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Key Event Title
NLRP3 inflammasome activity, increased
|Level of Biological Organization|
Key Event Components
|NLRP3 inflammasome complex assembly||NLRP3 inflammasome complex||increased|
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP||Point of Contact||Author Status||OECD 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 Do not cite|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 Do not cite|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 Do not cite|
Key Event Description
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
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
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).
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