The interplay between serine proteases and caspase-1 regulates the autophagy-mediated secretion of Interleukin-1 beta in human neutrophils

KEITELMAN, IRENE A.; SHIROMIZU, CAROLINA M.; ZGAJNAR, NADIA R.; DANIELIÁN, SILVIA; JANCIC, CAROLINA C.; MARTÍ, MARCELO A.; FUENTES, FEDERICO; YANCOSKI, JUDITH; VERA AGUILAR, DOUGLAS; ROSSO, DAVID A.; GORIS, VERÓNICA; BUDA, GUADALUPE; KATSICAS, MARÍA MARTHA; GALIGNIANA, MARIO D.; GALLETTI, JEREMÍAS G.; SABBIONE, FLORENCIA; TREVANI, ANALIA S.

Frontiers in Immunology

Frontiers Media S.A.

Año: 2022 vol. 13

Neutrophils play major roles against bacteria and fungi infections not only due to their microbicide properties but also because they release mediators like Interleukin-1 beta (IL-1β) that contribute to orchestrate the inflammatory response. This cytokine is a leaderless protein synthesized in the cytoplasm as a precursor (pro-IL-1β) that is proteolytically processed to its active isoform and released from human neutrophils by secretory autophagy. In most myeloid cells, pro-IL-1β is processed by caspase-1 upon inflammasome activation. Here we employed neutrophils from both healthy donors and patients with a gain-of-function (GOF) NLRP3-mutation to dissect IL-1β processing in these cells. We found that although caspase-1 is required for IL-1β secretion, it undergoes rapid inactivation, and instead, neutrophil serine proteases play a key role in pro-IL-1β processing. Our findings bring to light distinctive features of the regulation of caspase-1 activity in human neutrophils and reveal new molecular mechanisms that control human neutrophil IL-1β secretion.