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Event: 1895

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

NLRP3 inflammasome activity, increased

Short name

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inflammasome activity, increased

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Biological Context

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Level of Biological Organization
Molecular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place. For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable. For individual/population events, the organ context is not applicable. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Organ term

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor). Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Process	Object	Action
NLRP3 inflammasome complex assembly	NLRP3 inflammasome complex	increased

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help

AOP Name	Role of event in AOP	Point of Contact	Author Status
SARS-CoV2 to hyperinflammation	KeyEvent	Hasmik Yepiskoposyan (send email)	Under development: Not open for comment. Do not cite
SARS-CoV2 to pyroptosis	KeyEvent	Hasmik Yepiskoposyan (send email)	Under development: Not open for comment. Do not cite
TLR9 activation leading to Multi Organ Failure and ARDS	KeyEvent	Gillina Bezemer (send email)	Under development: Not open for comment. Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Life Stages

An indication of the the relevant life stage(s) for this KE. More help

Sex Applicability

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Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

The NLRP3 inflammasome is a critical component of the innate immune system that mediates Caspase 1 (CASP1) activation. The NLRP3 inflammasome is a multimolecular complex composed of the sensor molecule NLRP3, the adaptor protein PYCARD (commonly called ASC), and pro-caspase 1 (Yang et al, 2019b). In activated inflammasome pro-caspase 1 is cleaved into active CASP1 which subsequently cleaves and thus activates highly pro-inflammatory cytokines interleukin-1B (IL1B) and IL18 leading to increased inflammation (Kelley et al, 2019). NLRP3 inflammasome activation can also induce pyroptosis, an inflammatory form of a cell death (Bergsbaken et al, 2009). Inflammasome activation is associated with COVID-19 disease severity and poor clinical outcome (Rodrigues et al, 2021). NLRP3 inflammasomes can assemble in many cell types, including macrophages, dendritic cells, neutrophils, B cells and T cells, epithelial cells, adipocytes, fibroblasts, astrocytes, cardiomyocytes, hepatocytes, etc (Enni et al, 2020; Ershaid et al, 2019; Wree et al, 2014; Wu et al, 2020; Yang et al, 2019a; Zheng et al, 2020).

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

In activated inflammasome pro-caspase 1 is cleaved into active CASP1 which then cleaves and thus activates IL1B and IL18. A common method of detection of activated inflammasome is the measurement of secreted IL1B and/or IL18 levels with the enzyme-linked immunosorbent assay (ELISA) using specific antibodies (Martinez et al, 2015; Piancone et al, 2018; Shi et al, 2018; Sun et al, 2017; Yaron et al, 2015). Formation of ASC oligomers reflects inflammasome activation thus ASC oligomers are often used to assess NLRP3 activation. Various methods of ASC oligomer or ASC specks detection is described in a thorough review from Zito and co-authors with references to the studies where the discussed methods are used (Zito et al., 2020). For measuring CASP1 activity as a result of inflammasome assembly and activation, Caspase 1 Fluorescein (FLICA) Assay can be used (Guo et al, 2018; Yaron et al., 2015). FLICA allows active CASP1 enzyme fluorescent labelling that can be analyzed using fluorescence microscopy, fluorescence plate reader or flow cytometry. Furthermore, co-immunoprecipitation assays can be used for specific protein interaction detection (e.g. NLRP3 and ASC/PYCARD) as a result of NLRP3 inflammasome assembly (Zito et al., 2020).

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided). More help

Most of the studies on NLRP3 inflammasome activation are derived from mouse and human tissue experiments. The NLRP3 inflammasome activation and downstream inflammatory response is comprehensively documented in and thus applicable for Homo sapiens (Zito et al, 2020).

References

List of the literature that was cited for this KE description. More help

Farag NS, Breitinger U, Breitinger HG, El Azizi MA (2020) Viroporins and inflammasomes: A key to understand virus-induced inflammation. Int J Biochem Cell Biol 122: 105738

Guo C, Fu R, Wang S, Huang Y, Li X, Zhou M, Zhao J, Yang N (2018) NLRP3 inflammasome activation contributes to the pathogenesis of rheumatoid arthritis. Clin Exp Immunol 194: 231-243

Martinez GJ, Robertson S, Barraclough J, Xia Q, Mallat Z, Bursill C, Celermajer DS, Patel S (2015) Colchicine Acutely Suppresses Local Cardiac Production of Inflammatory Cytokines in Patients With an Acute Coronary Syndrome. J Am Heart Assoc 4: e002128

Piancone F, Saresella M, Marventano I, La Rosa F, Santangelo MA, Caputo D, Mendozzi L, Rovaris M, Clerici M (2018) Monosodium Urate Crystals Activate the Inflammasome in Primary Progressive Multiple Sclerosis. Front Immunol 9: 983

Shah A (2020) Novel Coronavirus-Induced NLRP3 Inflammasome Activation: A Potential Drug Target in the Treatment of COVID-19. Front Immunol 11: 1021

Shi J, Zhao W, Ying H, Zhang Y, Du J, Chen S, Li J, Shen B (2018) Estradiol inhibits NLRP3 inflammasome in fibroblast-like synoviocytes activated by lipopolysaccharide and adenosine triphosphate. Int J Rheum Dis 21: 2002-2010

Sun X, Hao H, Han Q, Song X, Liu J, Dong L, Han W, Mu Y (2017) Human umbilical cord-derived mesenchymal stem cells ameliorate insulin resistance by suppressing NLRP3 inflammasome-mediated inflammation in type 2 diabetes rats. Stem Cell Res Ther 8: 241

Xu H, Chitre SA, Akinyemi IA, Loeb JC, Lednicky JA, McIntosh MT, Bhaduri-McIntosh S (2020) SARS-CoV-2 viroporin triggers the NLRP3 inflammatory pathway. bioRxiv: 2020.2010.2027.357731

Yaron JR, Gangaraju S, Rao MY, Kong X, Zhang L, Su F, Tian Y, Glenn HL, Meldrum DR (2015) K(+) regulates Ca(2+) to drive inflammasome signaling: dynamic visualization of ion flux in live cells. Cell Death Dis 6: e1954

Zito G, Buscetta M, Cimino M, Dino P, Bucchieri F, Cipollina C (2020) Cellular Models and Assays to Study NLRP3 Inflammasome Biology. Int J Mol Sci 21