Spatial modelling of TNFα-induced canonical NF-κB signaling

Sina Glöckner

Mathematical Modelling of Cellular Processes, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany

"Spatial modelling of TNFα-induced canonical NF-κB signaling"

NF-κB signaling shapes the inflammatory response, and its dysregulation is linked with autoimmune, neurodegenerative, and cardiovascular diseases. After pathway activation, dimers of the NF-κB family act as transcription factors for a large set of target genes including positive and negative regulators of the upstream pathway. Important examples are cytokines, such as TNFα, that stimulates the pathway and therefore contributes to the intercellular communication of cells. While the cellular NF-κB pathway has been intensively studied via computational modeling the effect of intercellular coupling is less explored. To investigate this in spatial contexts, we build a multi-scale, multi-cell ordinary differential equation model where physiological cell properties are computed with a Cellular Potts Model using the Morpheus software. To elucidate the interaction between different cell types in the intestinal crypt we extend the model to two NF-κB expressing cell types: sentinel macrophages and epithelial cells. There, the LPS-activated macrophages secrete TNFα to elicit an immune response in the epithel. We evaluated the models in terms of sensitivity regarding signal transmission strength and speed as well as common single-cell measures, like maximum NF-κB activation and time thereoff.

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