Upstream eventOverproduction of IL-17
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Stimulation of TLR7/8 in dendric cells leading to Psoriatic skin disease||adjacent||High||High|
Life Stage Applicability
Key Event Relationship Description
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
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)
Resident memory tissue T cells (TRM cells) confer both resistance and immunity depending on the local microenvironment, and CD8 TRM can be tracked by phenotypic markers CD49a and CD103. Circulating effector T cells infiltrate the site of skin inflammation and turn into long-lived epidermal TRM cells when the skin inflammation is resolved. Epidermal TRM cells are thought to form pathological site-specific disease memory at the site of recurrent psoriasis.(Cheuk et al. 2014)
Single cell suspensions of epidermis and dermis were analyzed by flow cytometry within 30 hours of sampling. In active psoriasis, CD8 T cells increased about 100-fold in the epidermis compared to normal skin, whereas CD4 T cells increased 10-fold in the dermis. In healthy skin, 20-30% of epidermal CD8 T cells co-expressed integrin CD103 and CD49a, which are phenotypic markers of TRM cells. In active psoriasis, approximately half of epidermal CD8 T cells co-expressed these TRM phenotypic markers, a 100-fold increase compared to healthy skin.（Cheuk et al. 2014）
Uncertainties and Inconsistencies
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)
Quantitative Understanding of the Linkage
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)
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
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
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)
- 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.
- 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.
- 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.
- 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
- 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.
- 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.
- 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
- Kyowa Hakko Kirin Co., Ltd. Clinical pharmacology study, internal data
- 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.