The antimicrobial functions of neutrophils are facilitated by a defensive armamentarium of proteins stored in granules, and by the formation of neutrophil extracellular traps (NETs). However, the toxic nature of these structures poses a threat to highly vascularized tissues, such as the lungs. Here, we identified a cell-intrinsic program that modified the neutrophil proteome in the circulation and caused the progressive loss of granule content and reduction of the NET-forming capacity. This program was driven by the receptor CXCR2 and by regulators of circadian cycles. As a consequence, lungs were protected from inflammatory injury at times of day or in mouse mutants in which granule content was low. Changes in the proteome, granule content and NET formation also occurred in human neutrophils, and correlated with the incidence and severity of respiratory distress in pneumonia patients. Our findings unveil a ‘disarming’ strategy of neutrophils that depletes protein stores to reduce the magnitude of inflammation.

中性粒细胞的抗菌功能通过储存在颗粒中的蛋白质的防御性武器和中性粒细胞胞外陷阱 (NETs) 的形成来促进。然而，这些结构的毒性对高度血管化的组织（例如肺）构成威胁。在这里，我们确定了一个细胞内在程序，该程序修改了循环中的中性粒细胞蛋白质组，并导致颗粒含量的逐渐丧失和 NET 形成能力的降低。该程序由受体 CXCR2 和昼夜周期调节器驱动。因此，在一天中的某些时候或在颗粒含量低的小鼠突变体中，肺可以免受炎症损伤。蛋白质组、颗粒含量和 NET 形成的变化也发生在人类中性粒细胞中，并与肺炎患者呼吸窘迫的发生率和严重程度相关。我们的研究结果揭示了中性粒细胞的“解除武装”策略，该策略会消耗蛋白质储存以减少炎症的程度。