“…Although in our analyses we selected an in vitro experimental condition of PAD to demonstrate model utility and its potential translational application, the mechanistic setup of our model in terms of the pathways and mechanisms included is equally important for macrophages under general as well as other disease-specific scenarios. Still, the model certainly does not account for the full biology (an innate limitation even for large-scale models), as it is practically infeasible, due to relatively limited experimental data and high computational cost, to detail and calibrate every known pathway and mechanism that regulate macrophage polarization within a single modeling study while maintaining a high degree of model performance accuracy (Frohlich et al, 2018;Bouhaddou et al, 2018;Schmiester et al, 2020). Thus, our current model and its formulation can instead serve as a high-quality mechanistic computational platform that can be accordingly and continuously expanded and enriched with additional pathway details to further investigate macrophage functions in specific disease areas of interest, e.g., TLR pathways in various infectious disease settings (O'neill et al, 2009), CD47/SIRPa axis in macrophage-mediated cancer immunotherapy (Weiskopf, 2017), and cellular metabolic pathways in nonalcoholic fatty liver disease (Oates et al, 2019).…”