Neutrophils rapidly release nucleoli-stored IFNα during infection

Xu, S.; Smirnov, A.; Kinsella, R. L.; Wise-Mitchell, A. D.; Alexander, J. M.; Rankin, A.; Patty, B.; Mikhail, S. M.; Bello, R. M.; Kreamalmeyer, D.; Boluarte, S.; Khan, A.; Allsup, B. L.; Mahmud, S.; Bryson, B. D.; Mattila, J.; Greer, E. L.; Ding, S.; Clemens, R.; Monteith, A. J.; Calo, E.; Stallings, C. L.

doi:10.64898/2026.05.18.726057

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bioRxiv · 10.64898/2026.05.18.726057

Neutrophils rapidly release nucleoli-stored IFNα during infection

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Abstract

Type I interferons (IFN-I) are critical for antiviral defense but can drive severe pathology when dysregulated. 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 following sensing of microbial or host-derived inflammatory stimuli. Contrary to this paradigm, we find that neutrophils express IFN during development and store it in the nucleolus, a membrane-less intranuclear condensate classically functioning in ribosome biogenesis. TLR-mediated bacterial sensing induces a nucleolar stress response in neutrophils that triggers rapid release of nucleoli-stored IFN independent of de novo protein synthesis. These findings reveal that neutrophils have repurposed the nucleolus as a cytokine storage and secretory organelle, identify the first naturally occurring immunoregulatory function of nucleolar stress, and provide insight into the relationship between detrimental IFN-I levels and neutrophil accumulation.

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Xu, S., Smirnov, A., Kinsella, R. L., Wise-Mitchell, A. D., Alexander, J. M., Rankin, A., Patty, B., Mikhail, S. M., Bello, R. M., Kreamalmeyer, D., Boluarte, S., Khan, A., Allsup, B. L., Mahmud, S., Bryson, B. D., Mattila, J., Greer, E. L., Ding, S., Clemens, R., Monteith, A. J., Calo, E., Stallings, C. L.. 2026-05-20. Neutrophils rapidly release nucleoli-stored IFNα during infection. https://doi.org/10.64898/2026.05.18.726057

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