AUTHOR=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. TITLE=The interplay between serine proteases and caspase-1 regulates the autophagy-mediated secretion of Interleukin-1 beta in human neutrophils JOURNAL=Frontiers in Immunology VOLUME=13 YEAR=2022 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.832306 DOI=10.3389/fimmu.2022.832306 ISSN=1664-3224 ABSTRACT=

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.