Browsing by Author "Rajiv Kumar Mishra"

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A mathematical model for the co-activation of inflammatory genes mediated by NF-κB and IRF-3 following viral infections
(Elsevier Inc., 2025) Syona Tiwari; Rajiv Kumar Mishra; Soumen Basak; Rakesh Pandey
The innate immune responses in host cells are activated through molecular signaling pathways, such as NF-κB and IRF-3 in response to viral infections. These transcription factors regulate the expression of antiviral genes that encode type I interferons (IFNα/β). However, the precise mechanism that governs their complex context-dependent temporal activation remains elusive. Here, we have developed a probability-based mathematical model to study the co-regulation of the IFNβ gene by NF-κB and IRF-3. Our results suggest that the rapid and elevated as well as a delayed but persistent expression of IFNβ would be observed due to a temporal bias in the binding of NF-κB and IRF-3, highlighting the need for co-regulation of IFNβ by two different signaling pathways. Also, the model predicts that the binding affinity of NF-κB to the promoter of IFNβ would be equal to or greater than that of IRF-3 for a quick, strong and persistent antiviral response. © 2025 The Author(s)
Dynamics of a network mediated by IL-36 and involved in the pathogenesis of psoriasis
(Frontiers Media SA, 2024) Sneha Pandey; Syona Tiwari; Sulagna Basu; Rajiv Kumar Mishra; Rakesh Pandey
The pathogenesis of the inflammatory, chronic, and common skin disease psoriasis involves immune cells, skin cells (keratinocytes), and the cytokines they secrete. Hyperproliferation and abnormal differentiation of keratinocytes are hallmarks of the disease. The roles of cytokines such as TNFα, IL-15, IL-17, and IL-23 in psoriasis have been studied through mathematical/computational models as well as experiments. However, the role of proinflammatory cytokine IL-36 in the onset and progression of psoriasis is still elusive. To explore the role of IL-36, we construct a network embodying indirect cell–cell interactions of a few immune and skin cells mediated by IL-36 based on existing knowledge. We also develop a mathematical model for the network and perform a global sensitivity analysis. Our results suggest that the model is most sensitive to a parameter that represents the level of cytokine IL-36. In addition, a steady-state analysis of the model suggests that an increase in the level of IL-36 could lead to the hyperproliferation of keratinocytes and, thus, psoriasis. Our analysis also highlights that the plaque formation and progression of psoriasis could occur through either a gradual or a switch-like increase in the keratinocyte population. We propose that the switch-like increase would be due to a bistable behavior of the network toward either a psoriatic or healthy state and could be used as a novel treatment strategy. Copyright © 2024 Pandey, Tiwari, Basu, Mishra and Pandey.
Role of subnetworks mediated by TNF α , IL-23/IL-17 and IL-15 in a network involved in the pathogenesis of psoriasis
(Nature Research, 2021) Rakesh Pandey; Yusur Al-Nuaimi; Rajiv Kumar Mishra; Sarah K. Spurgeon; Marc Goodfellow
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 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 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 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. © 2021, The Author(s).