Macrophages employ quorum licensing to regulate collective activation.

Macrophage-initiated inflammation is tightly regulated to eliminate threats such as infections while suppressing harmful immune activation. However, individual cells' signaling responses to pro-inflammatory cues are heterogeneous, with subpopulations emerging with high or low activation states. Here, we use single-cell tracking and dynamical modeling to develop and validate a revised model for lipopolysaccharide (LPS)-induced macrophage activation that invokes a mechanism we term quorum licensing. The results show that bimodal phenotypic partitioning of macrophages is primed during the resting state, dependent on cumulative history of cell density, predicted by extrinsic noise in transcription factor expression, and independent of canonical LPS-induced intercellular feedback in the tumor necrosis factor (TNF) response. Our analysis shows how this density-dependent coupling produces a nonlinear effect on collective TNF production. We speculate that by linking macrophage density to activation, this mechanism could amplify local responses to threats and prevent false alarms.