RhoA determines disease progression by controlling neutrophil motility and restricting hyperresponsiveness
RhoA determines disease progression by controlling neutrophil motility and restricting hyperresponsiveness
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DOI：
10.1182/blood-2014-02-557843
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发表时间：
2014-06-05
期刊：
影响因子：
20.3
通讯作者：
Knaus, Ulla G.
中科院分区：
文献类型：
--
作者：
Jennings, Richard T.;Strengert, Monika;Knaus, Ulla G.
中性粒细胞反应是宿主保护和炎症的核心。中性粒细胞激活遵循一个两步过程，在这个过程中，启动放大了对激活刺激的反应。启动对于延长寿命、趋化性和呼吸爆发活动是必不可少的。在这里，我们展示了细胞骨架组织者RhoA通过福尔马林抑制中性粒细胞启动。Rho缺乏的中性粒细胞过早的颗粒胞吐激活了许多信号通路，并放大了超氧化物的产生。Rho的缺失通过同时增加尾足的伸长、前沿的形成和随机迁移改变了从前到后的协调性。伴随着β(2)整合素非依赖性迁移和β(2)整合素依赖性迁移的负性和正性调控，Rho在中性粒细胞对离散趋化药物的反应中是一个关键的决策点。尽管Rho缺乏的高活性中性粒细胞的限制性流入会加重脂多糖介导的肺损伤，但删除先天免疫细胞中的Rho在甲型流感病毒感染中具有高度的保护作用。因此，Rho是维持中性粒细胞静止和抑制高反应性的疾病进展的关键调节因子。
Neutrophil responses are central to host protection and inflammation. Neutrophil activation follows a 2-step process in which priming amplifies responses to activating stimuli. Priming is essential for life span extension, chemotaxis, and respiratory burst activity. Here we show that the cytoskeletal organizer RhoA suppresses neutrophil priming via formins. Premature granule exocytosis in Rho-deficient neutrophils activated numerous signaling pathways and amplified superoxide generation. Deletion of Rho altered front-to-back coordination by simultaneously increasing uropod elongation, leading edge formation, and random migration. Concomitant negative and positive regulation of beta(2) integrin-independent and beta(2) integrin-dependent migration, respectively, reveal Rho as a key decision point in the neutrophil response to discrete chemotactic agents. Although even restricted influx of Rho-deficient hyperactive neutrophils exacerbated lipopolysaccharide-mediated lung injury, deleting Rho in innate immune cells was highly protective in influenza A virus infection. Hence, Rho is a key regulator of disease progression by maintaining neutrophil quiescence and suppressing hyperresponsiveness.