Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3546-51. doi: 10.1073/pnas.0914351107. Epub 2010 Feb 8.
Neutrophil chemotaxis plays an essential role in innate immunity, but the underlying cellular mechanism is still not fully characterized. Here, using a small-molecule functional screening, we identified NADPH oxidase-dependent reactive oxygen species as key regulators of neutrophil chemotactic migration. Neutrophils with pharmacologically inhibited oxidase, or isolated from chronic granulomatous disease (CGD) patients and mice, formed more frequent multiple pseudopodia and lost their directionality as they migrated up a chemoattractant concentration gradient. Knocking down NADPH oxidase in differentiated neutrophil-like HL60 cells also led to defective chemotaxis. Consistent with the in vitro results, adoptively transferred CGD murine neutrophils showed impaired in vivo recruitment to sites of inflammation. Together, these results present a physiological role for reactive oxygen species in regulating neutrophil functions and shed light on the pathogenesis of CGD.
中性粒细胞趋化作用在先天免疫中起着至关重要的作用，但其中的细胞机制尚不完全清楚。在这里，我们通过小分子功能筛选，发现 NADPH 氧化酶依赖性活性氧是中性粒细胞趋化迁移的关键调节因子。用药物抑制氧化酶的中性粒细胞，或从慢性肉芽肿病（CGD）患者和小鼠中分离出的中性粒细胞，在沿着趋化因子浓度梯度迁移时，会形成更多的多发性伪足，并且失去方向性。在分化的中性粒细胞样 HL60 细胞中敲低 NADPH 氧化酶也会导致趋化作用缺陷。与体外结果一致的是，过继转移的 CGD 小鼠中性粒细胞显示出对炎症部位募集能力受损。总之，这些结果表明活性氧在调节中性粒细胞功能方面发挥了生理作用，并揭示了 CGD 的发病机制。
