Interleukin-1β in peripheral monocytes is associated with seizure frequency in pediatric drug-resistant epilepsy

Yamanaka, Gaku; Takamatsu, Tomoko; Morıchı, Shinichiro; Yamazaki, Takashi; Mizoguchi, Itaru; Ohno, Koko; Watanabe, Yusuke; Ishida, Yu; Oana, Shingo; Suzuki, Shinji; Kashiwagi, Yasuyo; Takata, Fuyuko; Sakuma, Hiroshi; Yoshimoto, Takayuki; Kato, Mitsuhiro; Kawashima, Hisashi

doi:10.1016/j.jneuroim.2021.577475

Cited by 17 publications

(13 citation statements)

References 26 publications

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“…In addition, the level of intracellular IL-1β in peripheral monocytes, but not the serum, of pediatric drug-resistant epilepsy was higher than that of controls. Furthermore, the level of intracellular IL-1β was correlated with the frequency of seizures, and we have confirmed the association between the clinical features and intracellular IL-1β levels [10].…”

Section: Pincipal Findingssupporting

confidence: 77%

“…In addition, the involvement of IL-1β in WS pathogenesis has not yet been investigated. However, flow cytometric analysis revealed that intracellular IL-1β levels in peripheral monocytes of pediatric patients with intractable epilepsy were higher than those in the controls and were associated with clinical symptoms [10].…”

Section: Introductionmentioning

confidence: 90%

“…To the best of our knowledge, this was the first study to examine the cells associated with the origin of cytokines using flow cytometry analysis in patients with WS; flow cytometry analysis in patients with intractable epilepsy has been performed [10]. The intracellular analysis of patients with Dravet syndrome revealed increased levels of proinflammatory cytokines, including IL-1β, in cells following the stimulation of monocytes with an in vitro vaccine [26].…”

Section: Pincipal Findingsmentioning

confidence: 96%

“…Various cytokines have been recognized as being potentially related to the pathogenesis of epilepsy. In particular, interleukin (IL)-1β is particularly relevant in epileptogenesis [9][10][11][12]. In an experimental mouse model of status epilepticus, IL-1β was found to be elevated after seizures at the mRNA level in hippocampal astrocytes, peaking at 24 h and returning to baseline after 5 days [11].…”

Section: Introductionmentioning

confidence: 99%

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Involvement of Peripheral Monocytes with IL-1β in the Pathogenesis of West Syndrome

Takamatsu

Yamanaka

Ohno

et al. 2022

JCM

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Neuroinflammation has been implicated in the pathogenesis of West syndrome (WS). Inflammatory cytokines, including interleukin-1β(IL-1β), have been reported to be associated with epilepsy. However, the assessment of cytokine changes in humans is not always simple or deterministic. This study aimed to elucidate the immunological mechanism of WS. We examined the intracellular cytokine profiles of peripheral blood cells collected from 13 patients with WS, using flow cytometry, and measured their serum cytokine levels. These were compared with those of 10 age-matched controls. We found that the WS group had significantly higher percentages of inter IL-1β, interleukin-1 receptor antagonist (IL-1RA)-positive monocytes, and interferon gamma (IFN-γ) in their CD8+ T cells than the control group. Interestingly, the group with sequelae revealed significantly lower levels of intracellular IFN-γ and IL-6 in their CD8+ T and CD4+ T cells, respectively, than the group without sequelae. There was no correlation between the ratios of positive cells and the serum levels of a particular cytokine in the WS patients. These cytokines in the peripheral immune cells might be involved in the neuroinflammation of WS, even in the absence of infectious or immune disease. Overall, an immunological approach using flow cytometry analysis might be useful for immunological studies of epilepsy.

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Section: Pincipal Findingssupporting

confidence: 77%

Section: Introductionmentioning

confidence: 90%

Section: Pincipal Findingsmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Involvement of Peripheral Monocytes with IL-1β in the Pathogenesis of West Syndrome

Takamatsu

Yamanaka

Ohno

et al. 2022

JCM

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“…From the clinical perspective, our recent flow cytometry analysis of pediatric patients with DRE demonstrated higher levels of intracellular cytokines, such as IL-1β, in the peripheral monocytes compared to the controls, which was correlated with the frequency of seizures [ 84 ]. The examination of other cells, including T cells, and natural killer and natural killer T cells, and plasma cytokines levels, including CCL2, TNF-α, and IL-6, did not yield such results [ 84 ]. Moreover, the analysis of the brain tissue of pediatric patients with DRE revealed that the seizure frequency was correlated with the number of infiltrating peripherally monocytes, but not that of the microglia [ 16 ].…”

Section: Reviewmentioning

confidence: 99%

Links between Immune Cells from the Periphery and the Brain in the Pathogenesis of Epilepsy: A Narrative Review

Yamanaka

Morıchı

Takamatsu

et al. 2021

IJMS

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Accumulating evidence has demonstrated that the pathogenesis of epilepsy is linked to neuroinflammation and cerebrovascular dysfunction. Peripheral immune cell invasion into the brain, along with these responses, is implicitly involved in epilepsy. This review explored the current literature on the association between the peripheral and central nervous systems in the pathogenesis of epilepsy, and highlights novel research directions for therapeutic interventions targeting these reactions. Previous experimental and human studies have demonstrated the activation of the innate and adaptive immune responses in the brain. The time required for monocytes (responsible for innate immunity) and T cells (involved in acquired immunity) to invade the central nervous system after a seizure varies. Moreover, the time between the leakage associated with blood–brain barrier (BBB) failure and the infiltration of these cells varies. This suggests that cell infiltration is not merely a secondary disruptive event associated with BBB failure, but also a non-disruptive event facilitated by various mediators produced by the neurovascular unit consisting of neurons, perivascular astrocytes, microglia, pericytes, and endothelial cells. Moreover, genetic manipulation has enabled the differentiation between peripheral monocytes and resident microglia, which was previously considered difficult. Thus, the evidence suggests that peripheral monocytes may contribute to the pathogenesis of seizures.

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Drug‐resistant seizures associated with hyperinflammatory monocytes in FIRES

Howe

Johnson

Overlee

et al. 2023

Ann Clin Transl Neurol

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Objective: Therapeutic strategies for patients with febrile infection-related epilepsy syndrome (FIRES) are limited, ad hoc, and frequently ineffective. Based on evidence that inflammation drives pathogenesis in FIRES, we used ex vivo stimulation of peripheral blood mononuclear cells (PBMCs) to characterize the monocytic response profile before and after therapy in a child successfully treated with dexamethasone delivered intrathecally six times between hospital Day 23 and 40 at 0.25 mg/kg/dose. Methods: PBMCs were isolated from serial blood draws acquired during refractory status epilepticus (RSE) and following resolution associated with intrathecal dexamethasone therapy in a previously healthy 9-year-old male that presented with seizures following Streptococcal pharyngitis. Cells were stimulated with bacterial or viral ligands and cytokine release was measured and compared to responses in age-matched healthy control PBMCs. Levels of inflammatory factors in the blood and CSF were also measured and compared to pediatric healthy control ranges. Results: During RSE, serum levels of IL6, CXCL8, HMGB1, S100A8/A9, and CRP were significantly elevated. IL6 was elevated in CSF. Ex vivo stimulation of PBMCs collected during RSE revealed hyperinflammatory release of IL6 and CXCL8 in response to bacterial stimulation. Following intrathecal dexamethasone, RSE resolved, inflammatory levels normalized in serum and CSF, and the PBMC hyperinflammatory response renormalized. Significance: FIRES may be associated with a hyperinflammatory monocytic response to normally banal bacterial pathogens. This hyperinflammatory response may induce a profound neutrophil burden and the consequent release of factors that further exacerbate inflammation and drive neuroinflammation. Intrathecal dexamethasone may resolve RSE by resetting this inflammatory feedback loop.

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Interleukin-1β in peripheral monocytes is associated with seizure frequency in pediatric drug-resistant epilepsy

Cited by 17 publications

References 26 publications

Involvement of Peripheral Monocytes with IL-1β in the Pathogenesis of West Syndrome

Involvement of Peripheral Monocytes with IL-1β in the Pathogenesis of West Syndrome

Links between Immune Cells from the Periphery and the Brain in the Pathogenesis of Epilepsy: A Narrative Review

Drug‐resistant seizures associated with hyperinflammatory monocytes in FIRES

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