RIPK3 activation: Necroptotic cell death and continued cytokine synthesis

Abstract

Billions of cells die in our body each day, and our immune system is given the challenging task of determining which of these cell death incidents are normal, homeostatic events, and which are potentially dangerous. Necroptosis is a form of non-apoptotic programmed cell death mediated by the kinase RIPK3 and its downstream effector, MLKL, and has been hypothesized to be inflammatory due to its necrotic-like morphology. However, how the immune system “sees” and responds to necroptotic cell death is not well understood. During my dissertation research, we first developed a system to directly activate RIPK3 and trigger necroptosis, independent of upstream signaling. Using this system, we found that RIPK3 activation lead to the upregulation of many pro-inflammatory cytokines and chemokines at the mRNA level, and only a subset of these was made at the protein level. Interestingly, cells that had undergone necroptosis and were seemingly “dead” were able to continue translating pro-inflammatory mediators. Furthermore, we found that ongoing translation of cytokines and chemokines by “corpses” contributes to necroptotic cell uptake by innate immune cells, as well as priming of adaptive immune responses to antigens associated with necroptotic corpses. The work carried out during my dissertation raises the possibility that necroptosis represents a program in which cell death and inflammatory transcription and translation are coordinated to optimize the immunogenicity of necroptotic cells.