DataSheet_1_The interplay between serine proteases and caspase-1 regulates the autophagy-mediated secretion of Interleukin-1 beta in human neutrophils.pdf

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.

中性粒细胞（Neutrophils）不仅凭借其杀菌特性，还通过释放白细胞介素-1β（IL-1β）等介质参与炎症应答的调控，在抵御细菌与真菌感染中发挥核心作用。该细胞因子为无引导序列蛋白质，在细胞质中以前体形式（pro-IL-1β）合成，经蛋白水解加工为活性亚型，并通过分泌型自噬（secretory autophagy）从人中性粒细胞中释放。在大多数髓系细胞（myeloid cells）中，pro-IL-1β会在炎性小体（inflammasome）激活时由半胱天冬酶-1（caspase-1）进行加工。本研究利用健康供者及携带功能获得性（gain-of-function, GOF）NLRP3突变患者的中性粒细胞，解析了此类细胞中IL-1β的加工机制。研究发现，尽管半胱天冬酶-1是IL-1β分泌所必需的，但其会快速失活；取而代之的是，中性粒细胞丝氨酸蛋白酶（neutrophil serine proteases）在pro-IL-1β的加工过程中发挥关键作用。本研究揭示了人中性粒细胞中半胱天冬酶-1活性调控的独特特征，并阐明了调控人中性粒细胞IL-1β分泌的全新分子机制。