An incoherent feedforward loop interprets NF?B/RelA dynamics to determine TNF-induced necroptosis decisions

Balancing cell death is essential to maintain healthy tissue homeostasis and prevent disease. Tumor necrosis factor (TNF) not only activates nuclear factor ?B (NF?B), which coordinates the cellular response to inflammation, but may also trigger necroptosis, a pro-inflammatory form of cell death. Whether TNF-induced NF?B affects the fate decision to undergo TNF-induced necroptosis is unclear. Live-cell microscopy and model-aided analysis of death kinetics identified a molecular circuit that interprets TNF-induced NF?B/RelA dynamics to control necroptosis decisions. Inducible expression of TNFAIP3/A20 forms an incoherent feedforward loop to interfere with the RIPK3-containing necrosome complex and protect a fraction of cells from transient, but not long-term TNF exposure. Furthermore, dysregulated NF?B dynamics often associated with disease diminish TNF-induced necroptosis. Our results suggest that TNF's dual roles in either coordinating cellular responses to inflammation, or further amplifying inflammation are determined by a dynamic NF?B-A20-RIPK3 circuit, that could be targeted to treat inflammation and cancer.