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Role of subnetworks mediated by TNFα, IL-23/IL-17 and IL-15 in a network involved in the pathogenesis of psoriasis

Pandey, R; Al-Nuaimi, Y; Mishra, RK; Spurgeon, SK; Goodfellow, M; (2021) Role of subnetworks mediated by TNFα, IL-23/IL-17 and IL-15 in a network involved in the pathogenesis of psoriasis. Scientific Reports , 11 , Article 2204. 10.1038/s41598-020-80507-7. Green open access

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Role of subnetworks mediated by [Formula see text], IL-23IL-17 and IL-15 in a network involved in the pathogenesis of psoria.pdf - Accepted Version

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Abstract

Psoriasis is a chronic inflammatory skin disease clinically characterized by the appearance of red colored, well-demarcated plaques with thickened skin and with silvery scales. Recent studies have established the involvement of a complex signalling network of interactions between cytokines, immune cells and skin cells called keratinocytes. Keratinocytes form the cells of the outermost layer of the skin (epidermis). Visible plaques in psoriasis are developed due to the fast proliferation and unusual differentiation of keratinocyte cells. Despite that, the exact mechanism of the appearance of these plaques in the cytokine-immune cell network is not clear. A mathematical model embodying interactions between key immune cells believed to be involved in psoriasis, keratinocytes and relevant cytokines has been developed. The complex network formed of these interactions poses several challenges. Here, we choose to study subnetworks of this complex network and initially focus on interactions involving [Formula: see text], IL-23/IL-17, and IL-15. These are chosen based on known evidence of their therapeutic efficacy. In addition, we explore the role of IL-15 in the pathogenesis of psoriasis and its potential as a future drug target for a novel treatment option. We perform steady state analyses for these subnetworks and demonstrate that the interactions between cells, driven by cytokines could cause the emergence of a psoriasis state (hyper-proliferation of keratinocytes) when levels of [Formula: see text], IL-23/IL-17 or IL-15 are increased. The model results explain and support the clinical potentiality of anti-cytokine treatments. Interestingly, our results suggest different dynamic scenarios underpin the pathogenesis of psoriasis, depending upon the dominant cytokines of subnetworks. We observed that the increase in the level of IL-23/IL-17 and IL-15 could lead to psoriasis via a bistable route, whereas an increase in the level of [Formula: see text] would lead to a monotonic and gradual disease progression. Further, we demonstrate how this insight, bistability, could be exploited to improve the current therapies and develop novel treatment strategies for psoriasis.

Type: Article
Title: Role of subnetworks mediated by TNFα, IL-23/IL-17 and IL-15 in a network involved in the pathogenesis of psoriasis
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/s41598-020-80507-7
Publisher version: https://doi.org/10.1038/s41598-020-80507-7
Language: English
Additional information: This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science > Dept of Electronic and Electrical Eng
URI: https://discovery.ucl.ac.uk/id/eprint/10121796
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