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Event: 1895

Key Event Title

The KE title should describe a discrete biological change that can be measured. It should generally define the biological object or process being measured and whether it is increased, decreased, or otherwise definably altered relative to a control state. For example “enzyme activity, decreased”, “hormone concentration, increased”, or “growth rate, decreased”, where the specific enzyme or hormone being measured is defined. More help

NLRP3 inflammasome activity, increased

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. The short name should be less than 80 characters in length. More help
inflammasome activity, increased

Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. Note, KEs should be defined within a particular level of biological organization. Only KERs should be used to transition from one level of organization to another. Selection of the level of biological organization defines which structured terms will be available to select when defining the Event Components (below). More help
Level of Biological Organization

Cell term

Further information on Event Components and Biological Context may be viewed on the attached pdf.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. More help

Organ term

Further information on Event Components and Biological Context may be viewed on the attached pdf.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. More help

Key Event Components

Further information on Event Components and Biological Context may be viewed on the attached pdf.Because one of the aims of the AOP-KB is to facilitate de facto construction of AOP networks through the use of shared KE and KER elements, authors are also asked to define their KEs using a set of structured ontology terms (Event Components). In the absence of structured terms, the same KE can readily be defined using a number of synonymous titles (read by a computer as character strings). In order to make these synonymous KEs more machine-readable, KEs should also be defined by one or more “event components” consisting of a biological process, object, and action with each term originating from one of 22 biological ontologies (Ives, et al., 2017; See List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling). 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 signalling 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. 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 OECD Status
SARS-CoV2 to hyperinflammation KeyEvent Arthur Author (send email) Under development: Not open for comment. Do not cite
SARS-CoV2 to pyroptosis KeyEvent Agnes Aggy (send email) Under development: Not open for comment. Do not cite
TLR9 activation leading to Multi Organ Failure and ARDS KeyEvent Cataia Ives (send email) Under development: Not open for comment. Do not cite


This is a structured field used to identify specific agents (generally chemicals) that can trigger the KE. Stressors identified in this field will be linked to the KE in a machine-readable manner, such that, for example, a stressor search would identify this as an event the stressor can trigger. NOTE: intermediate or downstream KEs in one AOP may function as MIEs in other AOPs, meaning that stressor information may be added to the KE description, even if it is a downstream KE in the pathway currently under development.Information concerning the stressors that may trigger an MIE can be defined using a combination of structured and unstructured (free-text) fields. For example, structured fields may be used to indicate specific chemicals for which there is evidence of an interaction relevant to this MIE. By linking the KE description to a structured chemical name, it will be increasingly possible to link the MIE to other sources of chemical data and information, enhancing searchability and inter-operability among different data-sources and knowledgebases. The free-text section “Evidence for perturbation of this MIE by stressor” can be used both to identify the supporting evidence for specific stressors triggering the MIE as well as to define broad chemical categories or other properties that classify the stressors able to trigger the MIE for which specific structured terms may not exist. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected from an ontology. 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

The structured ontology terms for life-stage are more comprehensive than those for taxa, but may still require further description/development and explanation in the free text section. More help

Sex Applicability

The authors must select from one of the following: Male, female, mixed, asexual, third gender, hermaphrodite, or unspecific. More help

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. For example, the biological state being measured could be the activity of an enzyme, the expression of a gene or abundance of an mRNA transcript, the concentration of a hormone or protein, neuronal activity, heart rate, etc. The biological compartment may be a particular cell type, tissue, organ, fluid (e.g., plasma, cerebrospinal fluid), etc. The role in the biology could describe the reaction that an enzyme catalyses and the role of that reaction within a given metabolic pathway; the protein that a gene or mRNA transcript codes for and the function of that protein; the function of a hormone in a given target tissue, physiological function of an organ, etc. Careful attention should be taken to avoid reference to other KEs, KERs or AOPs. Only describe this KE as a single isolated measurable event/state. This will ensure that the KE is modular and can be used by other AOPs, thereby facilitating construction of AOP networks. 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

One of the primary considerations in evaluating AOPs is the relevance and reliability of the methods with which the KEs can be measured. The aim of this section of the KE description is not to provide detailed protocols, but rather to capture, in a sentence or two, per method, the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements. Methods that can be used to detect or measure the biological state represented in the KE should be briefly described and/or cited. 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).Key considerations regarding scientific confidence in the measurement approach include whether the assay is fit for purpose, whether it provides a direct or indirect measure of the biological state in question, whether it is repeatable and reproducible, and the extent to which it is accepted in the scientific and/or regulatory community. Information can be obtained from the OECD Test Guidelines website and the EURL ECVAM Database Service on Alternative Methods to Animal Experimentation (DB-ALM). ?

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

This free text section should be used to elaborate on the scientific basis for the indicated domains of applicability and the WoE calls (if provided). While structured terms may be selected to define the taxonomic, life stage and sex applicability (see structured applicability terms, above) of the KE, the structured terms may not adequately reflect or capture the overall biological applicability domain (particularly with regard to taxa). Likewise, the structured terms do not provide an explanation or rationale for the selection. The free-text section on evidence for taxonomic, life stage, and sex applicability can be used to elaborate on why the specific structured terms were selected, and provide supporting references and background information.  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).


List of the literature that was cited for this KE description. Ideally, the list of references, should conform, to the extent possible, with the OECD Style Guide ( (OECD, 2015). 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