A bistable circuit regulates miRNA-155 levels in human macrophage inflammatory transitions

Macrophages are crucial immune regulators as they can either trigger or resolve inflammation. These properties rely on defined inflammatory states and make macrophages valuable therapeutic targets. Identification of stable steady states and bistability in inflammatory transitions provides deeper insights into immune regulation and facilitates the development of novel therapeutic strategies. We present a multiomic and systems biology approach for the top-down identification of bistable circuits in human macrophages polarized towards pro- and anti-inflammatory phenotypes. Using differential gene expression profiles, we identified three criteria to suspect bistability: two potential attractors, a hysteresis behavior between their transitions, and the presence of potential modules of coregulated genes. This was further confirmed by proteomics data pointing to mutually exclusive and time-dependent profiles of gene expression. By network simplification and creation of a novel pipeline for parameter estimation in bistable models, we obtained a minimal model of inflammatory transitions in which we identified ultrasensitivity and hysteresis. Our minimal model genes establish a regulatory circuit switching miR-155 expression, which in turn regulates the expression of inflammatory marker genes during inflammatory transitions.