Target of MCC950 in Inhibition of NLRP3 Inflammasome Activation: a Literature Review

Wu, Depei; Chen, Yefei; Sun, Yingjie; Gao, Qing; Li, Huhu; Yang, Zidong; Wang, Yangxue; Jiang, Xijuan; Yu, Bin

doi:10.1007/s10753-019-01098-8

Cited by 106 publications

(53 citation statements)

References 38 publications

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“…Moreover, activation of the NLRP3 inflammasome was also affected by ERS inhibition. MCC950 is a specific small molecule that selectively inhibits the NLRP3/ASC/Caspase1 signalling cascade [65]. At present, its therapeutic effects have been widely revealed in preclinical models of inflammation-associated diseases.…”

Section: Discussionmentioning

confidence: 99%

NLRP3 inflammasome and endoplasmic reticulum stress in the epileptogenic zone in temporal lobe epilepsy: molecular insights into their interdependence

Yue

Wei

Yang

et al. 2020

Neuropathology Appl Neurobio

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Aim Nod‐like receptor protein 3 (NLRP3) inflammasome‐mediated inflammation has emerged as a contributor to epileptogenesis. Endoplasmic reticulum stress (ERS) plays an important role in epilepsy‐induced neurodegeneration. NLRP3 activation and ERS reactions share the same induction factors, suggesting that these processes may be interdependent. However, the correlation between NLRP3 and ERS in TLE has not been confirmed. Methods The expression patterns of NLRP3 inflammasome and ERS‐related markers in the temporal neocortices of TLE patients were investigated by western blotting, immunohistochemistry and immunofluorescent labelling. Correlations between the protein levels of NLRP3 and the expression of ERS‐related markers were assessed using Spearman’s rank correlation test. To observe the relationship between the NLRP3 inflammasome and ERS, inhibitors were used in a status epilepticus (SE) model. Results Our results show that NLRP3 inflammasome components and ERS‐related markers were upregulated in the temporal neocortices of TLE patients, and were mainly localized to neurons, astrocytes and microglia. We found a positive correlation between the protein levels of NLRP3 and the expression of ERS‐related markers in the temporal neocortices of 20 TLE patients. Furthermore, after blocking the NLRP3 inflammasome with MCC950, the expression of ERS‐related markers was markedly decreased in the hippocampi of SE mice. Moreover, TUDCA, a specific ERS inhibitor, also reduced the expression of NLRP3 components in the hippocampus under SE conditions. Conclusion Taken together, our data reveal the interdependence of the NLRP3 inflammasome and ERS in the epileptogenic zone of TLE patients and in the hippocampi of mice in the early post‐SE phase.

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Section: Discussionmentioning

confidence: 99%

NLRP3 inflammasome and endoplasmic reticulum stress in the epileptogenic zone in temporal lobe epilepsy: molecular insights into their interdependence

Yue

Wei

Yang

et al. 2020

Neuropathology Appl Neurobio

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“…Some promising selective inhibitors and medicines already used to treat other diseases are found to target various aspects of inflammasome activation regulated by NEK7. These inhibitors may disrupt the upstream events or directly regulate the expression or modification of NEK7 and NLRP3 thus effecting their interaction (Zhang Y. et al, 2017;He et al, 2018;Chiu et al, 2019;Wu et al, 2019;Liu D. et al, 2020;Shi et al, 2020).…”

Section: Inhibitors and Their Application To Diseasesmentioning

confidence: 99%

Section: Inhibitors and Their Application To Diseasesmentioning

confidence: 99%

“…Among these inhibitors, MCC950 is the best characterized for its potent effect in many diseases with NEK7-NLRP3mediated inflammasome activation (Wu et al, 2019), including high glucose-induced human retinal endothelial cell dysfunction (diabetic retinopathy) (Zhang Y. et al, 2017), lung ischemiareperfusion injury (Xu et al, 2018), endometritis in cattle and peritonitis (Kelly et al, 2019). Although some studies are limited to in vitro applications, MCC950 is still considered to be a promising treatment, as it selectively blocks the interaction between NEK7 and NLRP3 (Wu et al, 2019). In addition, several inhibitors target genes that have been found to be involved in the regulation of NEK7-mediated NLRP3 inflammasome activation, such as C1-27 (GSTO1-1 inhibitor) (Hughes et al, 2019), IAA94 (CLIC inhibitor) (Tang et al, 2017), and JSH-23 (p65 inhibitor) (Chen X. et al, 2019).…”

Section: Inhibitors and Their Application To Diseasesmentioning

confidence: 99%

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Physiological and Pathological Roles of Mammalian NEK7

2020

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NEK7 is the smallest NIMA-related kinase (NEK) in mammals. The pathological and physiological roles of NEK7 have been widely reported in many studies. To date, the major function of NEK7 has been well documented in mitosis and NLRP3 inflammasome activation, but the detailed mechanisms of its regulation remain unclear. This review summarizes current advances in NEK7 research involving mitotic regulation, NLRP3 inflammasome activation, related diseases and potential inhibitors, which may provide new insights into the understanding and therapy of the diseases associated with NEK7, as well as the subsequent studies in the future.

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“…Third, how the neuronal autophagy affects neuronal function after hemorrhage and the related mechanism associated with NLRP3 should be more deeply evaluated. Recent studies and our present study have demonstrated the effectiveness of inhibiting NLRP3 expression by using MCC950 [54,55]. However, the time window and stability of MCC950 are very limited.…”

Section: Nucleotide-binding Oligomerization Domain-like Receptor Contmentioning

confidence: 62%

NLRP3 Inflammasome Activation Attenuates Neuronal Apoptosis by Upregulating Autophagy through AMPK/Beclin-1 Pathway after Intracerebral Hemorrhage with Ventricular Extension in Rats

Zhang¹,

Guo²,

Jia³

et al. 2021

Preprint

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BackgroundIn brain, NLRP3 inflammasome, mainly derived from macrophage/microglia, is involved in proinflammatory and neurodeficits after hemorrhage, and autophagy is vital for neuronal homeostasis and functions. Accumulating evidence suggested that NLRP3 inflammasome and autophagy played an important role in intracerebral hemorrhage (ICH). Thus, this study was designed to further explore the pathogenesis of neurodeficits after in posthemorrhagic hydrocephalus.MethodsAutologous blood injection model was induced to mimic ICH with ventricular extension (ICH-IVH) in Sprague-Dawley rats. To elucidate the underlying mechanism, the NLRP3 inflammasome inhibitor MCC950 was administered abdominally at 1 h after ICH-IVH. Magnetic resonance imaging, neurobehavioral tests, immunofluorescence, western blotting, Fluoro-Jade C- staining, Tunel staining, and Quantitative RNA Sequencing were performed.ResultsIn the acute phase of ICH-IVH, both the expression of NLRP3 inflammasome and the autophagy of neurons were upregulated. The activated NLRP3 in macrophage/microglia promoted the release of IL-1β to extracellular, which contributed to excessive autophagy, leading to neurons apoptosis both in vivo and in vitro. AMPK/Beclin-1 pathway played an important role in NLRP3-related neurons autophagy. Using MCC950(NLRP3 inflammasome specific inhibitor) treatment after ICH-IVH significantly reduced ventricles dilation, improved neurofunction, down-regulated the release of IL-1β, and alleviated neuroinflammation and excessive autophagy.ConclusionsOur finding demonstrated that NLRP3 inflammasome activated in microglia/macrophage aggravated neurological outcomes and neuronal apoptosis by upregulating autophagy after ICH-IVH, which was partly mediated by the AMPK/Beclin-1 pathway. Therefore, inhibiting the activation of NLRP3 may be a potential therapeutic strategy for the neurodeficits of ICH-IVH patients.

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Target of MCC950 in Inhibition of NLRP3 Inflammasome Activation: a Literature Review

Cited by 106 publications

References 38 publications

NLRP3 inflammasome and endoplasmic reticulum stress in the epileptogenic zone in temporal lobe epilepsy: molecular insights into their interdependence

NLRP3 inflammasome and endoplasmic reticulum stress in the epileptogenic zone in temporal lobe epilepsy: molecular insights into their interdependence

Physiological and Pathological Roles of Mammalian NEK7

NLRP3 Inflammasome Activation Attenuates Neuronal Apoptosis by Upregulating Autophagy through AMPK/Beclin-1 Pathway after Intracerebral Hemorrhage with Ventricular Extension in Rats

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