Role of subnetworks mediated by [Formula: see text], IL-23/IL-17 and IL-15 in a network involved in the pathogenesis of psoriasis.
Role of subnetworks mediated by [Formula: see text], IL-23/IL-17 and IL-15 in a network involved in the pathogenesis of psoriasis.
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DOI：
10.1038/s41598-020-80507-7
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发表时间：
2021-01-26
影响因子：
4.6
通讯作者：
Goodfellow M
中科院分区：
文献类型：
--
作者：
Pandey R;Al-Nuaimi Y;Mishra RK;Spurgeon SK;Goodfellow M
银屑病是一种慢性炎症性皮肤病，临床表现为红色、界限清晰的斑块，皮肤增厚，鳞片呈银色。最近的研究已经确定了细胞因子、免疫细胞和皮肤细胞（角质形成细胞）之间相互作用的复杂信号网络的参与。角质形成细胞形成皮肤最外层（表皮）的细胞。银屑病中的可见斑块是由于角化细胞的快速增殖和异常分化而形成的。尽管如此，这些斑块在细胞因子-免疫细胞网络中出现的确切机制尚不清楚。一个数学模型体现了被认为参与银屑病的关键免疫细胞、角化细胞和相关细胞因子之间的相互作用。这些相互作用形成的复杂网络带来了一些挑战。在这里，我们选择研究这个复杂网络的子网络，并首先关注涉及IL-23/IL-17和IL-15的相互作用。这些药物是根据其治疗效果的已知证据选择的。此外，我们还探讨了IL-15在银屑病发病机制中的作用及其作为未来新型治疗选择的药物靶点的潜力。我们对这些子网络进行了稳态分析，并证明当IL-23/IL-17或IL-15水平升高时，细胞之间的相互作用可能导致牛皮癣状态（角质形成细胞过度增殖）的出现。模型结果解释并支持抗细胞因子治疗的临床潜力。有趣的是，我们的研究结果表明，银屑病的发病机制取决于子网络的主导细胞因子的不同动态情景。我们观察到IL-23/IL-17和IL-15水平的增加可通过双稳态途径导致银屑病，而IL-17水平的增加将导致疾病的单调渐进进展。此外，我们展示了如何利用这种洞察力，双稳定性来改进当前的治疗方法并开发新的治疗策略。
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 , 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 , 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 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.
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