In vivo consequences of inducible cell death via direct activation of RIPK3

Abstract

Abstract Necroptosis is a form of programmed cell death and is distinct from apoptosis in its mechanism and morphology; apoptosis is thought to be a non-inflammatory form of cell death whereas necroptosis is thought to be inflammatory. Necroptosis occurs in response to viral infection and is important for control of DNA and RNA viruses in vivo. While much of the necroptotic pathway has been characterized in vitro, the effects of necroptosis are poorly understood in vivo. We recently described a system by which necroptosis can be triggered using a version of the pro-necroptotic kinase RIPK3 fused to a ligand binding domain. Here, we characterize a novel transgenic model in which this inducible form of RIPK3 is expressed in vivo, allowing induction of necroptosis in primary tissues. We find that widespread activation of necroptosis in vivo using this model triggers sepsis-like systemic inflammation.