Macrophages tune responses to pathogen dynamics through TLR4 stimulation memory and by licensing susceptibility to IL-10

Macrophages must scale inflammation to the trajectories of infections, escalating as pathogen loads rise, resolving as they fall. The cytokine IL-10 and its chromatin-level effector BCL-3 are critically important anti-inflammatory agents, yet how they avoid muting newly recruited cells before those cells read their own pathogen input has been unclear. Applying systematically varied consecutive TLR4 (Kdo2-Lipid A) stimuli to bone marrow-derived macrophages, we identify two coupled features. First, macrophages retain a quantitative memory of prior stimulation: only when a secondary TLR stimulus matches or exceeds a prior one, I{kappa}B degradation, NF-{kappa}B/MAPK activation, and cytokine output increase. Second, IL-10 susceptibility is itself gated by TLR4 history: even a 100-fold IL-10 excess fails to suppress TNF- in weakly primed cells. Both trace to history- and IL-10-dependent BCL-3 recruitment with p65 displacement at the Tnf {kappa}B site. Modeling shows how this licensing logic enables trajectory-aware responses that clear pathogens while limiting tissue damage.