Role of subnetworks mediated by $$\hbox {TNF}\alpha$$, 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, 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.

Dynamics of a network mediated by IL-36 and involved in the pathogenesis of psoriasis

“…We also observed that the route of the plaque formation and or progression of psoriasis could be via a gradual or switch-like increase in the population of keratinocytes. This switch-like behavior could be used as a new treatment strategy, as argued in a few recent studies (Pandey et al, 2021;Pandey et al, 2023). TABLE 1 IL-36 cytokines with their source and effect on different cell types.…”

Interleukins and Psoriasis

“…In a xenograft psoriasis mouse model, in vivo injection of anti-IL-15 monoclonal antibodies significantly reduced epidermal hyperplasia, dyskeratosis, and inflammatory cell infiltration, demonstrating these findings. 133 Pandey et al 134 demonstrated the link between IL-15 and T-cells, dendritic cells, and keratogenic through a numerical model of the network developed. Results after analyzing the dynamics of sub-networks involving IL-15 suggest that increased intracellular levels of IL-15 may lead to a substantial increase in keratogenic cell populations, thus causing psoriasis.…”

Exploring Mast Cell–CD8 T Cell Interactions in Inflammatory Skin Diseases

“…Histopathologically, psoriasis has three principal features: abnormal keratinocyte proliferation, dilated blood vessels, and a dermal inflammatory infiltration of immune cells, including macrophages, MCs, neutrophils, and lymphocytes [ 133 ]. It is well established from research on human and mouse models that the TNF-α-IL-23-IL-17 axis plays a central role in the pathogenesis of psoriasis [ 135 , 136 ]. In accordance with this, FDA-approved biologic agents targeting this axis have shown high efficacy for psoriasis treatment [ 137 , 138 ].…”