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Key Event: 2009

Key Event Title

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

Activation of inflammation pathway

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. More help
Activation, inflammation pathway
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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help
Level of Biological Organization
Cellular

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

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

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

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
PM-induced respiratory toxicity KeyEvent li qing (send email) Under development: Not open for comment. Do not cite
Vascular disrupting effects KeyEvent Yanhong Wei (send email) Under development: Not open for comment. Do not cite
The AOP framework on ROS-mediated oxidative stress induced vascular disrupting effects KeyEvent Yanhong Wei (send email) Under development: Not open for comment. Do not cite
MPs & Cd induced inflammation-to-cancer transition in liver KeyEvent Wei Mu (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
Term Scientific Term Evidence Link
mammals mammals High NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help
Life stage Evidence
Not Otherwise Specified High

Sex Applicability

An indication of the the relevant sex for this KE. More help
Term Evidence
Unspecific High

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

Cell damage activates inflammatory pathways through signals both inside and outside the cell. Under stress, breakdown of the mitochondrial membrane (MOMP) releases damage signals into the cell fluid such as mitochondrial DNA (mtDNA) [1]and double-stranded RNA (dsRNA)[2, 3], and reducing protective proteins (IAPs)[4]. These released signals turn on major inflammation pathways. At the same time, the loss of IAPs activat,es NF-κB to produce inflammatory cytokines[5, 6]. Also, Toll-like receptors (TLRs) may recognize damage and pathogen signals through two main pathways: MyD88-dependent and TRIF-dependent[7]. The MyD88 pathway turns on NF-κB and MAPK to release inflammatory cytokines[8], while the TRIF pathway activates IRF3 to produce type I interferons. Together, these pathways work to strengthen and maintain the overall inflammatory response.

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

1. Sequencing & Transcriptomics: Bulk RNA-seq and single-cell RNA-seq to quantify gene expression dynamics, activation states, and downstream transcriptional pathways[9, 10] ;

2. Proteomics & Epigenomics: Mass spectrometry-based proteomics and chromatin accessibility profiling (e.g., ATAC-seq) to evaluate protein expression profiles and accessible transcription factor binding motifs (e.g., RUNX1, KLF6, RELB, IRF5, JUNB, RFX2) [9, 11, 12];

3. Protein Modifications & Translocation: Western blotting, phospho-flow cytometry, and nuclear/cytoplasmic fractionation to detect intracellular kinase phosphorylation cascades (e.g., ERK1/2, p38 MAPK, JNK, AKT, SYK, Src, JAK1/2, STAT3, MEK, PKC, TAK1), nuclear translocation of transcription factors (e.g., STAT3, NF-κB/p65, ERK), and membrane spatial redistribution of regulators like PTEN[1, 7];

4. Cytometry & Surface Marker Profiling: Flow cytometry and Cytometry by Time-of-Flight (CyTOF / Mass Cytometry) to quantify cell surface receptor dynamics and classify distinct activation subpopulations[13,14].

Domain of Applicability

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

Representative studies focused on mammals (humans, lab mice, lab rats).

References

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

[1] Vringer E, Tait SWG. Mitochondria and cell death-associated inflammation. Cell Death Differ. 2023 Feb;30(2):304-312. doi: 10.1038/s41418-022-01094-w. Epub 2022 Nov 29. PMID: 36447047; PMCID: PMC9950460.

[2] Tigano M, Vargas DC, Tremblay-Belzile S, Fu Y, Sfeir A. Nuclear sensing of breaks in mitochondrial DNA enhances immune surveillance. Nature. 2021 Mar;591(7850):477-481. doi: 10.1038/s41586-021-03269-w. Epub 2021 Feb 24. PMID: 33627873.

[3] Dhir A, Dhir S, Borowski LS, Jimenez L, Teitell M, Rötig A, Crow YJ, Rice GI, Duffy D, Tamby C, Nojima T, Munnich A, Schiff M, de Almeida CR, Rehwinkel J, Dziembowski A, Szczesny RJ, Proudfoot NJ. Mitochondrial double-stranded RNA triggers antiviral signalling in humans. Nature. 2018 Aug;560(7717):238-242. doi: 10.1038/s41586-018-0363-0. Epub 2018 Jul 25. PMID: 30046113; PMCID: PMC6570621.

[4] Giampazolias E, Zunino B, Dhayade S, Bock F, Cloix C, Cao K, Roca A, Lopez J, Ichim G, Proïcs E, Rubio-Patiño C, Fort L, Yatim N, Woodham E, Orozco S, Taraborrelli L, Peltzer N, Lecis D, Machesky L, Walczak H, Albert ML, Milling S, Oberst A, Ricci JE, Ryan KM, Blyth K, Tait SWG. Mitochondrial permeabilization engages NF-κB-dependent anti-tumour activity under caspase deficiency. Nat Cell Biol. 2017 Sep;19(9):1116-1129. doi: 10.1038/ncb3596. Epub 2017 Aug 28. PMID: 28846096; PMCID: PMC5624512.

[5] Vince JE, De Nardo D, Gao W, Vince AJ, Hall C, McArthur K, Simpson D, Vijayaraj S, Lindqvist LM, Bouillet P, Rizzacasa MA, Man SM, Silke J, Masters SL, Lessene G, Huang DCS, Gray DHD, Kile BT, Shao F, Lawlor KE. The Mitochondrial Apoptotic Effectors BAX/BAK Activate Caspase-3 and -7 to Trigger NLRP3 Inflammasome and Caspase-8 Driven IL-1β Activation. Cell Rep. 2018 Nov 27;25(9):2339-2353.e4. doi: 10.1016/j.celrep.2018.10.103. PMID: 30485804.

[6] Chauhan D, Bartok E, Gaidt MM, Bock FJ, Herrmann J, Seeger JM, Broz P, Beckmann R, Kashkar H, Tait SWG, Müller R, Hornung V. BAX/BAK-Induced Apoptosis Results in Caspase-8-Dependent IL-1β Maturation in Macrophages. Cell Rep. 2018 Nov 27;25(9):2354-2368.e5. doi: 10.1016/j.celrep.2018.10.087. PMID: 30485805.

[7] Zhang F, Xia Y, Su J, Quan F, Zhou H, Li Q, Feng Q, Lin C, Wang D, Jiang Z. Neutrophil diversity and function in health and disease. Signal Transduct Target Ther. 2024 Dec 6;9(1):343. doi: 10.1038/s41392-024-02049-y. PMID: 39638788; PMCID: PMC11627463.

[8] Xu G, Deng F, Zuo Q, Liu L, Dou K, Cheng Z, Cao W, Luo C, Yu C, Liu S, Zhu Y. Virus-inducible IGFALS facilitates innate immune responses by mediating IRAK1 and TRAF6 activation. Cell Mol Immunol. 2021 Jun;18(6):1587-1589. doi: 10.1038/s41423-021-00649-0. Epub 2021 Mar 4. PMID: 33664485; PMCID: PMC8167138.

[9] Coppin L, Jannin A, Ait Yahya E, Thuillier C, Villenet C, Tardivel M, Bongiovanni A, Gaston C, de Beco S, Barois N, van Seuningen I, Durand E, Bonnefond A, Vienne JC, Vamecq J, Figeac M, Vincent A, Delacour D, Porchet N, Pigny P. Galectin-3 modulates epithelial cell adaptation to stress at the ER-mitochondria interface. Cell Death Dis. 2020 May 12;11(5):360. doi: 10.1038/s41419-020-2556-3. PMID: 32398681; PMCID: PMC7217954.

[10] Salcher S, Sturm G, Horvath L, Untergasser G, Kuempers C, Fotakis G, Panizzolo E, Martowicz A, Trebo M, Pall G, Gamerith G, Sykora M, Augustin F, Schmitz K, Finotello F, Rieder D, Perner S, Sopper S, Wolf D, Pircher A, Trajanoski Z. High-resolution single-cell atlas reveals diversity and plasticity of tissue-resident neutrophils in non-small cell lung cancer. Cancer Cell. 2022 Dec 12;40(12):1503-1520.e8. doi: 10.1016/j.ccell.2022.10.008. Epub 2022 Nov 10. PMID: 36368318; PMCID: PMC9767679.

[11] Santos JC, Dick MS, Lagrange B, Degrandi D, Pfeffer K, Yamamoto M, Meunier E, Pelczar P, Henry T, Broz P. LPS targets host guanylate-binding proteins to the bacterial outer membrane for non-canonical inflammasome activation. EMBO J. 2018 Mar 15;37(6):e98089. doi: 10.15252/embj.201798089. Epub 2018 Feb 19. PMID: 29459437; PMCID: PMC5852652.

[12] Li P, Jiang W, Yu Q, Liu W, Zhou P, Li J, Xu J, Xu B, Wang F, Shao F. Ubiquitination and degradation of GBPs by a Shigella effector to suppress host defence. Nature. 2017 Nov 16;551(7680):378-383. doi: 10.1038/nature24467. Epub 2017 Oct 11. PMID: 29144452.

[13] Wigerblad G, Cao Q, Brooks S, Naz F, Gadkari M, Jiang K, Gupta S, O'Neil L, Dell'Orso S, Kaplan MJ, Franco LM. Single-Cell Analysis Reveals the Range of Transcriptional States of Circulating Human Neutrophils. J Immunol. 2022 Aug 15;209(4):772-782. doi: 10.4049/jimmunol.2200154. PMID: 35858733; PMCID: PMC9712146.

[14] Montaldo E, Lusito E, Bianchessi V, Caronni N, Scala S, Basso-Ricci L, Cantaffa C, Masserdotti A, Barilaro M, Barresi S, Genua M, Vittoria FM, Barbiera G, Lazarevic D, Messina C, Xue E, Marktel S, Tresoldi C, Milani R, Ronchi P, Gattillo S, Santoleri L, Di Micco R, Ditadi A, Belfiori G, Aleotti F, Naldini MM, Gentner B, Gardiman E, Tamassia N, Cassatella MA, Hidalgo A, Kwok I, Ng LG, Crippa S, Falconi M, Pettinella F, Scapini P, Naldini L, Ciceri F, Aiuti A, Ostuni R. Cellular and transcriptional dynamics of human neutrophils at steady state and upon stress. Nat Immunol. 2022 Oct;23(10):1470-1483. doi: 10.1038/s41590-022-01311-1. Epub 2022 Sep 22. PMID: 36138183; PMCID: PMC7615267.