Macrophages tune responses to pathogen dynamics through TLR4 stimulation memory and by licensing susceptibility to...

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, IκBα degradation, NF-κB/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-α in weakly primed cells. Both trace to history- and IL-10-dependent BCL-3 recruitment with p65 displacement at the Tnf κB site. Modeling shows how this licensing logic enables trajectory-aware responses that clear pathogens while limiting tissue damage.