Upstream eventCovalent Binding, Protein
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Directness||Weight of Evidence||Quantitative Understanding|
|Covalent Protein binding leading to Skin Sensitisation||directly leads to||Strong|
Life Stage Applicability
How Does This Key Event Relationship Work
Uptake of the hapten-protein complex by keratinocytes activates multiple events, including the release of pro-inflammatory cytokines and the induction of cyto-protective cellular pathways. Activation of the pro-inflammatory cytokine IL-18 results from cleavage of inactive IL-18 precursor protein by inflammasome-associated caspase-1. Hapten-protein complexes can activate the inflammasome (;) and in so doing induce IL-18 production. Intracellular Nod-like receptors (NLR) contain sensors for a number of cellular insults. Upon activation (by a currently unknown mechanism), NLRs oligomerise form molecular complexes (i.e. inflammasomes) that are involved in the activation of inflammatory-associated caspases, including caspase-1. Keratinocyte exposure to hapten-protein complex also results in induction of antioxidant/electrophile response element ARE/EpRE-dependent pathways. Briefly, reactive chemicals bind to Keap1 (Kelch-like ECH-associates protein 1) that normally inhibits the nuclear erythroid 2-related factor 2 (Nrf2). Released Nrf2 interacts with other nuclear proteins and binds to and activates ARE/EpREdependent pathways, including the cytoprotective genes NADPH-quinone oxidoreductase 1 (NQO1) and glutathione S-transferase (GSHST), among others (;).
This KER description is based only on the OECD document 2012 and needs updating.
Weight of Evidence
Empirical Support for Linkage
Using a series of thiol-reactive cages fluorescent haptens (i.e. bromobimanes) deployed in combination with two photon fluorescence microscopy, immunohistochemistry, and proteomics, Simonson et al. (2011) identified the possible hapten targets in proteins in human skin. Key target found were the basal keratinocytes and the keratins K5 and K14. In a review about murine contact sensitivity, Honda et al. reported that haptens can activate keratinocytes in an NLR-dependent manner. Among the NLR family, NLRP3 controls the production of proinflammatory cytokines through activation of caspase-1. Without NLRP3 or its adaptor protein ASC;;, the production of IL-1β and IL-18 from keratinocytes was inhibited;;.
Uncertainties or Inconsistencies
Quantitative Understanding of the Linkage
Evidence Supporting Taxonomic Applicability
- Martinon F, Mayor A, Tschopp J. 2009. The inflammasomes: guardians of the body. Ann. Rev. Immunol. 27: 229-265.
- Sutterwala FS, Ogura Y, Szczepanik M, Lara-Tejero M, Lichtenberger GS, Grant EP, Bertin J, Coyle AJ, Galán JE, Askenase PW, Flavell RA. 2006. Critical role for NALP3/CIAS1/Cryopyrin in innate and adaptive immunity through its regulation of caspase-1. Immunity 24: 317-327.
- Watanabe H, Gaide O, Pétrilli V, Martinon F, Contassot E, Roques S, Kummer JA, Tschopp J, French LE. 2007. Activation of the IL-1beta-processing inflammasome is involved in contact hypersensitivity. J. Invest. Dermatol. 127: 1956-1963.
- Natsch A and Emter R. 2008. Skin sensitizers induce antioxidant response element dependent genes: Application to the in vitro testing of the sensitisation potential of chemicals. Toxicol. Sci. 102: 110-119.
- Ade N, Leon F, Pallardy M, Pfeiffer JL, Kerdine-Romer S, Tissier MH, Bonnet PA, Fabre I Ourlin JC. 2009. HMOX1 and NQO1 genes are upregulated in response to contact sensitizers in dendritic cells and THP-1 cell line: role of the Keap1/Nrf2 pathway. Toxicol. Sci. 107: 451-460.
- Honda T, Egawa G, Grabbe S, Kabashima K. 2013. Update of immune events in the murine contact hypersensitivity model: toward the understanding of allergic contact dermatitis. J. Invest. Dermatol. 133: 303-315.
- Erkes DA, Selvan RS. 2014. Hapten-induced contact hypersensitivity, autoimmune reactions, and tumour regression: plausibility of mediating antitumor immunity. J. Immunol. Res. Article ID 175265.
- Simonsson C, Andersson SI, Stenfeldt AL, Bergstrom J, Bauer B, Jonsson CA, Ericson MB, Broo KS. 2011. Caged fluorescent haptens reveal the generation of cryptic epitopes in allergic contact dermatitis. J.Invest. Immunol. 131: 1486-1493.
- Watanabe H, Gehrke S, Contassot E, et al. 2008. Danger signalling through the inflammasone acts as a master switch between tolerance and sensitization. J. Immunol. 180:5826-5832.
- Antonopoulos C, Cumberbatch M, Dearman RJ, Daniel RJ, Kimber I, Groves RW. 2001. Functional caspase-1 is required for Langerhans cell migration and optimal contact sensitization in mice. J. Immunol. 166: 3672-3677.
- Nakae S, Komiyama Y, Narumi S, Sudo K, Horai R, Tagawa Y, Matsushima K, Asano M, Iwakura Y. 2003. IL-1-induced tumor necrosis factor-alpha elicits inflammatory cell infiltration in the skin by inducing IFN-γ-inducible protein 10 in the elicitation phase of the contact hypersensitivity response. Int. Immunol. 15(2): 251-260.
- Antonopoulos C, Cumberbatch M, Mee JB, Dearman RJ, Wei XQ, Liew FY, Kimber I, Groves RW. 2008. IL-18 is a key proximal mediator of contact hypersensitivity and allergen-induced Langerhans cell migration in murine epidermis. J. Leukocyte Biol. 83: 361-367.