Requirement for multiple activation signals by anti-inflammatory feedback in macrophages

Pathogen killing is one of the primary roles of macrophages, utilizing potent effectors such as nitric oxide (NO) and involving other cellular machinery including iron regulatory apparatus. Macrophages become strongly activated upon receipt of appropriate signaling with cytokines and pathogen-derived endotoxins. However, they must resist activation in the absence of decisive signaling due to the energetic demands of activation coupled with the toxic nature of effector molecules to surrounding tissues. We have developed a mathematical model of the modular biochemical network of macrophages involved with activation, pathogen killing and iron regulation. This model requires synergistic interaction of multiple activation signals to overcome the quiescent state. To achieve a trade-off between macrophage quiescence and activation, strong activation signals are modulated via negative regulation by NO. In this way a single activation signal is insufficient for complete activation. In addition, our results suggest that iron regulation is usually controlled by activation signals. However, under conditions of partial macrophage activation, exogenous iron levels play a key role in regulating NO production. This model will be useful for evaluating macrophage control of intracellular pathogens in addition to the biochemical mechanisms examined here.