs (Fig. 2F) and GCs (Fig. 2G, H) both expressed IL-17. Moreover, most of the IL-17 + glial cells were the GFAP + astrocytes (Fig. 2E) and HLA + microglia (Fig. 2I). In this study, we also observed a few CD4 + (Fig. 2J) but not CD8 + (Fig. 2K) cells that expressed IL-17 in the TSC ...Context 11
... were dramatically higher than those in the CTX samples (Table 2). Double-labeling experiments revealed that NF200-positive (NF200 + ) DNs (Fig. 2F) and GCs (Fig. 2G, H) both expressed IL-17. Moreover, most of the IL-17 + glial cells were the GFAP + astrocytes (Fig. 2E) and HLA + microglia (Fig. 2I). In this study, we also observed a few CD4 + (Fig. 2J) but not CD8 + (Fig. 2K) cells that expressed IL-17 in the TSC ...Context 12
... than those in the CTX samples (Table 2). Double-labeling experiments revealed that NF200-positive (NF200 + ) DNs (Fig. 2F) and GCs (Fig. 2G, H) both expressed IL-17. Moreover, most of the IL-17 + glial cells were the GFAP + astrocytes (Fig. 2E) and HLA + microglia (Fig. 2I). In this study, we also observed a few CD4 + (Fig. 2J) but not CD8 + (Fig. 2K) cells that expressed IL-17 in the TSC ...Citations
... Recently, the hyperactivation of mTOR kinase has been implicated in neuroinflammation; this process likely mediates the inflammatory response in the central nervous system, and could contribute to epileptogenesis in patients with TSC (16) and other neurodevelopmental diseases (17,18). Previous studies have confirmed that proinflammatory factors are increased in the resected brain tissues of patients with TSC and TSC mouse models (15,19); for example, toll-like receptor 4 (TLR-4), interleukin 1β (IL-1β), and complement components, as well as increased expression of interleukin 17 (IL-17), tumor necrosis factor α (TNF-α), and nuclear factor κB (NF-κB) (10,20). These factors are released by the activated astrocytes and microglia cells, which represent the primary immune cells in the processes (21). ...
Background:
Tuberous sclerosis complex (TSC) is a genetic disorder associated with multiple neurological manifestations. Cortical tubers (CT) are recognized as the hallmark brain lesions of TSC and contribute to neurological and psychiatric symptoms. To understand the molecular mechanism of neuropsychiatric features of TSC, the differentially expressed genes (DEGs) in CT from patients with TSC and those in normal cortex (NC) from participants acting as healthy controls were investigated.
Methods:
The dataset of GSE16969, which had already been published and described (https://onlinelibrary.wiley.com/doi/10.1111/j.1750-3639.2009.00341.x), was downloaded from the Gene Expression Omnibus (GEO), including samples of 4 CT and 4 NC. The R package "limma" was used to screen DEGs in CT and NC. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enrichment analyses of the DEGs were conducted using the R package "clusterProfiler". The online software Ingenuity Pathway Analysis (IPA) was used to explore activation/inaction of canonical pathways. The hub gene was selected based on the protein-protein interaction (PPI) network constructed using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database and Cytoscape software. Subsequently, the hub genes at messenger (mRNA) and transcriptional levels were tested. We also explored immune cell-type enrichment using the online database xCell, and assessed the correlation between cell types and C3 expression. Then, we verified the source of C3 by constructing TSC2 knockout cells in the U87 astrocyte cell line. The human neuronal cell line SH-SY5Y was used to examine the effects of excessive complement C3 levels.
Results:
A total of 455 DEGs were identified. A large number of pathways were involved in the immune response process based on the results of GO, KEGG, and IPA. C3 was identified as a hub gene. Complement C3 was also upregulated in the human CT and peripheral blood. Furthermore, based on the enrichment of functions and signaling pathways, complement C3 played a critical role in immune injury in CT of TSC. In the in vitro experiments, we found that excessive complement C3 was derived from TSC2 knockout U87 cells, and there was an increased intracellular reactive oxygen species (ROS) level in SH-SY5Y cells.
Conclusions:
Complement C3 is activated in patients with TSC and can mediate immune injury.
... Therefore, recurrent, persistent seizures could induce microglial activation in the surrounding and/or propagated areas of the refractory seizure group. Furthermore, proinflammatory mediators have been reported to induce neuronal excitation, reduce seizure threshold (Galic et al., 2012), and activate astrocytes, which have epileptogenic properties (He et al., 2013). These findings are consistent with our result of a strong correlation between the severity of epilepsy and microglia extension. ...
Background and objectives: Neuroinflammation contributes to the severity of various neurological disorders, including epilepsy. Tuberous sclerosis complex (TSC) is a condition that results in the overactivation of the mammalian target of rapamycin (mTOR) pathway, which has been linked to the activation of microglia responsible for neuroinflammation. To clarify the involvement of neuroinflammation in the neuropathophysiology of TSC, we performed a positron emission tomography (PET) study using the translocator protein (TSPO) radioligand, [11C] DPA713, and investigated microglial activation in relation to neurological manifestations, especially epilepsy and cognitive function. Methods: This cross-sectional study included 18 patients with TSC (6 in the no-seizure group, 6 in the refractory seizure group, and 6 in the mTOR-inhibitor [mTOR-i] group). All participants underwent [11C] DPA713-PET. PET results were superimposed with a 3D T2-weighted fluid-attenuated inversion-recovery (FLAIR) and T1-weighted image (T1WI) to evaluate the location of cortical tubers. Microglial activation was assessed using the standardized uptake value ratio (SUVr) of DPA713 binding. The volume ratio of the DPA713-positive area to the intracranial volume (volume ratio of DPA713/ICV) was calculated to evaluate the extent of microglial activation. A correlation analysis was performed to examine the relationship between volume ratio of DPA713/ICV and severity of epilepsy and cognitive function. Results: Most cortical tubers with hyperintensity on FLAIR and hypo- or isointensity on T1WI showed microglial activation. The extent of microglial activation was significantly greater in the refractory seizure group than in the no-seizure or mTOR-i groups (p
... IL-17R deficiency ameliorated seizure activity in animal models of status epilepticus induced by kainic acid, which confirmed the regulatory effect of IL-17 on neuronal excitability (Xu et al., 2018). Studies also proved that the elevated IL-17 in the brain of epilepsy patients with multiple etiologies, such as mesial temporal lobe epilepsy (MTLE), focal cortical dysplasia (FCD), and tuberous sclerosis complex (TSC) (He et al., 2013a(He et al., , 2013b(He et al., , 2016. In addition to its influence on idiopathic epilepsies, IL-17 also plays a vital role in the pathogenesis of acquired epilepsies, a common subtype of epilepsy secondary to brain insults such as traumas, strokes, or infections (Banerjee et al., 2009). ...
... From that on, the neuroinflammatory mechanism of IL-17 in epilepsy has received increasing attention, as the activation of both innate and adaptive immunity is a significant characteristic in epileptogenesis (Bauer et al., 2017). It was found that the expression of IL-17 was significantly upregulated and distributed specifically in the innate immunity cells (dysmorphic neurons, balloon cells, giant cells, astrocytes, and microglia) and adaptive immunity cells (T-lymphocytes) in intractable epilepsy (He et al., 2013a(He et al., , 2013b(He et al., , 2016. Furthermore, IL-17 can promote the secretion of epileptogenic pro-inflammatory factors, for instance, IL-1α, IL-6, and TNF-α, from glial cells in the brain, and the increased pro-inflammatory factors can stimulate the expression of IL-17 in reverse (Ma et al., 2010). ...
... Similar results were also observed by Rahman et al., whose study reported that the permeability of BBB for 40 kDa dextran-fluorescein was significantly increased after IL-17 stimulation (Rahman et al., 2018). It was also reported that IL-17 and IL-17R were overexpressed in the cerebrovascular endothelial cells of patients with medically intractable epilepsy related to BBB impairment (He et al., 2013a(He et al., , 2013b(He et al., , 2016. ...
Epilepsy is a common neurological disorder that seriously affects human health. It is a chronic central nervous system dysfunction caused by abnormal discharges of neurons. About 50 million patients worldwide are affected by epilepsy. Although epileptic symptoms of most patients are controllable, some patients with refractory epilepsy have no response to antiseizure medications. It is necessary to investigate the pathogenesis of epilepsy and identify new therapeutic targets for refractory epilepsy. Epileptic disorders often accompany cerebral inflammatory reactions. Recently, the role of inflammation in the onset of epilepsy has increasingly attracted attention. The activation of both innate and adaptive immunity plays a significant role in refractory epilepsy. According to several clinical studies, interleukin-17, an essential inflammatory mediator linking innate and adaptive immunity, increased significantly in the body liquid and epileptic focus of patients with epilepsy. Experimental studies also indicated that interleukin-17 participated in epileptogenesis through various mechanisms. This review summarized the current studies about interleukin-17 in epilepsy and aimed at finding new therapeutic targets for refractory epilepsy.
... В ряде исследований изучено состояние системы IL-17/IL-17R в патологически измененных зонах коры мозга у детей с хроничес кой ЛУЭПЛ различного генеза, подвергнутых хирургической резекции этих участков. Изучены хирургические образцы коры мозга детей с ЛУЭПЛ, вызванной нарушением кортикального развития [25] или генетическим заболеванием [26]. Среди нарушений кортикального развития у детей с ЛУЭПЛ превалируют фокальные кортикальные дисплазии (ФКД, FCD) разных типов, при которых ЭПЛ манифестирует в возрасте от нескольких недель до 7 лет [6]. ...
... Генетическая аутосомно-доминантная болезнь -туберозно-склерозный комплекс (TSC), возникает в результате мутации одного из двух генов: TSC1 (ген гамартина) или TSC2 (ген туберина), характеризуясь образованием гамартом в разных органах, включая мозг. Кортикальные узлы (tubers) TSC представляют собой области FCD с нарушением нормальной 6-слойной структуры коры, астроглиозом, наличием измененных клеток -диспластических нейронов (DN) и гигантских клеток (GC) [26]. He J. и соавт. ...
... He J. и соавт. [26] изучили экспрессию IL-17 и IL-17R в хирургических образцах TSC от 16 пациентов с ЛУЭПЛ в возрасте от 2 до 11 лет и сравнили полученные показатели с соответствующими показателями контрольных образцов коры мозга. Обнаружена повышенная экспрессия IL-17 и IL-17R в кортикальных узлах TSC, при этом IL-17R экспрессировали DN и GC, а также клетки глии и эндотелия сосудов. ...
In this Section we provide new data on the pathogenetic factors in pediatric convulsive syndrome, including a prominent role of viral infection in developing seizures and epilepsy (EPL) in children, as evidenced by clinical and experimental studies. Various forms of convulsive syndrome associated with viral infection include febrile convulsions and febrile epileptic status, encephalitis-related acute symptomatic seizures, and postencephalitic epilepsy. The human
herpesvirus-6 isolated in temporal lobe epilepsy is a frequent causative agent of febrile seizures and febrile epileptic status. Febrile seizures and, especially, febrile epileptic status are associated with further developing epilepsy. Of special note is the febrile infection-related epileptic syndrome (FIRES) more often affecting school-aged children and characterized by extremely severe course and unfavorable outcome. Convulsive syndrome is associated with systemic inflammation and overproduced pro-inflammatory cytokines that increase permeability of the blood-brain barrier and functional activity of brain-resident cells, which are involved in eliciting seizures and maintaining epileptogenesis. Taking into consideration the key role of inflammation underlying convulsive syndrome, in recent decades cytokines and chemokines have been widely studied as possible prognostic criteria for epileptogenesis. Neuron-specific proteins are examined as markers of brain cell damage in various inflammatory diseases of the central nervous system. The first Section
of the review presented current understanding on systemic and local cytokine/chemokine response in viral encephalitis. Here we present clinical trials published within the last 5–7 years assessing cytokines/chemokines and neuron-specific proteins in children with various forms of convulsive syndrome, including epilepsy. Association between biomarker level and disease clinical parameters as well as potential for their use to diagnose and predict its further course are discussed.
... Besides the reported changes in potassium buffering, glutamate clearance, and adenosine homeostasis, TSC is also characterized by inflammatory changes, and astrocytes are supposed to be both source and target of inflammatory signaling therein (92)(93)(94)(95). Indeed, human tuber and SEGA tissue also display activation of inflammation in astrocytes, in particular, the toll-like receptor 4 (TLR-4), interleukin 1β (IL-1β), and complement pathways, as well as increased expression of IL-17, intercellular adhesion molecule 1, tumor necrosis factor α (TNF-α), and nuclear factor κB (NF-κB) (61)(62)(63)(96)(97)(98). In particular, several large-scale RNA-sequencing studies confirmed that neuroinflammation is a hallmark of TSC-associated lesions, and the retrieved data were enriched for both astrocyte and microglial specific genes (21, 63,99,100). ...
Tuberous sclerosis complex (TSC) represents the prototypic monogenic disorder of the mammalian target of rapamycin (mTOR) pathway dysregulation. It provides the rational mechanistic basis of a direct link between gene mutation and brain pathology (structural and functional abnormalities) associated with a complex clinical phenotype including epilepsy, autism, and intellectual disability. So far, research conducted in TSC has been largely neuron-oriented. However, the neuropathological hallmarks of TSC and other malformations of cortical development also include major morphological and functional changes in glial cells involving astrocytes, oligodendrocytes, NG2 glia, and microglia. These cells and their interglial crosstalk may offer new insights into the common neurobiological mechanisms underlying epilepsy and the complex cognitive and behavioral comorbidities that are characteristic of the spectrum of mTOR-associated neurodevelopmental disorders. This review will focus on the role of glial dysfunction, the interaction between glia related to mTOR hyperactivity, and its contribution to epileptogenesis in TSC. Moreover, we will discuss how understanding glial abnormalities in TSC might give valuable insight into the pathophysiological mechanisms that could help to develop novel therapeutic approaches for TSC or other pathologies characterized by glial dysfunction and acquired mTOR hyperactivation.
... The neural and immune systems closely interact and regulate each other at multiple levels (Dantzer, 2017; Fig. 3). For instance, in many species CNS receptors have been identified for IL-1α, IL-1 β, IL-4 (Chen et al., 2007), IL-6 (Mehler and Kessler, 1997), IL-7 (Szot et al., 2017), IL-8 (Xia et al., 1997), IL-10 (Wong et al., 1997), IL-11 (Yanagisawa et al., 2000), IL-12 (Suzumura et al., 1998), IL-15 (Hanisch et al., 1997), IL-17 (He et al., 2013), IL-19 (Horiuchi et al., 2015), IL-21 (Tzartos et al., 2011), IL-22 (Perriard et al., 2015), IL-26 (Sheikh et al., 2004), IL-34 (Nandi et al., 2013), IFN-γ (Wei et al., 2000), TNF (Botchkina et al., 1997) and TGF (Ata et al., 1997). In both humans and animals, cytokines also induce overt physiological and behavioral changes (Shattuck and Muehlenbein, 2015). ...
Despite the high prevalence of neural and immune disorders, their etiology and molecular mechanisms remain poorly understood. As the zebrafish (Danio rerio) is increasingly utilized as a powerful model organism in biomedical research, mounting evidence suggests these fish as a useful tool to study neural and immune mechanisms and their interplay. Here, we discuss zebrafish neuro-immune mechanisms and their pharmacological and genetic modulation, the effect of stress on cytokines, as well as relevant models of microbiota-brain interplay. As many human brain diseases are based on complex interplay between the neural and the immune system, here we discuss zebrafish models, as well as recent successes and challenges, in this rapidly expanding field. We particularly emphasize the growing utility of zebrafish models in translational immunopsychiatry research, as they improve our understanding of pathogenetic neuro-immune interactions, thereby fostering future discovery of potential therapeutic agents.
... The microRNA expression pattern appears to represent a progression from non-onset/ AMT-cold tubers to onset/AMT-hot tubers, with onset/AMT-cold tubers an intermediate type. The inflammatory signaling events that are believed to drive the development of seizures in TSC (Boer et al., 2008;Zhang et al., 2015;He et al., 2013;Aronica and Crino, 2011) may be causing induction of these microRNAs, which subsequently repress known epilepsy risk genes and many genes involved in synaptic signaling. We will explore this mechanistic model in subsequent studies. ...
Tuberous sclerosis complex (TSC) is characterized by hamartomatous lesions in various organs and arises due to mutations in the TSC1 or TSC2 genes. TSC mutations lead to a range of neurological manifestations including epilepsy, cognitive impairment, autism spectrum disorders (ASD), and brain lesions that include cortical tubers. There is evidence that seizures arise at or near cortical tubers, but it is unknown why some tubers are epileptogenic while others are not. We have previously reported increased tryptophan metabolism measured with α[(11)C]-methyl-l-tryptophan (AMT) positron emission tomography (PET) in epileptogenic tubers in approximately two-thirds of patients with tuberous sclerosis and intractable epilepsy. However, the underlying mechanisms leading to seizure onset in TSC remain poorly characterized. MicroRNAs are enriched in the brain and play important roles in neurodevelopment and brain function. Recent reports have shown aberrant microRNA expression in epilepsy and TSC. In this study, we performed microRNA expression profiling in brain specimens obtained from TSC patients undergoing epilepsy surgery for intractable epilepsy. Typically, in these resections several non-seizure onset tubers are resected together with the seizure-onset tubers because of their proximity. We directly compared seizure onset tubers, with and without increased tryptophan metabolism measured with PET, and non-onset tubers to assess the role of microRNAs in epileptogenesis associated with these lesions. Whether a particular tuber was epileptogenic or non-epileptogenic was determined with intracranial electrocorticography, and tryptophan metabolism was measured with AMT PET. We identified a set of five microRNAs (miR-142-3p, 142-5p, 223-3p, 200b-3p and 32-5p) that collectively could distinguish among the three primary groups of tubers: non-onset/AMT-cold (NC), onset/AMT-cold (OC), and onset/AMT-hot (OH). These microRNAs were significantly upregulated in OH tubers compared to the other two groups, and microRNA expression was most significantly associated with AMT-PET uptake. The microRNAs target a group of genes enriched for synaptic signaling and epilepsy risk, including SLC12A5, SYT1, GRIN2A, GRIN2B, KCNB1, SCN2A, TSC1, and MEF2C. We confirmed the interaction between miR-32-5p and SLC12A5 using a luciferase reporter assay. Our findings provide a new avenue for subsequent mechanistic studies of tuber epileptogenesis in TSC.
... In a study of 16 patients with tuberous sclerosis, Jiao-Jiang at al. reported increased IL-17 and IL-17R in the cortical lesions of patients with focal cortical dysplasia. In addition to refractory seizures, infantile spasm-type seizure was identified in 4 patients [23]. Mao et al. reported significantly higher IL-17A levels in patients with epilepsy compared to a healthy control group [24]. ...
Purpose:
Infantile spasm is an age-dependent epileptic syndrome seen in infancy or early childhood. Although studies have investigated the epilepsy-cytokine relationship, there has been insufficient research into the relation between cytokines and infantile spasm. The purpose of this study was to examine the role of cytokines in the pathogenesis of infantile spasm by investigating cytokine levels before and 1month after adrenocorticotropic hormone (ACTH) therapy in patients diagnosed with the condition.
Method:
Twenty patients aged between 1month and 2years and diagnosed with infantile spasm at the Karadeniz Technical University Medical Faculty Department of Child Health and Diseases Pediatric Neurology Clinic, Turkey, and 20 healthy children were included in the study. Patients received 11 doses of ACTH on 2days a week. Levels of TNF-alpha and IL-2, the main cytokines involved in inflammation and recently associated with infantile spasm, and of IL-1beta, IL-6 and IL-17A, associated with epileptic seizures, and serum levels of the IL-17A activator IL-23 were investigated in all patients at the start of treatment and 1month after completion of treatment.
Results:
No statistically significant difference was observed between pre- and post-treatment patient group and control group IL-1beta, IL-2, IL-23 or TNF-alpha levels. Pre-treatment IL-6 and IL-17A levels were significantly higher in the untreated patient group compared to the healthy control group (p<0.001 and p=0.002).
Conclusion:
Our study supports the recent idea that IL-6 and IL-17A are cytokines involved in the pathogenesis of infantile spasm.
... In the present study, we investigated the levels and expression pattern of CD47, SIRP-α, CD200, and CD200R in surgically resected brain tissues from patients with FCD IIb and TSC. To assess the potential roles of CD47 and CD200 on the epileptogenesis of 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. We also evaluated the level of IL-4, which has been shown to increase the expression of CD200 [31,32]. ...
... Previous studies have revealed that many proinflammatory cytokines are upregulated in epileptogenic lesions and play pivotal roles in the epileptogenesis of FCD IIb and TSC patients, including IL1-β, IL-6, and IL-17 [15][16][17]30]. It has been demonstrated that CD47 Fc could decrease proinflammatory cytokine release, including IL-6, IL-12, tumor necrosis factor α, and interferon-γ, by binding to its receptor, SIRP-α, in human dendritic cells [24]. ...
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. 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. 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.
Epilepsy is a chronic neurological disorder with recurrent unprovoked seizures, affecting ~ 65 million worldwide. Evidence in patients with epilepsy and animal models suggests a contribution of neuroinflammation to epileptogenesis and the development of epilepsy. Interleukins (ILs), as one of the major contributors to neuroinflammation, are intensively studied for their association and modulatory effects on ictogenesis and epileptogenesis. ILs are commonly divided into pro- and anti-inflammatory cytokines and therefore are expected to be pathogenic or neuroprotective in epilepsy. However, both protective and destructive effects have been reported for many ILs. This may be due to the complex nature of ILs, and also possibly due to the different disease courses that those ILs are involved in. In this review, we summarize the contributions of different ILs in those processes and provide a current overview of recent research advances, as well as preclinical and clinical studies targeting ILs in the treatment of epilepsy.
