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

Niloofar Nikaein; Kedeye Tuerxun; Gunnar Cedersund; Daniel Eklund; Robert Kruse; Eva Särndahl; Eewa Nånberg; Antje Thonig; Dirk Repsilber; Alexander Persson; Elin Nyman; X-HiDE Consortium

doi:10.1016/j.jbc.2023.105205

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

J Biol Chem. 2023 Oct;299(10):105205. doi: 10.1016/j.jbc.2023.105205. Epub 2023 Sep 1.

Authors

Affiliations

¹ Faculty of Medicine and Health, School of Medical Sciences, Örebro University, Örebro, Sweden. Electronic address: X-HiDE@oru.se.
² Faculty of Medicine and Health, School of Medical Sciences, Örebro University, Örebro, Sweden; Faculty of Medicine and Health, Inflammatory Response and Infection Susceptibility Centre (iRiSC), Örebro University, Örebro, Sweden.
³ Faculty of Medicine and Health, School of Medical Sciences, Örebro University, Örebro, Sweden; Faculty of Medicine and Health, Inflammatory Response and Infection Susceptibility Centre (iRiSC), Örebro University, Örebro, Sweden; Department of Biomedical Engineering, Linköping University, Linköping, Sweden; Center for Medical Image Science and Visualization (CMIV), Linköping University, Linköping, Sweden.
⁴ Faculty of Medicine and Health, Inflammatory Response and Infection Susceptibility Centre (iRiSC), Örebro University, Örebro, Sweden; Faculty of Medicine and Health, Department of Clinical Research Laboratory, Örebro University, Örebro, Sweden.
⁵ Faculty of Medicine and Health, Inflammatory Response and Infection Susceptibility Centre (iRiSC), Örebro University, Örebro, Sweden; Faculty of Medicine and Health, School of Health Sciences, Örebro University, Örebro, Sweden.
⁶ Faculty of Medicine and Health, School of Medical Sciences, Örebro University, Örebro, Sweden.
⁷ Department of Biomedical Engineering, Linköping University, Linköping, Sweden. Electronic address: elin.nyman@liu.se.

Abstract

Inflammation is one of the vital mechanisms through which the immune system responds to harmful stimuli. During inflammation, proinflammatory and anti-inflammatory cytokines interplay to orchestrate fine-tuned and dynamic immune responses. The cytokine interplay governs switches in the inflammatory response and dictates the propagation and development of the inflammatory response. 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 by mathematical models that 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 proinflammatory and anti-inflammatory cytokines with a focus on tumor necrosis factor and interleukin 10 (IL-10) in lipopolysaccharide-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 perform simulations to disentangle the role of IL-10 feedbacks during an acute inflammatory event. 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-tumor necrosis factor 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.

Keywords: NF-κB; computational biology; computer modeling; cytokine; endotoxin; human monocytes; inflammation; interleukin 10; lipopolysaccharide; mathematical modeling; ordinary differential equations; signal transduction; systems biology; tumor necrosis factor.