The innate immune response to ischemic injury: a multiscale modeling perspective

Elena Dimitrova, Leslie A. Caromile, Reinhard Laubenbacher, Linda H. Shapiro

Cell death as a result of ischemic injury triggers powerful mechanisms regulated by germline-encoded Pattern Recognition Receptors (PRRs) with shared specificity that recognize invading pathogens and endogenous ligands released from dying cells, and as such are essential to human health. Alternatively, dysregulation of these mechanisms contributes to extreme inflammation, deleterious tissue damage and impaired healing in various diseases. The Toll-like receptors (TLRs) are a prototypical family of PRRs that may be powerful anti-inflammatory targets if agents can be designed that antagonize their harmful effects while preserving host defense functions. This requires an understanding of the complex interactions and consequences of targeting the TLR-mediated pathways as well as technologies to analyze and interpret these, which will then allow the simulation of perturbations targeting specific pathway components, predict potential outcomes and identify safe and effective therapeutic targets. We constructed a multiscale mathematical model that spans the tissue and intracellular scales, and captures the consequences of targeting various regulatory components of injury-induced TLR4 signal transduction on potential pro-inflammatory or pro-healing outcomes. We applied known interactions to simulate how inactivation of specific regulatory nodes affects dynamics in the context of injury and to predict phenotypes of potential therapeutic interventions. We propose rules to link model behavior to qualitative estimates of pro-inflammatory signal activation, macrophage infiltration, production of reactive oxygen species and resolution. We tested the validity of the model by assessing its ability to reproduce published data not used in its construction. These studies will enable us to form a conceptual framework focusing on TLR4-mediated ischemic repair to assess potential molecular targets that can be utilized therapeutically to improve efficacy and safety in treating ischemic/inflammatory injury.