Emerging Mechanisms and Targeted Therapy of Pyroptosis in Central Nervous System Trauma

Yang, Biao; Zhong, Weijie; Gu, Ying; Li, Yang

doi:10.3389/fcell.2022.832114

Cited by 10 publications

(10 citation statements)

References 105 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Pyroptosis is involved in the pathogenesis of various central nervous system diseases, such as cerebral hemorrhage, Parkinson's disease, and Alzheimer's disease. Intervening in pyroptosis can exert neuroprotective effects and improve disease outcomes [7]. Recent studies have shown that the levels of NLRP3 and Caspase-1 are upregulated in a PTZ mouse model, and inhibiting NLRP3 can improve seizure activity [37], indicating that pyroptosis may play an important role in the pathogenesis of epilepsy, and inhibiting pyroptosis could be a potential therapeutic approach for epilepsy.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

IRAK4 in the hippocampus increases susceptibility to seizures through NF-κB/NLRP3-mediated neuronal pyroptosis

Zhao,

张,

Cui

et al. 2024

Preprint

View full text Add to dashboard Cite

Background Interleukin-1 receptor-associated kinase 4 (IRAK4) plays an important role in immune modulation in various central nervous system disorders. Previous studies have found that the IRAK4 pathway is involved in lead-induced cell pyroptosis. However, there is no report on the role of IRAK4 in epilepsy models and its involvement in regulating cell pyroptosis in epilepsy, both in animal and clinical studies. Method Firstly, we performed transcriptome sequencing, qPCR, and Western blot analysis on hippocampal tissues of refractory epilepsy patients to detect the mRNA and protein levels of IRAK4 and pyroptosis-related proteins. Secondly, we successfully established a Pentylenetetrazol (PTZ)-induced seizure mouse model. We conducted behavioral tests, electroencephalography (EEG), virus injection, and molecular biology experiments to investigate the role of IRAK4 in seizure activity regulation. Results IRAK4 is upregulated in the hippocampal lesions of epilepsy patients and in the hippocampus of PTZ-induced seizure mice. In PTZ mice, IRAK4 expression is observed in neurons. Knocking out IRAK4 in PTZ mice downregulates pyroptosis-related proteins and alleviates seizure activity. Conversely, overexpressing IRAK4 in naïve mice upregulates pyroptosis-related proteins and increases PTZ-induced neuronal abnormal discharges. PDTC can reverse the increased expression of pyroptosis-related proteins caused by PTZ. PF-06650833 can alleviate seizure activity and inhibit pyroptosis in PTZ-induced seizure mice. Conclusion In summary, we hypothesize that IRAK4 promotes the expression of pyroptosis-related proteins through the NF-κB/NLRP3 pathway, suggesting that IRAK4 may promote seizure activity by mediating pyroptosis. IRAK4 plays a crucial role in epilepsy and may serve as a potential therapeutic target for this neurological disorder.

show abstract

Section: Discussionmentioning

confidence: 99%

“…Pyroptosis is involved in the pathophysiological processes of various central nervous system diseases, such as brain hemorrhage [4], Alzheimer's disease [5], and Parkinson's disease [6], and intervention in pyroptosis can improve the outcomes of these diseases [7]. Studies have shown a link between epilepsy and pyroptosis.…”

Section: Introductionmentioning

confidence: 99%

IRAK4 in the hippocampus increases susceptibility to seizures through NF-κB/NLRP3-mediated neuronal pyroptosis

Zhao,

张,

Cui

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…Intact cell membrane, normal nuclear morphology, atrophy of mitochondria, increased density of mitochondrial membrane, and reduced or disappeared density of mitochondrial cristae Iron accumulation and lipid peroxidation GPX4, SLC7A11, TFR1, Nrf2, NCOA4, ACSL4, FSP1 [6,7] Necroptosis Organelle swelling, loss of plasma membrane integrity, and the breakdown of cell membranes leads to the release of cell contents RIPK1, RIPK3, MLKL phosphorylation and ubiquitination, and formation of necrotic complexes in the cytoplasm RIPK1, RIPK3, MLKL [8][9][10][11][12][13] Pyroptosis Cell swelling and formation of pores in the plasma membrane Inflammasome formation, caspase and gasdermin activation and the release of numerous pro-inflammatory factors caspase-1, GSDMD [14][15][16][17] Apoptosis Nucleus fragmentation, plasma membrane blistering, cell contraction…”

Section: Ferroptosismentioning

confidence: 99%

Induction Mechanism of Ferroptosis, Necroptosis, and Pyroptosis: A Novel Therapeutic Target in Nervous System Diseases

Tang

Liu

et al. 2023

IJMS

View full text Add to dashboard Cite

In recent years, three emerging cell deaths, ferroptosis, necroptosis and pyroptosis, have gradually attracted everyone’s attention, and they also play an important role in the occurrence and development of various diseases. Ferroptosis is an idiographic iron-dependent form regulated cell death with the hallmark of accumulation of the intracellular reactive oxygen species (ROS). Necroptosis is a form of regulated necrotic cell death mediated by the receptor-interacting protein kinase 1(RIPK1) and receptor-interacting protein kinase 3RIPK3. Pyroptosis, also known as cell inflammatory necrosis, is a programmed cell necrosis mediated by Gasdermin D (GSDMD). It is manifested by the continuous swelling of the cells until the cell membrane ruptures, resulting in the release of the cell contents and the activation of a strong inflammatory response. Neurological disorders remain a clinical challenge and patients do not respond well to conventional treatments. Nerve cell death can aggravate the occurrence and development of neurological diseases. This article reviews the specific mechanisms of these three types of cell death and their relationship with neurological diseases and the evidence for the role of the three types of cell death in neurological diseases; understanding these pathways and their mechanisms is helpful for the treatment of neurological diseases.

show abstract

“…Like caspase-1, activated caspase-4/5/11 cleave GSDMD to induce pyroptosis ( Shi et al, 2015 ). Notably, while caspase4/5/11 cannot process pro-IL-1β/18 directly, they can facilitate the maturation and secretion of the IL-1β/18 via the activation of the NLRP3 in an indirect way ( Humphries et al, 2018 ; Yang et al, 2022 ). The receptors in the inflammasome complex belong in most cases to the Nod-like receptor (NLR) and absent in melanoma (AIM) 2-like receptor (ALR) families.…”

Section: Overview: Pyroptosismentioning

confidence: 99%

Pyroptosis in spinal cord injury

Yin

Gong²,

Wan³

et al. 2022

Front. Cell. Neurosci.

View full text Add to dashboard Cite

Spinal cord injury (SCI) often brings devastating consequences to patients and their families. Pathophysiologically, the primary insult causes irreversible damage to neurons and glial cells and initiates the secondary damage cascade, further leading to inflammation, ischemia, and cells death. In SCI, the release of various inflammatory mediators aggravates nerve injury. Pyroptosis is a new pro-inflammatory pattern of regulated cell death (RCD), mainly mediated by caspase-1 or caspase-11/4/5. Gasdermins family are pore-forming proteins known as the executor of pyroptosis and the gasdermin D (GSDMD) is best characterized. Pyroptosis occurs in multiple central nervous system (CNS) cell types, especially plays a vital role in the development of SCI. We review here the evidence for pyroptosis in SCI, and focus on the pyroptosis of different cells and the crosstalk between them. In addition, we discuss the interaction between pyroptosis and other forms of RCD in SCI. We also summarize the therapeutic strategies for pyroptosis inhibition, so as to provide novel ideas for improving outcomes following SCI.

show abstract

Emerging Mechanisms and Targeted Therapy of Pyroptosis in Central Nervous System Trauma

Cited by 10 publications

References 105 publications

IRAK4 in the hippocampus increases susceptibility to seizures through NF-κB/NLRP3-mediated neuronal pyroptosis

IRAK4 in the hippocampus increases susceptibility to seizures through NF-κB/NLRP3-mediated neuronal pyroptosis

Induction Mechanism of Ferroptosis, Necroptosis, and Pyroptosis: A Novel Therapeutic Target in Nervous System Diseases

Pyroptosis in spinal cord injury

Contact Info

Product

Resources

About