Mathematical models disentangle the role of IL-10 feedbacks in human monocytes upon proinflammatory activation

Abstract

AbstractInflammation is one of the vital mechanisms through which the immune system responds to harmful stimuli. During inflammation, pro and anti-inflammatory cytokines interplay to orchestrate fine-tuned, dynamic immune responses. The cytokine interplay governs switches in the inflammatory response and dictates the propagation of inflammation. Molecular pathways underlying the interplay are complex, and time-resolved monitoring of mediators and cytokines is necessary as a basis to study them in detail. Our understanding can be advanced byin silicomodels which enable to analyze the system of interactions and their dynamical interplay in detail. We, therefore, used a mathematical modeling approach to study the interplay between prominent pro and anti-inflammatory cytokines with a focus on Tumor Necrosis Factor (TNF) and Interleukin 10 (IL-10) in lipopolysaccharide (LPS)-primed primary human monocytes. Relevant time-resolved data were generated by experimentally adding or blocking IL-10 at different time points. The model was successfully trained and could predict independent validation data and was further used to performin silicoexperiments to disentangle the role of IL-10 feedbacks in acute inflammation. We used the insight to obtain a reduced predictive model including only the necessary IL-10-mediated feedbacks. Finally, the validated reduced model was used to predict early IL-10 – TNF switches in the inflammatory response. Overall, we gained detailed insights into fine-tuning of inflammatory responses in human monocytes and present a model for further use in studying the complex and dynamic process of cytokine-regulated acute inflammation.