A Neutrophil Timer Coordinates Immune Defense and Vascular Protection
A Neutrophil Timer Coordinates Immune Defense and Vascular Protection
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DOI：
10.1016/j.immuni.2019.01.002
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发表时间：
2019-02-19
期刊：
影响因子：
32.4
通讯作者：
Hidalgo, Andres
中科院分区：
文献类型：
--
作者：
Adrover, Jose M.;del Fresno, Carlos;Hidalgo, Andres
中性粒细胞可以有效地消灭病原体，但如果它们在血管内过度激活，则会对宿主造成严重损害。目前尚不清楚免疫如何解决在保持血管健康的同时建立有效的抗微生物防御的困境。在这里，我们确定了一个中性粒细胞内在程序，使两者。Bmal1基因调控趋化因子cxcr2的表达，诱导趋化因子受体cxcr2依赖性循环中性粒细胞转录和迁移特性的昼夜变化。这些昼夜变化被称为中性粒细胞老化，被CXCR4 （C-X-C趋化因子受体4型）拮抗，并调节中性粒细胞的外部拓扑结构，以促进夜间从血管中稳态输出，从而提高组织中的抗微生物活性。改造成组成性中性粒细胞老化的小鼠对感染具有抵抗力，但血管内老化中性粒细胞的持续存在使它们易于发生血栓炎症和死亡。因此，中性粒细胞的昼夜区隔，由内部计时器驱动，协调免疫防御和血管保护。
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.