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Relationship: 2019


The title of the KER should clearly define the two KEs being considered and the sequential relationship between them (i.e., which is upstream and which is downstream). Consequently all KER titles take the form “upstream KE leads to downstream KE”.  More help

Th17 cell migration and inflammation induction leads to Skin disease

Upstream event
Upstream event in the Key Event Relationship. On the KER page, clicking on the Event name under Upstream Relationship will bring the user to that individual KE page. More help
Downstream event
Downstream event in the Key Event Relationship. On the KER page, clicking on the Event name under Upstream Relationship will bring the user to that individual KE page. More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes. Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

This table is automatically generated upon addition of a KER to an AOP. All of the AOPs that are linked to this KER will automatically be listed in this subsection. Clicking on the name of the AOP in the table will bring you to the individual page for that AOP. More help
AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Stimulation of TLR7/8 in dendric cells leading to Psoriatic skin disease adjacent High High Hiroyuki Komatsu (send email) Under development: Not open for comment. Do not cite Under Development

Taxonomic Applicability

Select one or more structured terms that help to define the biological applicability domain of the KER. In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. Authors can indicate the relevant taxa for this KER in this subsection. The process is similar to what is described for KEs (see pages 30-31 and 37-38 of User Handbook) More help

Sex Applicability

Authors can indicate the relevant sex for this KER in this subsection. The process is similar to what is described for KEs (see pages 31-32 of the User Handbook). More help

Life Stage Applicability

Authors can indicate the relevant life stage for this KER in this subsection. The process is similar to what is described for KEs (see pages 31-32 of User Handbook). More help

Key Event Relationship Description

Provide a brief, descriptive summation of the KER. While the title itself is fairly descriptive, this section can provide details that aren’t inherent in the description of the KEs themselves (see page 39 of the User Handbook). This description section can be viewed as providing the increased specificity in the nature of upstream perturbation (KEupstream) that leads to a particular downstream perturbation (KEdownstream), while allowing the KE descriptions to remain generalised so they can be linked to different AOPs. The description is also intended to provide a concise overview for readers who may want a brief summation, without needing to read through the detailed support for the relationship (covered below). Careful attention should be taken to avoid reference to other KEs that are not part of this KER, other KERs or other AOPs. This will ensure that the KER is modular and can be used by other AOPs. More help

Th17 cells produce the cytokines IL-17 and IL-22. IL-17 is inflammatory, promotes the migration of neutrophils to psoriatic lesions, contributes to the formation of Munro's micro-abscess, and through DCL and memory T cells, including Th17 cells and CCR6, via CCL20 Incorporate into the affected area. IL-22 causes abnormal keratinocyte proliferation by down-regulating genes that control terminal differentiation, leading to altered differentiation and keratinization. Both IL-17 and IL-22 induce keratinocyte expression of the antibacterial S100A7 (psoriacin).(Nograles et al. 2008)

STAT3 is important for Th17 differentiation. Cytokine signaling SOCS3-deficient mice show increased IL-17 expression by increasing STAT3 activity in response to IL-23 binding to IL-17. Associated with increased activity of STAT3 in response to IL-23 capable of binding to IL-17 and IL-17F promoters. STAT3 overexpression promotes Th17 differentiation, whereas STAT3 deficiency inhibits Th17 differentiation. STAT3 signaling from IL-6, IL-21, IL-23 regulates the expression of lineage specific master transcription factors RORγt22, 63, 66 and RORα67. It has been found that patients with psoriasis with mutations in STAT3 cannot generate a Th17 response.(Martinez et al. 2008)

Evidence Supporting this KER

Assembly and description of the scientific evidence supporting KERs in an AOP is an important step in the AOP development process that sets the stage for overall assessment of the AOP (see pages 49-56 of the User Handbook). To do this, biological plausibility, empirical support, and the current quantitative understanding of the KER are evaluated with regard to the predictive relationships/associations between defined pairs of KEs as a basis for considering WoE (page 55 of User Handbook). In addition, uncertainties and inconsistencies are considered. More help
Biological Plausibility
Define, in free text, the biological rationale for a connection between KEupstream and KEdownstream. What are the structural or functional relationships between the KEs? For example, there is a functional relationship between an enzyme’s activity and the product of a reaction it catalyses. Supporting references should be included. However, it is recognised that there may be cases where the biological relationship between two KEs is very well established, to the extent that it is widely accepted and consistently supported by so much literature that it is unnecessary and impractical to cite the relevant primary literature. Citation of review articles or other secondary sources, like text books, may be reasonable in such cases. The primary intent is to provide scientifically credible support for the structural and/or functional relationship between the pair of KEs if one is known. The description of biological plausibility can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured (see page 40 of the User Handbook for further information).   More help

The biological activity of the combination of cytokines was investigated. The combination of IL-17A and IFN-γ or IL-17A and TNF-α has a synergistic effect on CXCL8 production by keratinocytes. IL-17A and IL-22 exert a synergistic effect in upregulation of β-defensin 2: BD-2 and S100A9 production] IL-1α, IL-17, IL-22, Oncostatin M: OSM, and TNFα binding are associated with increased expression of inflammatory molecules such as soriacin / S100A7 or BD-2, IL-8 in vitro by NHEK Although very potent synergistic, removal of IL-22 from the cytokine mixture reduces CXCL8 and BD-2 expression by 30% and removal of IL-17 reduces it by 70%.

Ex vivo studies on human skin explants showed upregulation of BD-2, S100A7, and CXCL8 expression in response to the same combination of cytokines, and intradermal injection of cytokines into mice resulted in neutrophil infiltration and early epidermis CXCL1, CXCL2, CXCL3, S100A9, and BD-3 expression related to epidermal thickening was increased. (Bernard et aaal. 2012)

Uncertainties and Inconsistencies
In addition to outlining the evidence supporting a particular linkage, it is also important to identify inconsistencies or uncertainties in the relationship. Additionally, while there are expected patterns of concordance that support a causal linkage between the KEs in the pair, it is also helpful to identify experimental details that may explain apparent deviations from the expected patterns of concordance. Identification of uncertainties and inconsistencies contribute to evaluation of the overall WoE supporting the AOPs that contain a given KER and to the identification of research gaps that warrant investigation (seep pages 41-42 of the User Handbook).Given that AOPs are intended to support regulatory applications, AOP developers should focus on those inconsistencies or gaps that would have a direct bearing or impact on the confidence in the KER and its use as a basis for inference or extrapolation in a regulatory setting. Uncertainties that may be of academic interest but would have little impact on regulatory application don’t need to be described. In general, this section details evidence that may raise questions regarding the overall validity and predictive utility of the KER (including consideration of both biological plausibility and empirical support). It also contributes along with several other elements to the overall evaluation of the WoE for the KER (see Section 4 of the User Handbook).  More help

Cytokines cannot be specified for genes associated with abnormalities in psoriatic skin. Many genes that are up-regulated in psoriatic lesions can be attributed to IFN-γ, including IL-17 and IL-22. Cytokines synthesized by Th1 / Th17 cells regulate different gene expression pathways in epidermal keratinocytes and other skin resident cells. The psoriatic transcriptome may result from activation of multiple independent pathways.(Nograles et al. 2008)

After daily topical application of Aldara containing imiquimod (IMQ) to humans, significant skin thickening, redness and scaling were observed 3 days later (doi: 10.1172 / JCI61862DS1). The clinical course of plaque formation on the ear and back skin and histopathology were similar. Aldara treatment resulted in impaired keratinocyte hyperproliferation and epidermal differentiation, as indicated by epidermal thickening and hyperkeratosis. There was a terminal neutrophil accumulation in the stratum corneum reminiscent of a Munro micro-abscess in psoriasis. Extensive leukocyte infiltration was observed in the dermis.(Pantelyushin et al. 2012)

Response-response Relationship
This subsection should be used to define sources of data that define the response-response relationships between the KEs. In particular, information regarding the general form of the relationship (e.g., linear, exponential, sigmoidal, threshold, etc.) should be captured if possible. If there are specific mathematical functions or computational models relevant to the KER in question that have been defined, those should also be cited and/or described where possible, along with information concerning the approximate range of certainty with which the state of the KEdownstream can be predicted based on the measured state of the KEupstream (i.e., can it be predicted within a factor of two, or within three orders of magnitude?). For example, a regression equation may reasonably describe the response-response relationship between the two KERs, but that relationship may have only been validated/tested in a single species under steady state exposure conditions. Those types of details would be useful to capture.  More help


High levels of Th17 cytokines were observed in psoriatic skin induced by CD4 + T cells. IL-23 p40 subunit or IL-22 significantly prevented the development of skin lesions.

IL-22-induced acantosis and inflammation were reduced in IL-22-deficient mice compared to WT mice. Blocking IL-22 increases IL-1α, IL-1β, IL-6, IL-17, IL-17F, and TNF-α. (K. A. et al. 2013)


Anti-IL-17 antibody administration results in decreased keratinocyte proliferation and differentiation, leukocyte infiltration, and keratinocyte release of inflammatory cytokines. In psoriatic lesioned keratinocytes, changes in mRNA and protein expression of IL-17 regulatory products occurred. Within 2 weeks of antibody administration, the expression of LL37 (cathelicidin), β-defensin 2, S100A7, and S100A8 proteins was markedly decreased in keratinocytes, and the expression reached normal levels after 6 weeks.(Krueger et al. 2012)

This sub-section should be used to provide information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). This can be useful information both in terms of modelling the KER, as well as for analyzing the critical or dominant paths through an AOP network (e.g., identification of an AO that could kill an organism in a matter of hours will generally be of higher priority than other potential AOs that take weeks or months to develop). Identification of time-scale can also aid the assessment of temporal concordance. For example, for a KER that operates on a time-scale of days, measurement of both KEs after just hours of exposure in a short-term experiment could lead to incorrect conclusions regarding dose-response or temporal concordance if the time-scale of the upstream to downstream transition was not considered. More help

Epidermal keratinocyte expression genes that were elevated in psoriatic lesions of patients with psoriasis with stage-type skin eruption: mRNA expression level of keratin6a and 16, s100A7A, S100A12, DEFB4, IL-1F6, CCL20, IL-17C, etc. was rapidly reduced by 700㎎  single intravenous dose of brodalumab and decreased to non-lesional skin level 2 weeks after administration. On the other hand, leukocyte expression genes with increased expression in psoriatic lesion skin: IL-17A, IL-17F, IL-23F, IL-12B, IL-22, IFN-γ and other mRNA expression levels decreased with brodalumab administration. However, at 2 weeks after administration, the level did not decrease to the level of the non-lesional skin. Since the expression of pathophysiology-related genes is reduced prior to the decrease in the expression of leukocyte expression genes is reduced prior to the  decrease in the expression of leukocyte expression genes and the decrease in the PASI score, Brodalumab is reduced expression of  pathophysiology-related genes by blocking IL-17 signaling in the epidermal keratinocytes of psoriatic lesions It is possible to improve the skin eruption promptly. (Kyowa Hakko Kirin Co., Ltd.)

Known modulating factors
This sub-section presents information regarding modulating factors/variables known to alter the shape of the response-response function that describes the quantitative relationship between the two KEs (for example, an iodine deficient diet causes a significant increase in the slope of the relationship; a particular genotype doubles the sensitivity of KEdownstream to changes in KEupstream). Information on these known modulating factors should be listed in this subsection, along with relevant information regarding the manner in which the modulating factor can be expected to alter the relationship (if known). Note, this section should focus on those modulating factors for which solid evidence supported by relevant data and literature is available. It should NOT list all possible/plausible modulating factors. In this regard, it is useful to bear in mind that many risk assessments conducted through conventional apical guideline testing-based approaches generally consider few if any modulating factors. More help
Known Feedforward/Feedback loops influencing this KER
This subsection should define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits? In some cases where feedback processes are measurable and causally linked to the outcome, they should be represented as KEs. However, in most cases these features are expected to predominantly influence the shape of the response-response, time-course, behaviours between selected KEs. For example, if a feedback loop acts as compensatory mechanism that aims to restore homeostasis following initial perturbation of a KE, the feedback loop will directly shape the response-response relationship between the KERs. Given interest in formally identifying these positive or negative feedback, it is recommended that a graphical annotation (page 44) indicating a positive or negative feedback loop is involved in a particular upstream to downstream KE transition (KER) be added to the graphical representation, and that details be provided in this subsection of the KER description (see pages 44-45 of the User Handbook).  More help

Domain of Applicability

As for the KEs, there is also a free-text section of the KER description that the developer can use to explain his/her rationale for the structured terms selected with regard to taxonomic, life stage, or sex applicability, or provide a more generalizable or nuanced description of the applicability domain than may be feasible using standardized terms. More help

Initiation of plaque formation in the Aldara psoriasis mouse model is dependent on RORγt +, skin infiltrating γδ T cells, and innate lymphocyte cells (ILC). Vγ4 + γδT cells and innate lymphoid cells (ILC) are the dominant and important sources of IL-17A, IL-17F, and IL-22 in the formation of acute psoriatic lesions, rather than Th cells (Pantelyushin et al. 2012).

Amyloid A: SAA, an inflammatory marker, is high in the serum of patients with psoriasis. When C57B6 mice were given SAA protein subcutaneously on the back, epidermal thickening and inflammatory cell wetting were frequent on days 5-7. Skin inflammation was significantly suppressed when IL-12 / IL-23p40 protein, a target molecule of psoriasis biologics, was administered in advance. By SAA administration, a similar reaction to psoriatic eruption was formed in the immunological reaction, and a psoriatic eruption model mouse was established. (J Dermatolog Trest. 2013; 24 (6): 477-80)


List of the literature that was cited for this KER description using the appropriate format. Ideally, the list of references should conform, to the extent possible, with the OECD Style Guide (OECD, 2015). More help
  1. K. E. Nograles, L.C. Zaba, E. Guttman, J. Fuentes-Duculan, M. Suarez-Farinas, I. Cardinale, A. Khatcherian, J. Gonzalez, K. C. Pierson, T. R. White, C. Pensabene, I. Novitskaya, M. A. Lowes, and J. G. Krueger. Th17 cytokines interleukin(IL)-17 and IL-22 modulate distinct inflammatory and kerationocyte-response pathways. Br J Dermatol 2008 Nov.; 159(5): 1092-1102.
  2. Gustavo J. Martinez, Roza I. Nurieva, Xuexian O. Yang, and Chen Dong. Regulation and Function of Proinflammatory TH17 Cells. Ann N. Y. Acead Sci. 2008 Nov; 1143: 188-211.
  3. Francois-Xaver Bernard, Franck Morel, Magalie Camus, Nathalie Pedretti, Christine Barrault, Julien Garnier, and Jean-Claude Lecron. Keratinocytes under Fire of Proinflammatory Cytokines: Bone Fide Innate Immune Cells Involved in the Physiopathology of Chronic Atopic Dermatitis and Psoriasis. Journal of Allergy. 2012. Article ID 718725, 10.
  4. Stanley Cheuk, Maria Wiken, Lennart Blomqvist, Susanne Nylen, Toomas Taqlme, Mona Stahle and Liv Eidsmo. Epidermal Th22 and Tc17 Cells From a Localized Disease Memory in Clinically Healed Psoriasis. J Immunol. 2014 Apr 1; 192(7): 3111-3120. 2014
  5. Stanislav Pantelyushin, Stefan Haak, Barbara Ingold, Paulina Kulig, Frank L. Hepponer, Alexander A. Navarini, and Burkhand Becher. Roryt innate lymphocytes and yo T cells intiate psoriasiform plaque foemation in mice. J Clin Invest. 2012 Jun 1; 122(6): 2252-2256.
  6. K.A. Papp, R.G. Langley, B. Sigurgeirsson, M. Abe,D.R. Baker, P. Konno, S. Haemmerle, H.J. Thurston, C. Papavassilis, H.B. Richards. Efficacy and safety of secukinumab in the treatment of moderate-to-severe plaque psoriasis: a randomized, double-blind,placebo-controlled phase II dose-ranging study. Br. J. Dermatol. 2013, 168, 412-421.
  7. James G Krueger, Scott Fretzin, Mayte Suarez-Farinas, Patrick A Haslett, Krista M Phipps, Gregory S Cameron, Juliet Mccolm, Artemis Katcherian, Inna Cueto, Traci White, Subhashis Banerjee, and Robert W Hoffman. IL-17A is essential for cell activation and inflammatory gene ciorcuits in subjects with psoriasis. Jourmal of Allergy and Clinical Immunology 2012, 130(1): 145-154
  8. Kyowa Hakko Kirin Co., Ltd. Clinical pharmacology study, internal data
  9. Tanizaki H, Nakahigashi K, Miyachi Y, and Kabashima K. Comparison of the efficacy of fexofenadine 120 and 240 mg/day on chronic idiopathic urticarial and histamine-induced skin responses in Japanese populations. J Dermatolog Treat. 2013; Dec; 24(6): 477-80.