Tonic TNF conditioning of macrophages safeguards stimulus‐specific inflammatory responses

Tumor necrosis factor (TNF) is a key inflammatory cytokine that warns recipient cells of a nearby infection or tissue damage. Acute exposure to TNF activates characteristic oscillatory dynamics of the transcription factor NFκB and induces a characteristic gene expression program; these are distinct from the responses of cells directly exposed to pathogen‐associated molecular patterns (PAMPs). Here, we report that tonic TNF exposure is critical for safeguarding TNF's specific functions. In the absence of tonic TNF conditioning, acute exposure to TNF causes (i) NFκB signaling dynamics that are less oscillatory and more like PAMP‐responsive NFκB dynamics, (ii) immune gene expression that is more similar to the Pam3CSK4 response program, and (iii) broader epigenomic reprogramming that is characteristic of PAMP‐responsive changes. We show that the absence of tonic TNF signaling effects subtle changes to TNF receptor availability and dynamics such that enhanced pathway activity results in non‐oscillatory NFκB. Our results reveal tonic TNF as a key tissue determinant of the specific cellular responses to acute paracrine TNF exposure, and their distinction from responses to direct exposure to PAMPs.