The Role of NF-κB/NLRP3 Inflammasome Signaling Pathway in Attenuating Pyroptosis by Melatonin Upon Spinal Nerve Ligation Models

Wang, Yihao; Gao, Xiao; Tang, Yuru; Yu, Yang; Sun, Mingjie; Chen, F.; Li, Yan

doi:10.1007/s11064-021-03450-7

Cited by 14 publications

(12 citation statements)

References 41 publications

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“…The NLRP3 inflammasome has been reported to play an important role in inflammation-associated acute CNS diseases, such as SAH [40][41][42][43][44]. The NLRP3 signaling pathway participates in almost all well-known mechanisms of cell death, including pyroptosis [43,[45][46][47]. GSDMD is a substrate of Caspase-1, and its cleavage at the predicted site (N-terminal gasdermin domain and GSDMD-N) is required for pyroptosis during inflammasome activation [48].…”

Section: Discussionmentioning

confidence: 99%

Hemoglobin Derived from Subarachnoid Hemorrhage-Induced Pyroptosis of Neural Stem Cells via ROS/NLRP3/GSDMD Pathway

Yue

Chen

et al. 2023

Oxidative Medicine and Cellular Longevity

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Accumulating evidence has demonstrated that neural stem cells (NSCs) have regenerative capacity after brain injuries, such as in aneurysmal subarachnoid hemorrhage (SAH). The reactive oxygen species (ROS)-induced NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome triggers inflammatory responses and pyroptosis of cells; however, whether ROS-induced neuroinflammation modulates the fate of endogenous NSCs after SAH remains largely unknown. In this study, the level of IL-1β was increased in the cerebrospinal fluid (CSF) of patients with SAH. In an endovascular perforation model of SAH in mice, the secretion of IL-1β increased to a peak at 24 h following SAH, and the expression of Caspase1 and NLRP3 was elevated in the hippocampus. Primary cultured NSCs were incubated with hemoglobin (Hb) to mimic SAH in vitro. The cell viability, LDH release, intracellular ROS levels, scanning electron microscopy (SEM), and the expression of NLRP3 and pyroptosis indicators (GSDMD, ASC, and Caspase-1) in NSCs after SAH were examined to investigate the process of pyroptosis. We found that pyroptotic death featuring cellular swelling, cell membrane pore formation and elevated IL-1β was increased in cultured primary NSCs after Hb treatment, as was the expression of NLRP3, ASC, Caspase-1, and GSDMD. In addition, we found that ROS-induced pyroptosis of NSCs by activating the NLRP3/GSDMD pathway. These findings suggest that pyroptosis of NSCs induced by Hb can impede neural regeneration after SAH.

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Section: Discussionmentioning

confidence: 99%

Hemoglobin Derived from Subarachnoid Hemorrhage-Induced Pyroptosis of Neural Stem Cells via ROS/NLRP3/GSDMD Pathway

Yue

Chen

et al. 2023

Oxidative Medicine and Cellular Longevity

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“…The phospholipid cardiolipin translocates from the inner to the outer membrane of the mitochondria to bind to NLRP3 and promote its activation. The accumulation of mtDNA in the cytosol results in an antiviral immune response, and the oxidation of mtDNA and cardiolipin leads to the activation of the inflammasome that ultimately induces a pro-inflammatory response that should resolve in time ( Kelley et al, 2019 ; Deo et al, 2020 ; Wang et al, 2022b ; Harapas et al, 2022 ).…”

Section: Part Ii: Mitochondrial Dysfunction and Its Involvement In Di...mentioning

confidence: 99%

Mitochondria: It is all about energy

et al. 2023

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Mitochondria play a key role in both health and disease. Their function is not limited to energy production but serves multiple mechanisms varying from iron and calcium homeostasis to the production of hormones and neurotransmitters, such as melatonin. They enable and influence communication at all physical levels through interaction with other organelles, the nucleus, and the outside environment. The literature suggests crosstalk mechanisms between mitochondria and circadian clocks, the gut microbiota, and the immune system. They might even be the hub supporting and integrating activity across all these domains. Hence, they might be the (missing) link in both health and disease. Mitochondrial dysfunction is related to metabolic syndrome, neuronal diseases, cancer, cardiovascular and infectious diseases, and inflammatory disorders. In this regard, diseases such as cancer, Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis (ALS), chronic fatigue syndrome (CFS), and chronic pain are discussed. This review focuses on understanding the mitochondrial mechanisms of action that allow for the maintenance of mitochondrial health and the pathways toward dysregulated mechanisms. Although mitochondria have allowed us to adapt to changes over the course of evolution, in turn, evolution has shaped mitochondria. Each evolution-based intervention influences mitochondria in its own way. The use of physiological stress triggers tolerance to the stressor, achieving adaptability and resistance. This review describes strategies that could recover mitochondrial functioning in multiple diseases, providing a comprehensive, root-cause-focused, integrative approach to recovering health and treating people suffering from chronic diseases.

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“…To further determine the effect of C/EBPβ-Clec7a on neuropathic pain and exclude the off-target effect of RNA interference experiment involves C/EBPβ and Clec7a knockdown, the 5 µl of concentrated lentivirustransduced shCebpb, overexpressing-Clec7a and/or vector alone without insertion (1x10 9 transducing units/ml) were injected into CCI rats on postoperative day 7 to knockdown C/EBPβ and/or enforce Clec7a expression (Fig. 5A).…”

Section: Disruption Of the C/ebpβ-clec7a Axis Relieves Neuropathic Pa...mentioning

confidence: 99%

“…7 Recent studies have observed that some damaged neurocytes associated with neuropathic pain may exhibit pathological changes similar to pyroptosis, implying that this type of regulated cell death may contribute signi cantly to the pathology of neuropathic pain. 8 Of note, a previous study of Wang et al 9 reported that the spinal nerve ligation modeling signi cantly up-regulated the in ammatory cytokines associated with the excessive activation of NOD-like receptor family pyrin domain-3 (NLRP3) components and NF-κB signaling, as well as a marked pyroptosis activation. However, the involvement of pyroptosis in neuropathic pain development and progression, and its therapeutic potentials have not fully elucidated.…”

Section: Introductionmentioning

confidence: 99%

Disruption of C/EBPβ-Clec7a Axis Exacerbates Neuroinflammatory Injury via NLRP3 Inflammasome-mediated Pyroptosis in Experimental Neuropathic Pain

ZHANG

Zhao

et al. 2022

Preprint

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Background Growing evidence shows that C-Type Lectin Domain Containing 7A (Clec7a) may be involved into neuroinflammatory injury of various neurological diseases. However, its roles in neuropathic pain remain unclear. Methods A chronic constriction injury (CCI) rat model was established, and gene expression profilings in spinal cord tissues of CCI-insulted rats were detected by both microarray and RNA-seq studies. A series of bioinformatics analyses identified C/EBPβ-Clec7a to be a candidate axis involved into neuropathic pain. Then, its roles in mechanical allodynia, and pathological and molecular changes during CCI progression were determined by various gain-of-function and loss-of-function experiments in vivo and in vitro. Results Significant upregulation of Clec7a at both mRNA and protein levels were verified in spinal cord tissues of CCI-insulted rats. Clec7a knockdown markedly attenuated CCI-induced mechanical allodynia, obstructed Syk, ERK and JNK phosphorylation, inhibited NLRP3 inflammasome and caspase-1 activation, GSDMD cleavage, and consequently reduced the release of pro-inflammatory cytokines (all P < 0.05). Mechanically, the rat Clec7a promoter was predicted to bind with transcription factor C/EBPβ, confirmed by Luciferase assay and ChIP-qPCR. Both in vivo and in vitro assays demonstrated that C/EBPβ knockdown significantly suppressed CCI- or LPS/ATP-induced Clec7a upregulation, and subsequently reduced Syk, ERK and JNK phosphorylation, NLRP3 oligomerization, caspase-1 activation, GSDMD expression and pyroptosis, which were markedly reversed by the co-transfection of Clec7a expression vector. Conclusions This pre-clinical investigation reveals that C/EBPβ-Clec7a axis may be a potential target for relieving neuropathic pain through alleviating neuroinflammation, paving its way for clinical translation as a promising approach for neuropathic pain therapy.

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The Role of NF-κB/NLRP3 Inflammasome Signaling Pathway in Attenuating Pyroptosis by Melatonin Upon Spinal Nerve Ligation Models

Cited by 14 publications

References 41 publications

Hemoglobin Derived from Subarachnoid Hemorrhage-Induced Pyroptosis of Neural Stem Cells via ROS/NLRP3/GSDMD Pathway

Hemoglobin Derived from Subarachnoid Hemorrhage-Induced Pyroptosis of Neural Stem Cells via ROS/NLRP3/GSDMD Pathway

Mitochondria: It is all about energy

Disruption of C/EBPβ-Clec7a Axis Exacerbates Neuroinflammatory Injury via NLRP3 Inflammasome-mediated Pyroptosis in Experimental Neuropathic Pain

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