The mechanisms of NLRP3 inflammasome/pyroptosis activation and their role in Parkinson's disease

Wang, Shuo; Yuan, Yu‐He; Chen, Nai‐Hong; Wang, Hongbo

doi:10.1016/j.intimp.2018.12.019

Cited by 316 publications

(213 citation statements)

References 106 publications

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“…Finally, we confirmed in RA-SH-SY5Y cells the H 2 O 2 potency to induce ICE-like protease, caspase-1 activity (Jantas et al 2018a) which was significantly attenuated only by Nec-1 + Curc combination (Table 3). Activation of this enzyme participates in another form of cell damage, namely pyroptosis (Espinosa-Oliva et al 2019;Wang et al 2019). Since previous data showed the activation of this proinflammatory protease in neuronal cell type, including SH-SY5Y cells and neuroprotective potency of its inhibitors (Chen et al 2019;Knaryan et al 2014;Nath et al 1996;Zhao et al 2019a, b), it is highly probable that this mechanisms could be responsible for synergistic protective action of Nec-1 and curcumin against H 2 O 2 -evoked cell damage, observed in the present study.…”

Section: Discussionsupporting

confidence: 62%

Neuroprotective Effects of Necrostatin-1 Against Oxidative Stress–Induced Cell Damage: an Involvement of Cathepsin D Inhibition

et al. 2020

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Necroptosis, a recently discovered form of non-apoptotic programmed cell death, can be implicated in many pathological conditions including neuronal cell death. Moreover, an inhibition of this process by necrostatin-1 (Nec-1) has been shown to be neuroprotective in in vitro and in vivo models of cerebral ischemia. However, the involvement of this type of cell death in oxidative stress-induced neuronal cell damage is less recognized. Therefore, we tested the effects of Nec-1, an inhibitor of necroptosis, in the model of hydrogen peroxide (H 2 O 2)-induced cell damage in human neuroblastoma SH-SY5Y and murine hippocampal HT-22 cell lines. The data showed that Nec-1 (10-40 μM) attenuated the cell death induced by H 2 O 2 in undifferentiated (UN-) and neuronal differentiated (RA-) SH-SY5Y cells with a higher efficacy in the former cell type. Moreover, Nec-1 partially reduced cell damage induced by 6-hydroxydopamine in UN-and RASH -SY5Y cells. The protective effect of Nec-1 was of similar magnitude as the effect of a caspase-3 inhibitor in both cell phenotypes and this effect were not potentiated after combined treatment. Furthermore, the non-specific apoptosis and necroptosis inhibitor curcumin augmented the beneficial effect of Nec-1 against H 2 O 2-evoked cell damage albeit only in RASH -SY5Y cells. Next, it was found that the mechanisms of neuroprotective effect of Nec-1 against H 2 O 2induced cell damage in SH-SY5Y cells involved the inhibition of lysosomal protease, cathepsin D, but not caspase-3 or calpain activities. In HT-22 cells, Nec-1 was protective in two models of oxidative stress (H 2 O 2 and glutamate) and that effect was blocked by a caspase inhibitor. Our data showed neuroprotective effects of the necroptosis inhibitor, Nec-1, against oxidative stress-induced cell damage and pointed to involvement of cathepsin D inhibition in the mechanism of its action. Moreover, a cell type-specific interplay between necroptosis and apoptosis has been demonstrated.

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Section: Discussionsupporting

confidence: 62%

Neuroprotective Effects of Necrostatin-1 Against Oxidative Stress–Induced Cell Damage: an Involvement of Cathepsin D Inhibition

et al. 2020

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“…By contrary, the plasma IL-17 and IL-23 levels at baseline (< 1 h post ROSC) did not differ between survivors and non-survivors. It is well-established that the ischemia/reperfusion-induced injury in organs such as heart and brain is closely related to activation of neutrophils/macrophages and extensive releases of pro-inflammatory cytokines and inflammasome [27][28][29]. During this procedure, oxidative stress and endoplasmic reticulum stress also contribute to the cardiac injury [30,31].…”

Section: Discussionmentioning

confidence: 99%

High plasma levels of pro-inflammatory factors interleukin-17 and interleukin-23 are associated with poor outcome of cardiac-arrest patients: a single center experience

Zhuang

Chen

Zhou

et al. 2020

BMC Cardiovasc Disord

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Background: Systemic inflammation is an important feature of post-cardiac arrest syndrome (PCAS). This study was designed to determine whether the plasma concentrations of some circulating pro-inflammatory cytokines , IL-22, IL-23 and IL-33) are of value in predicting the outcome of patients after return of spontaneous circulation (ROSC) during the post-cardiac arrest period. Methods: This was a prospective observational clinical study. In total, 21 patients (survivors, n = 10; non-survivors, n = 11) who experienced cardiac arrest and successful ROSC with expected survival of at least 7 days were consecutively enrolled from January 2016 to December 2017. Of the 21 enrolled patients, ten survived were designated "survivors". The other eleven patients died between 2 days and 1 months post ROSC. Venous blood was drawn at three time-points: baseline (< 1 h post ROSC), 2 days post ROSC and 7 days post ROSC. Plasma IL-8, IL-22, IL-23 and IL-33 were determined using commercial enzyme-linked immunosorbent assays. Results: Plasma creatinine levels, but aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, were elevated in non-survivors compared with survivors. Plasma levels of IL-17, IL-22, IL-23 and IL-33 of the 21 total patients did not change at 2 or 7 days post ROSC compared to baseline. In survivors, the plasma levels of IL-17 and IL-23 at 2 or 7 days post ROSC were lower than baseline. In non-survivors, plasma levels of IL-17 increased compared with baseline. Receiver operating characteristic curve analysis showed that the plasma levels of IL-17 and IL-23 at 2 or 7 days post ROSC were able to predict the mortality of PCAS patients, and positively correlated with Acute Physiology and Chronic Health Evaluation (APACHE)-II score and time to ROSC.Conclusion: These results provide the first evidence that the elevated plasma IL-17 and IL-23 levels are associated with poor outcome in PCAS patients. The role of IL-17/IL-23 axis post ROSC is worth paying attention to in PCAS patients.Trial registration: Clinicaltrial.gov NCT02297776, 2014-11-21.

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“…33 They help injured (activated) cells "decide" if they should repair themselves or die through cellular mechanisms such as apoptosis and pyroptosis. 34 As noted, release of Caspase-1 through canonical immune pathways results in upregulation of critical inflammatory cytokines such as IL-1β, IL-18, but Caspase-1 can also cleave Pro-IL-1α and Pro-IL-33 through non-canonical immune pathways. 35 Regardless of the pathway, expression of Caspase-1 is linked directly to formation and activation of NLRP Inflammasomes.…”

Section: Caspase-1: a Measure Of Nlrp Inflammasome Activationmentioning

confidence: 96%

<p>In vitro expression of NLRP inflammasome-induced active Caspase-1 expression in normal human epidermal keratinocytes (NHEK) by various exogenous threats and subsequent inhibition by naturally derived ingredient blends</p>

Gruber¹,

Holtz²

2019

JIR

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Background: The discovery of the nod-like receptor protein (NLRP) inflammasomes in 2002 has led to the rapid identification of these unique cellular proteins as key targets for studies on innate inflammation pathways. The NLRP inflammasomes have been shown to be expressed in normal human epidermal keratinocytes (NHEK) and human dermal fibroblasts (HDF). NLRP inflammasomes in keratinocytes are interesting as these skin cells are the first living cells in the skin to contact external exogenous threats such as UV energy, chemicals, physical trauma, and bacteria and viruses. Activation of the NLRP Inflammasomes by exogenous threats results in the release of active Caspase-1 (ACasp-1), a key protease enzyme, which targets inactive forms of IL-1β, IL-18 as well as IL-1α and IL-33. Purpose: This article discusses efforts to examine the release of active Caspase-1 from NHEKs activated by various exogenous threats including UVB energy, ATP, Nigericin and Urban Dust. The work further examines if, after inflammasome activation and Caspase-1 release, certain naturally derived botanical ingredients known to have anti-inflammatory effects can function to inhibit upregulation of active Caspase-1. Methods: NHEK were treated with various doses of UVB, ATP and Nigericin and with a single dose of Urban Dust. ACasp-1 expression was measured after 3 and 20 hours using the Promega Caspase Glo-1 bioluminescent assay. After confirmation that 60 mJ/cm 2 of UVB and 5mM of ATP were effective to activate NHEK ACasp-1 release after 20 hrs, these conditions were employed to examine the influence of three botanical blends of ingredients on their ability to inhibit ACasp-1 expression. Results: Initial results demonstrate that NHEKs can be activated to release active Caspase-1 by ATP and UVB, but not by Nigericin or Urban Dust. In addition, it was unexpectedly found that, while ATP and UVB activated NHEKs, the release of ACasp-1-did not happen within the first 3 hours after exposure but did become significant after 20 hours. Additional results indicate that a blend of polysaccharides and two blends of antioxidants, one oilsoluble and the other water-soluble, known for their anti-inflammatory effects, can reduce expression of active Caspase-1 in activated NHEKs when applied extracellularly. Conclusion: Expression of NLRP activated release of ACasp-1 was found to be influenced by UVB and ATP but not by Nigericin or Urban Dust. The effects were also time dependent. Several botanical extract blends were found to reduce ACasp-1 expression in previously activated NHEKs. Links between these inflammatory effects and processes of cellular inflammaging are discussed.

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The mechanisms of NLRP3 inflammasome/pyroptosis activation and their role in Parkinson's disease

Cited by 316 publications

References 106 publications

Neuroprotective Effects of Necrostatin-1 Against Oxidative Stress–Induced Cell Damage: an Involvement of Cathepsin D Inhibition

Neuroprotective Effects of Necrostatin-1 Against Oxidative Stress–Induced Cell Damage: an Involvement of Cathepsin D Inhibition

High plasma levels of pro-inflammatory factors interleukin-17 and interleukin-23 are associated with poor outcome of cardiac-arrest patients: a single center experience

<p>In vitro expression of NLRP inflammasome-induced active Caspase-1 expression in normal human epidermal keratinocytes (NHEK) by various exogenous threats and subsequent inhibition by naturally derived ingredient blends</p>

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