Quantitative control of macrophage signaling and inflammatory thresholds

Innate immune signaling must be tightly regulated to allow robust inflammatory responses to invasive infection, while avoiding unwanted inflammation in response to minor challenges. Using quantitative approaches, we found divergent signaling thresholds that dictate stimulus strength-dependent macrophage responses. Inflammatory mediator production had a threshold controlled by switch-like MAPK activation, whereas NF-κB activity and restricted gene expression occurred at ligand concentrations below this threshold. Amongst induced genes, we observed a significant relationship between MAPK dependence and ligand sensitivity, highlighting the role of this signaling dichotomy in partitioning innate responses downstream of a single receptor. MAPK have been targeted therapeutically in a variety of inflammatory diseases including rheumatoid arthritis, atherosclerosis, chronic obstructive pulmonary disease, and neurodegenerative disorders. However, in most cases these trials have failed. In an effort to support rational target identification in MAPK driven disease, we have undertaken an iterative rule-based modeling approach to elucidate mechanisms controlling the magnitude and duration of MAPK activity upon macrophage stimulation. We have included signal-induced phosphatase activity into our model to reproduce the experimentally observed MAPK dynamics and predict novel feedback mechanisms reliant on rapid post-translational activation of protein phosphatases. We are currently exploring how MAPK sensitivity to activation and inhibition is altered in macrophages from older mice and humans.