Neutrophils eliminate pathogens efficiently but can inflict severe damage to the host if they over-activate within blood vessels. It is unclear how immunity solves the dilemma of mounting an efficient anti-microbial defense while preserving vascular health. Here, we identify a neutrophil-intrinsic program that enabled both. The gene Bmal1 regulated expression of the chemokine CXCL2 to induce chemokine receptor CXCR2-dependent diurnal changes in the transcriptional and migratory properties of circulating neutrophils. These diurnal alterations, referred to as neutrophil aging, were antagonized by CXCR4 (C-X-C chemokine receptor type 4) and regulated the outer topology of neutrophils to favor homeostatic egress from blood vessels at night, resulting in boosted anti-microbial activity in tissues. Mice engineered for constitutive neutrophil aging became resistant to infection, but the persistence of intravascular aged neutrophils predisposed them to thrombo-inflammation and death. Thus, diurnal compartmentalization of neutrophils, driven by an internal timer, coordinates immune defense and vascular protection.

中性粒细胞可有效清除病原体，但如果它们在血管中过度活化，则会对宿主造成严重损害。尚不清楚免疫如何解决在维持血管健康的同时解决有效的抗微生物防御难题。在这里，我们确定了一个中性粒细胞固有的程序，可以同时启用这两种程序。基因Bmal1调节趋化因子CXCL2的表达，诱导趋化因子受体CXCR2依赖的循环中性粒细胞的转录和迁移特性的昼夜变化。这些昼夜变化，称为嗜中性白细胞衰老，被CXCR4（CXC趋化因子受体4型）所拮抗，并调节嗜中性白细胞的外部拓扑结构，以利于夜间从血管中排出体内稳态，从而增强了组织中的抗微生物活性。为组成型中性粒细胞衰老而工程化的小鼠变得对感染具有抵抗力，但血管内中性粒细胞的持久存在使它们易于血栓发炎和死亡。因此，由内部计时器驱动的嗜中性粒细胞的昼夜间隔可协调免疫防御和血管保护作用。