Role of subnetworks mediated by $$\hbox {TNF}\alpha$$ TNF α , IL-23/IL-17 and IL-15 in a network involved in the pathogenesis of psoriasis
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,...
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Nature Portfolio
2021
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oai:doaj.org-article:65d69cfa367d40c381dbfe22157afe1e2021-12-02T14:16:57ZRole of subnetworks mediated by $$\hbox {TNF}\alpha$$ TNF α , IL-23/IL-17 and IL-15 in a network involved in the pathogenesis of psoriasis10.1038/s41598-020-80507-72045-2322https://doaj.org/article/65d69cfa367d40c381dbfe22157afe1e2021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-80507-7https://doaj.org/toc/2045-2322Abstract 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 $$\hbox {TNF}_{\alpha }$$ TNF α , 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 $$\hbox {TNF}_{\alpha }$$ TNF α , 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 $$\hbox {TNF}_{\alpha }$$ TNF α 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.Rakesh PandeyYusur Al-NuaimiRajiv Kumar MishraSarah K. SpurgeonMarc GoodfellowNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021) |
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DOAJ |
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EN |
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Medicine R Science Q |
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Medicine R Science Q Rakesh Pandey Yusur Al-Nuaimi Rajiv Kumar Mishra Sarah K. Spurgeon Marc Goodfellow Role of subnetworks mediated by $$\hbox {TNF}\alpha$$ TNF α , IL-23/IL-17 and IL-15 in a network involved in the pathogenesis of psoriasis |
| description |
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 $$\hbox {TNF}_{\alpha }$$ TNF α , 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 $$\hbox {TNF}_{\alpha }$$ TNF α , 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 $$\hbox {TNF}_{\alpha }$$ TNF α 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. |
| format |
article |
| author |
Rakesh Pandey Yusur Al-Nuaimi Rajiv Kumar Mishra Sarah K. Spurgeon Marc Goodfellow |
| author_facet |
Rakesh Pandey Yusur Al-Nuaimi Rajiv Kumar Mishra Sarah K. Spurgeon Marc Goodfellow |
| author_sort |
Rakesh Pandey |
| title |
Role of subnetworks mediated by $$\hbox {TNF}\alpha$$ TNF α , IL-23/IL-17 and IL-15 in a network involved in the pathogenesis of psoriasis |
| title_short |
Role of subnetworks mediated by $$\hbox {TNF}\alpha$$ TNF α , IL-23/IL-17 and IL-15 in a network involved in the pathogenesis of psoriasis |
| title_full |
Role of subnetworks mediated by $$\hbox {TNF}\alpha$$ TNF α , IL-23/IL-17 and IL-15 in a network involved in the pathogenesis of psoriasis |
| title_fullStr |
Role of subnetworks mediated by $$\hbox {TNF}\alpha$$ TNF α , IL-23/IL-17 and IL-15 in a network involved in the pathogenesis of psoriasis |
| title_full_unstemmed |
Role of subnetworks mediated by $$\hbox {TNF}\alpha$$ TNF α , IL-23/IL-17 and IL-15 in a network involved in the pathogenesis of psoriasis |
| title_sort |
role of subnetworks mediated by $$\hbox {tnf}\alpha$$ tnf α , il-23/il-17 and il-15 in a network involved in the pathogenesis of psoriasis |
| publisher |
Nature Portfolio |
| publishDate |
2021 |
| url |
https://doaj.org/article/65d69cfa367d40c381dbfe22157afe1e |
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