Role of HMGB1/TLR4 and IL-1β/IL-1R1 Signaling Pathways in Epilepsy

Zhang, Shaohui; Chen, Feng; Zhai, Feng; Liang, Shuli

doi:10.3389/fneur.2022.904225

Cited by 32 publications

(29 citation statements)

References 62 publications

(108 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Chen et al reported that NLRP3 primarily aggregates into several small puncta before being combined into a big speck with ASC, and these puncta were veri ed to be the active form of NLRP3 in their cell experiments (32). Recent studies suggested that IL-1β was not only a downstream in ammatory factor produced by the NLRP3 in ammasome but also an in ammatory signal that promotes the synthesis of NLRP3 in the nucleus via the IL-1R1 (15,33,34). We assume that there is a feedback mechanism about IL-1β-IL-1R1-NLRP3 in ammasome existing in the pathological process of brain injury induced by peripheral surgery.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

NLRP3 inflammasome-IL-1β-IL-1R1 signaling pathway is involved in surgery- induced neuroinflammation in mice

Jiang

Liu

Ren

et al. 2023

Preprint

View full text Add to dashboard Cite

OBJECTIVE Previous studies have shown that the activation of NLRP3 inflammasome and associated IL-1β/IL-1R1 pathway plays a crucial role in the occurrence and development of inflammation-induced impairment of diverse diseases, inflammation-induced pulmonary fibrosis pathological process. However, the impact of NLRP3 inflammasome-IL-1β-IL-1R1 signaling pathway in surgery-induced neuroinflammation still remains unknown. METHODS Firstly, male C57BL/6J mice were adopted to randomly devided into control group and different time point group (0.5h, 6h, 12h, 18h, 24h) after surgery treated with carotid artery exploration surgery. Moreover, to further investigate the effect of blockage of NLRP3, 4 groups including control group, surgery group, surgery + AAV group and surgery + NEG group, were added to our experiments. After the surgery, the levels of proteins related to the NLRP3 inflammasome, IL-1R1, IL-1β, and IL-18 in diverse groups were measured by immunofluorescence assay, quantitative polymerase chain reaction (qPCR), western blot, and enzyme-linked immunosorbent assay (ELISA), respectively. Microglia and monocytes were separately determined by flow cytometry. The pathological changes in the brain were detected by Nissl staining. RESULTS Peripheral surgery resulted in monocyte activation and an increase in the expression of IL-1β in the circulatory system. IL-1R1, NLRP3, activated caspase-1 (caspase-1 P10), IL-1β, and IL-18 were upregulated in the hippocampus. Subsequently, the expression of microglia cells considerably increased and neuronal damage was observed. These effects were attenuated by AAV-NLRP3 treatment. CONCLUSIONS The peripheral surgery induced an increase of IL-1β, IL-1R1, NLRP3, and neuron injury in the hippocampus, inhibiting the expression of NLRP3 can alleviate inflammatory factors expression and neuron damage. We assumed that there is a feedback mechanism about IL-1β-IL-1R1-NLRP3 inflammasome existing in the brain after peripheral surgery.

show abstract

Section: Discussionmentioning

confidence: 99%

“…One of the prerequisites for the production of IL-1β is the activation of NLRP3 in ammasome. Several in ammatory signaling molecules can activate the NLRP3 in ammasome, such as IL-1R1 (13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

NLRP3 inflammasome-IL-1β-IL-1R1 signaling pathway is involved in surgery- induced neuroinflammation in mice

Jiang

Liu

Ren

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Of these pro-in ammatory cytokines, HMGB1 and IL-1β are key initiators of neuroin ammation contributing not only to the generation of FS, but also to the epileptogenesis after prolonged FS [12,13,[25][26][27][28][29][30]. Experimental studies have shown that increased levels of HMGB1 and IL-1β contribute to chronic in ammation, neuronal excitotoxicity and reduction of seizure threshold [12,14,17,[27][28][29][31][32][33].…”

Section: Discussionmentioning

confidence: 99%

“…The role of HMGB1 and IL-1β in generating and perpetuating seizures is well documented [14]. Physiologically, HMGB1 fundamentally resides in the nucleus translocates to the cytosol under stress conditions and is subsequently released into the extracellular [15].…”

mentioning

confidence: 99%

Increased expression of NLRP3 associate with elevated levels of HMGB1 in children with febrile seizures: a case control study

She

et al. 2023

Preprint

View full text Add to dashboard Cite

Background High mobility group box-1 (HMGB1) is an endogenous danger signal that mediates activation of the innate immune response including NLR pyrin domain containing 3 (NLRP3) inflammasome activation and pro-inflammatory cytokine release. Although HMGB1 and NLRP3 have been implicated in the pathophysiology of seizures, the correlation between HMGB1 and NLRP3 has not been determined in children with febrile seizures (FS). To explore the relationship between extra-cellular HMGB1 and NLRP3 in children with FS, we analyzed serum HMGB1, NLRP3, Capase-1, and pro-inflammatory cytokines of patients with FS. Methods Thirty FS children and thirty age-matched febrile controls were included in this study. Blood was obtained from the FS children within 1 hour of the time of the seizure; subsequently, the content of HMGB1, NLRP3, Capase-1, interleukin (IL)-1β, interleukin (IL)-6, and tumor necrosis factor-α (TNF-α) were determined by enzyme-linked immunosorbent assay. The Mann-Whitney U test was used to compare serum cytokine levels between FS patients and controls. The Spearman’s rank correlation coefficient was calculated to detect significant correlations between cytokine levels. Results Serum levels of HMGB1, NLRP3, Capase-1, IL-1β, IL-6, and TNF-α were significantly higher in FS patients than febrile controls (p < 0.05). Serum levels of HMGB1 were significantly correlated with levels of NLRP3 and Capase-1 (both, p < 0.05). Serum levels of Capase-1 were significantly correlated with levels of IL-1β (p < 0.05). Serum levels of IL-1β were significantly correlated with levels of IL-6 and TNF-α (p < 0.05). Conclusions HMGB1 are up-regulated in peripheral serum of FS patients, what may be responsible, at least in part, for the increased expression of NLRP3 and Caspase-1. Increased expression of Capase-1 was significantly associated with elevated serum levels of and IL-1β. Given that activated Caspase-1 directly regulates the expression of mature IL-1β and positively correlates with activation of NLRP3 inflammasome, our data suggest that increased levels of peripheral HMGB1 possibly mediate IL-1β secretion through the activation of NLRP3 inflammasome in children with FS. Thus, both HMGB1 and NLRP3 might be the potential target for preventing or limiting FS.

show abstract

“…The pathogenesis of epilepsy is complex and has not been fully elucidated; consequently, there is a limited clinical cure rate. Recent studies have suggested that a variety of signaling pathways may be associated with epilepsy ( 54 ). These pathways include the Phosphatidylinositol-3-kinase (PI3K) / protein kinase B (Akt) / mammalian target of rapamycin (mTOR) signaling pathway that regulates the autophagy process in neurodegenerative diseases ( 55 ), the Wnt/β-catenin signaling pathway ( 56 ), mitogen-activated protein kinase (MAPK) signaling pathway ( 57 ) and the TLR4/ NF-κB pathway ( 58 ) that is associated with neurogenesis and neuronal death.…”

Section: Discussionmentioning

confidence: 99%

Low-intensity exercise combined with sodium valproate attenuates kainic acid-induced seizures and associated co-morbidities by inhibiting NF-κB signaling in mice

et al. 2022

View full text Add to dashboard Cite

Sodium valproate (VPA) is a broad-spectrum anticonvulsant that is effective both in adults and children suffering from epilepsy, but it causes psychiatric and behavioral side effects in patients with epilepsy. In addition, 30% of patients with epilepsy develop resistance to VPA. At present, regular physical exercise has shown many benefits and has become an effective complementary therapy for various brain diseases, including epilepsy. Therefore, we wondered whether VPA combined with exercise would be more effective in the treatment of seizures and associated co-morbidities. Here, we used a mouse model with kainic acid (KA)-induced epilepsy to compare the seizure status and the levels of related co-morbidities, such as cognition, depression, anxiety, and movement disorders, in each group using animal behavioral experiment and local field potential recordings. Subsequently, we investigated the mechanism behind this phenomenon by immunological means. Our results showed that low-intensity exercise combined with VPA reduced seizures and associated co-morbidities. This phenomenon seems to be related to the Toll-like receptor 4, activation of the nuclear factor kappa B (NF-κB), and release of interleukin 1β (IL-1β), tumor necrosis factor α (TNF-α), and IL-6. In brief, low-intensity exercise combined with VPA enhanced the downregulation of NF-κB-related inflammatory response, thereby alleviating the seizures, and associated co-morbidities.

show abstract

Role of HMGB1/TLR4 and IL-1β/IL-1R1 Signaling Pathways in Epilepsy

Cited by 32 publications

References 62 publications

NLRP3 inflammasome-IL-1β-IL-1R1 signaling pathway is involved in surgery- induced neuroinflammation in mice

NLRP3 inflammasome-IL-1β-IL-1R1 signaling pathway is involved in surgery- induced neuroinflammation in mice

Increased expression of NLRP3 associate with elevated levels of HMGB1 in children with febrile seizures: a case control study

Low-intensity exercise combined with sodium valproate attenuates kainic acid-induced seizures and associated co-morbidities by inhibiting NF-κB signaling in mice

Contact Info

Product

Resources

About