Abstract
Balancing cell death is essential to maintain healthy tissue homeostasis and prevent disease. Tumor necrosis factor (TNF) not only activates nuclear factor κB (NFκB), which coordinates the cellular response to inflammation, but may also trigger necroptosis, a pro‐inflammatory form of cell death. Whether TNF‐induced NFκB 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 NFκB/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 NFκB 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 NFκB‐A20‐RIPK3 circuit, that could be targeted to treat inflammation and cancer.
Highlights
The cytokine tumor necrosis factor (TNF) mediates diverse cell fate decisions in response to inflammation (Figure EV1A) (Beutler et al, 1985a; Newton & Dixit, 2012)
Using time-lapse microscopy, we identified an incoherent feedforward loop involving TNF-induced nuclear factor kB (NFkB)/RelA activity and de novo expressed A20 protein, which provides potent, though transient protection to RIPK3-mediated necroptosis
We demonstrated that this molecular circuit ensures that a majority of cells survives transient TNF exposures, but, because of the transience of A20 expression, does not protect from long-lasting TNF exposure
Summary
The cytokine tumor necrosis factor (TNF) mediates diverse cell fate decisions in response to inflammation (Figure EV1A) (Beutler et al, 1985a; Newton & Dixit, 2012). TNF-induced activation of nuclear factor kB (NFkB) regulates the expression of hundreds of inflammatory response genes involved in eliminating pathogens, resolving inflammation and healing (Cheng et al, 2017; Wallach et al, 1999). TNF is a cell killing agent (Beutler et al, 1985a; Carswell et al, 1975) and may trigger apoptotic or necroptotic cell death programs with distinct pathophysiological consequences (Vandenabeele et al, 2010). While apoptotic cells fragment into membrane bound vesicles, which allows their removal and resolution of inflammation (Galluzzi et al, 2018), necroptotic cells spill damage-associated molecular patterns (DAMPs) into the microenvironment, which promotes inflammation (Pasparakis & Vandenabeele, 2015; Wallach et al, 2016). Too little is known about the regulatory network controlling necroptosis to allow for predictable manipulation as a therapeutic strategy (Annibaldi & Meier, 2018)
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