LAUSR

Inflammatory caspase‐11 (rodent) and caspases‐4/5 (humans) detect the Gram‐negative bacterial component LPS within the host cell cytosol, promoting activation of the non‐canonical inflammasome. Although non‐canonical inflammasome‐induced pyroptosis and IL‐1‐related cytokine release are crucial to mount an efficient immune response against various bacteria, their unrestrained activation drives sepsis. This suggests that cellular components tightly control the threshold level of the non‐canonical inflammasome in order to ensure efficient but non‐deleterious inflammatory responses. Here, we show that the IFN‐inducible protein Irgm2 and the ATG8 family member Gate‐16 cooperatively counteract Gram‐negative bacteria‐induced non‐canonical inflammasome activation, both in cultured macrophages and in vivo. Specifically, the Irgm2/Gate‐16 axis dampens caspase‐11 targeting to intracellular bacteria, which lowers caspase‐11‐mediated pyroptosis and cytokine release. Deficiency in Irgm2 or Gate16 induces both guanylate binding protein (GBP)‐dependent and GBP‐independent routes for caspase‐11 targeting to intracellular bacteria. Our findings identify molecular effectors that fine‐tune bacteria‐activated non‐canonical inflammasome responses and shed light on the understanding of the immune pathways they control.