Cytokines driven by caspase-1 and RIPK3 are antagonistic
Li, L.; Guo, J.; Wang, Y.; Lacey, C. A.; Liu, Y.; Li, Y.-M.; Peng, J.; Larson, H. N.; Pratt, M. N.; Tummers, B.; Green, D. R.; Miao, E. A.
Show abstract
Pyroptosis, apoptosis, and necroptosis are thought to provide redundant protection against intracellular pathogens. We found that mice lacking inflammasome signaling together with caspase-8 and MLKL were highly susceptible to infection by an environmental cytosol-invasive bacterium. Surprisingly, deletion of Ripk3 completely restored resistance despite the continued absence of all three cell death pathways. The outcome of the infection was determined not through cell death, but instead via the production of antagonistic cytokines arising from these pathways. Deleting Casp8 and Mlkl initiated an effector-triggered immunity-like response, in which RIPK3 induced type I interferons causing catastrophic susceptibility. Opposing this, caspase-1-dependent IL-1{beta} production counteracted these type I interferons and restored resistance. Thus, susceptibility arose not from failure of regulated cell death, but from the activation of a RIPK3-driven type I interferons unopposed by caspase-1-driven IL-1{beta}. Antagonistic cytokines embedded within cell death pathways, distinct from cell death itself, dictates the immune response to intracellular infection.
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