Neutrophil nucleolar stress rapidly releases nucleoli-stored IFNα during infection

Excess IFN-I is associated with prominent neutrophil accumulation, however, the contribution of neutrophils to IFN-I overproduction remains underexplored. In all cell types previously studied, IFN-I is synthesized de novo upon pathogen sensing.

Contrary to this paradigm, we find that neutrophils express IFNα during development and store it in the nucleolus, an intranuclear condensate classically functioning in ribosome biogenesis. TLR-mediated bacterial sensing induces nucleolar stress and rapid secretion of nucleoli-stored IFNα from neutrophils independent of de novo protein synthesis. These findings reveal roles for the neutrophil nucleolus in IFN-I storage and secretion, identify the first naturally occurring regulatory function of nucleolar stress, and provide insight into the relationship between detrimental IFN-I levels and neutrophil accumulation.